Lanthanide Nanoparticles

Review
pubs.acs.org/CR
Lanthanide Nanoparticles: From Design toward Bioimaging and

Therapy
Hao Dong, Shuo-Ren Du, Xiao-Yu Zheng, Guang-Ming Lyu, Ling-Dong Sun,* Lin-Dong Li,
Pei-Zhi Zhang, Chao Zhang, and Chun-Hua Yan*
Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Rare Earth Materials Chemistry and Applications,
PKU-HKU Joint Laboratory in Rare Earth Materials and Bioinorganic Chemistry, College of Chemistry and Molecular Engineering,
Peking University, Beijing 100871, China
4.1. Mechanisms of Ln3+ Upconversion Emissions
4.2. Multicolor Modulation of Upconversion
Emissions
4.2.1. Controlling Ln3+ Doping Concentration
4.2.2. Incorporating Multiple Activators
4.2.3. Screening Host Matrixes
4.2.4. Luminescence Resonance Energy Transfer
4.3. Eciency Enhancement of Upconversion
Emissions
4.3.1. Tailoring the Local Symmetry of the
Luminescent Center
4.3.2. Surface Passivation with Core/Shell
Structure
4.3.3. Plasmonic Enhancement with Noble
Metals
4.4. Upconversion Excitation Modulation
4.4.1. Energy Transfer between Lanthanide
Ions
4.4.2. Introducing Near-Infrared Antenna Ligand
4.5. Upconversion Nanoparticles for Biosensing
4.5.1. Upconversion Nanoparticle-Based Thermometers
4.5.2. Upconversion Nanoparticles as Indicators for Hazardous Substances
4.5.3. UCNPs as Indicators of Health Condition
4.6. Upconversion Nanoparticles for Bioimaging
4.6.1. Cellular Imaging
4.6.2. In Vivo Imaging
4.7. Upconversion Nanoparticles for Imaging
Guided Therapy
4.7.1. Photodynamic Therapy
4.7.2. Photothermal Therapy
4.8. Upconversion Nanoparticles for Drug Delivery and Chemotherapy
4.8.1. UCL Imaging for Drug Delivery
4.8.2. Photoactivation/Photorelease for Therapeutics
5. Near-Infrared Emitting Lanthanide Nanoparticles
for Bioimaging and Therapy
CONTENTS
1. Introduction
2. Typical Synthetic Procedures for Lanthanide
Nanoparticles
2.1. Thermal Decomposition
2.2. Hydrothermal/Solvothermal Synthesis
2.3. Precipitation/Coprecipitation
2.3.1. Precipitation/Coprecipitation in Aqueous Solution
2.3.2. Precipitation/Coprecipitation in Organic
Solution
2.4. Other Synthetic Procedures
3. Lanthanide Nanoparticles as MRI Contrast
Agents
3.1. Introduction of MRI and MRI Contrast
Agents
3.2. Lanthanide-Based Nanoparticles for T1Weighted MRI
3.2.1. Gd-Based Nanoparticles for T 1 Weighted MRI
3.2.2. Factors That Determine Relaxivity
3.3. Lanthanide Nanoparticles for T2-Weighted
MRI
3.3.1. Gd-Based Nanoparticles for T 2 Weighted MRI
3.3.2. Other Ln3+-Based Nanoparticles for T2Weighted MRI
3.3.3. Factors That Determine Relaxivity
3.3.4. Field Strength Eect on Relaxivity
3.4. Lanthanide Nanoparticles for T1 and T2 DualMode MRI
4. Lanthanide Upconversion Nanoparticles for Biosensing, Bioimaging, and Therapy
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Special Issue: Nanoparticles in Medicine
Received: February 11, 2015
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DOI: 10.1021/acs.chemrev.5b00091
Chem. Rev. XXXX, XXX, XXXXXX
Chemical Reviews
5.1. Basic Mechanisms of Lanthanide Near-Infrared Emissions
5.2. Near-Infrared Bioimaging and Therapeutic
Applications
6. Lanthanide Nanoparticles for Dual- and Multimode Imaging
6.1. Lanthanide Nanoparticles for X-ray and CT
Imaging
6.1.1. Basic Principles of X-ray and CT Imaging
6.1.2. Lanthanide Nanoparticles for CT Imaging
6.2. Lanthanide Nanoparticles for PET and SPECT
6.2.1. Basic Principles of PET and SPECT
6.2.2. Lanthanide Radionuclides for SPECT
6.3. Lanthanide Nanoparticles for UCL-Based
Dual-Mode Imaging
6.3.1. UCL/MRI Dual-Mode Imaging
6.3.2. UCL/CT Dual-Mode Imaging
6.3.3. UCL/SPECT Dual-Mode Imaging
6.3.4. UCL/X-ray Dual-Mode Imaging
6.3.5. UCL/PET Dual-Mode Imaging
6.4. Lanthanide Nanoparticles for Multimode
Imaging
7. Nanoceria for Nanomedicine
7.1. Roles of Reactive Oxygen/Nitrogen Species
in Diseases
7.2. Potential Antioxidant Mechanisms of Nanoceria
7.3. Key Factors Inuencing the Antioxidant
Properties of Nanoceria
7.3.1. Eects of Particle Size
7.3.2. Eects of Particle Shape
7.3.3. Eects of Surface Charge
7.3.4. Eects of Surface Coatings
7.3.5. Eects of Doping and Loading
7.3.6. Eects of External Factors
7.4. Nanoceria as Therapeutic Agents
7.4.1. Cancer Therapy
7.4.2. Neurological Disorder Treatments
7.4.3. Retinal Damage Treatments
7.4.4. Potential for Treating Diabetic Complications
7.4.5. Reduction of Chronic Inammation
7.4.6. Treatments of Other Oxidative StressRelated Diseases
7.5. Nanoceria for Bioanalytical Applications
7.5.1. CeO2 as a Peroxidase Mimetic
7.5.2. CeO2 as an Oxidase Mimetic
7.5.3. CeO2 as a Phosphatase Mimetic
7.5.4. Other Utilizations of the Surface Properties of Nanoceria
8. Biosafety Evaluations of Lanthanide Nanomaterials
8.1. In Vitro Toxicity Evaluation
8.1.1. Cell Viability
8.1.2. Cell Proliferation and Dierentiation
8.1.3. Hemolysis
8.2. In Vivo Toxicity Evaluation
8.2.1. In Vivo Toxicity in C. elegans
8.2.2. In Vivo Toxicity in Zebrash
8.2.3. In Vivo Toxicity in Murine Models
8.3. Autophagy-Inducing Ability of Lanthanide
Nanoparticles
Review
9. Conclusions and Prospects

Author Information
Corresponding Authors
Notes
Biographies
Acknowledgments
References
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1. INTRODUCTION
Lanthanides refer to the 15 elements located at the sixth period
and IIIB group in the periodic table, ranging from lanthanum to
lutetium, with the electronic conguration of [Xe]4fn15d016s2
(n = 115). The studies on lanthanide elements date back to
the 18th century. With the development of lanthanide
chemistry for more than two centuries, these elements have
found a wealth of applications in military, chemical industry,
agriculture, and biomedicine. Trivalent lanthanide ions (Ln3+)
are the most common and stable oxidation state of lanthanides,
except for Ce4+, Tb4+, and Yb2+, for which the f orbitals are
empty, half-, or full-occupied, repectively.
The unique properties of lanthanides come from their 4f
electrons. The number of unpaired electrons in 4f orbitals that
possess strong unquenched angular momentum can be up to
seven, inducing eective spinorbit coupling and signicant
paramagnetic properties (except La3+ and Lu3+). The magnetic
moments, magnetic susceptibilities, and electronic relaxation
time of Ln3+ are determined by their 4f electron congurations,
and dier dramatically along the series.13 The symmetric
electron ground state of Gd3+ results in weak spinorbit
coupling and consequently long electronic relaxation time,
while the asymmetric electron ground states of Tb3+, Dy3+,
Ho3+, and Er3+ endow them with short electronic relaxation
time but larger magnetic moments and magnetic susceptibilities. These have been utilized in nuclear relaxation acceleration
and resonant frequency shifting; for example, some Gd3+containing complexes are extensively used as contrast agents
(CAs) in magnetic resonance imaging (MRI) to aord
shortened relaxation time of protons and enhanced image
contrast.4
In addition, the lanthanides are attractive for optical
applications. The large quantum numbers (n = 4, l = 3)
feature them with rich spectroscopic terms.5 Although the
intracongurational transitions are principally forbidden for
Ln3+, the incorporation of eigenstates leads to partially allowed
intracongurational transitions, conferring advantageous optical
characteristics to Ln3+ activated materials including excellent
photostability, large Stokes/anti-Stokes shifts, long luminescent
lifetimes, and sharp-band emissions.6,7 Therefore, Ln3+ are
considered as promising luminescent supporters for applications including bioimaging,8 sensing,9 therapy,1012 lighting and
displays,13 and photovoltaic devices.14 According to the
involved transition pathways, the luminescence of Ln3+ can
be categorized as down-shifting, quantum-cutting (also known
as downconversion), and upconversion. For both down-shifting
and quantum-cutting processes, excitation with high-energy
photon is required, whereas upconversion involves the
triggering of lower energy photons, typically near-infrared
(NIR) light, for frequency upconverting.15
With the rapid developments of nanoscience and nanotechnology over the past few decades, uniform Ln3+-based
nanoparticles retaining the intracongurational transitions and
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intrinsic paramagnetism of Ln3+ have been reported for

promising bioapplications. The tunable size and morphology,
as well as surface bioimmobilization, have been developed to
meet the in vivo studies. Furthermore, through doping and/or
surface functionalization, such nanoparticles could serve as
multifunctional platforms for bioapplications.
Ln3+ nanoparticulate MRI CAs, for example, exhibit attractive
features for diagnostic applications. As compared to Gd chelate
complexes, each nanoparticle contains a high payload of metal
ions, which ensures high local contrast.16 Furthermore, the
dissociation and the consequent leakage of Gd3+ are minimized
because they are located in rigid inorganic crystal structure.17
Superparamagnetic iron oxide nanoparticles (SPIO), as MRI
CAs, have been approved for clinical use;18 however, their
ecacies are limited by their saturated magnetization in
ultrahigh magnetic eld.19 Ln3+ nanoparticles, with well
controlled size, crystallinity, and unique magnetic behaviors,
may oer great opportunities for CAs.20
Ln3+-doped upconversion nanoparticles (UCNPs) have also
evoked considerable interest in biological applications.21 As
compared to conventional biomarkers like semiconductor
quantum dots (QDs), organic dyes, or uorescent proteins,
Ln3+-doped UCNPs have been found unique for their high
resistance to photobleaching, as well as the minimized
photoblinking, cross-talked emissions, and autouorescence
from organisms they aord.22 Furthermore, the NIR excitation
nature of these UCNPs allows for deeper penetration into
biological tissues than traditional bioimaging probes that usually
require visible/UV excitation.23 Although simultaneous twophoton absorption processes have been veried in some QDs
and organic dyes, these systems often require a high power
femtosecond pulsed laser (106109 W/cm2), and exhibit rather
low luminescence eciency.24 On the contrary, a low power
continuous-wave laser (1103 W/cm2) has been proved
ecient enough to initiate Ln3+ upconversion processes.25
Beneting from their unique optical behaviors, UCNPs have
been recognized and used as a powerful tool for biomedical
applications such as photodynamic therapy (PDT)26 and
photothermal therapy (PTT).27 On the other hand, Ln3+based down-shifting nanomaterials with NIR emissions located
in the second transparent biological window, where less
biological tissue scattering is given, have also been developed to
achieve highly sensitive in vivo bioimaging.28
Dierent from Ln3+-doped materials, cerium oxide (CeO2),
which adopts a cubic uorite structure, benets from its redox
behavior due to the coexistence and facile reversible conversion
of Ce4+/Ce3+ couple to nd wide industrial applications.2934
Mimicking the functions of certain natural enzymes,3540 CeO2
nanoparticles have shown great potential in antioxidant
applications,4143 and their unique regenerative antioxidant
property has been recently utilized for long-term internal
treatments.44
In general, lanthanides-based functional nanoparticles have
been considered as attractive tools in biomedical applications. It
is the aim of this Review to present a systematic discussion on
the basic principles and recent progress achieved on bioimaging
and therapy applications of these Ln3+-based nanoparticles
(Scheme 1), to gain insights into future development into the
use of biosensing, various bioimaging techniques, including
NIR imaging, X-ray computed tomography (CT) imaging,
single-photon emission computed tomography (SPECT)
imaging, etc., and antioxidant therapies.
Scheme 1. Schematic Illustration of the Main Topics of This

Review
2. TYPICAL SYNTHETIC PROCEDURES FOR

LANTHANIDE NANOPARTICLES
The controlled synthesis of monodispersed Ln3+-based nanoparticles is essential for extended bioimaging and therapeutic
applications. In the past decade, wet chemical (solution-based)
synthetic methods have been explored to prepare various Ln3+based nanoparticles. Synthetic parameters, including reaction
temperature, duration time, pH, concentration of precursors
and surfactants, etc., can be exibly adjusted with the wet
chemical synthesis. The phase structure, size distribution,
morphology, and even the facets of nanoparticles are managed
to be controlled. To date, a few wet chemical synthetic methods
including thermal decomposition, hydrothermal/solvothermal
method, precipitation/coprecipitation, microwave and microemulsion-assisted approaches, etc., have been developed.
Among these synthetic routes, thermal decomposition and
hydrothermal/solvothermal methods are the most popular and
eective to prepare high-quality target nanoparticles. In this
section, we will discuss these typical synthetic procedures for
Ln3+-based nanoparticles. Readers may refer to those recently
published specic reviews on the synthesis of Ln3+-based
nanoparticles for more detailed information.4548
2.1. Thermal Decomposition
The thermal decomposition design involves the oxygen-free

decomposition of the organometallic precursors in high-boilingpoint organic solvents. In general, the organometallic
precursors are Ln3+-based organic salts, such as triuoroacetates, acetates, and so forth. Octadecene (ODE) is the most
frequently used high-boiling-point organic solvents. Meanwhile,
oleic acid (OA) and oleylamine (OM) with polar capping
groups are also adopted as capping reagents to control the size
and morphology of nanoparticles by selective adsorption on
specic facets. As the temperature elevates, CF bond breaking
and nucleation could happen toward target nanoparticles. It is
noteworthy that the crystal nucleation and growth processes,
which are the two key steps for uniform nanoparticles, can be
precisely adjusted by modulating the synthetic parameters, like
temperature, heating rate, or concentration of precursors, etc.
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Figure 1. Transmission electron microscopy (TEM) images of LaF3 (a), LaOF:Eu (b), LaOCl (c), cubic phased NaYF4 (d), hexagonal phased
NaYF4 (e), hexagonal phased NaYF4:Yb,Er (f), KPrF4 (g), LiErF4 (h), DyF3 (i), TbF3 (j), CeO2 (k), and CeO2 (l) nanoparticles synthesized from
thermal decomposition. (a) Reprinted with permission from ref 49. Copyright 2005 American Chemical Society. (b) Reprinted with permission
from ref 51. Copyright 2008 American Chemical Society. (c) Reprinted with permission from ref 53. Copyright 2009 American Chemical Society.
(df) Reprinted with permission from ref 54. Copyright 2006 American Chemical Society. (g,h) Reprinted with permission from ref 55. Copyright
2009 Royal Society of Chemistry. (i,j) Reprinted with permission from ref 60. Copyright 2013 Nature Publishing Group. (k) Reprinted with
permission from ref 63. Copyright 2008 Wiley-VCH Verlag GmbH & Co. KGaA. (l) Reprinted with permission from ref 64. Copyright 2012
American Chemical Society.
thermolysis of Na(CF3COO) and RE(CF3COO)3.54 Except

the general reaction parameters, the molar ratio of [Na]/[RE]
is important for the phase transition from cubic to hexagonal.
Furthermore, near-monodispersed cubic KLaF4 and KCeF4
wormlike nanowires, nanocubes, and nanopolyhedra, KREF4
(RE = Pr to Gd, Y) nanopolyhedra (Figure 1g), LiREF4 (RE =
Tb to Lu, Y) rhombic nanoplates (Figure 1h), have been
synthesized via the thermolysis of K(CF3COO) or Li(CF3COO) and RE(CF3COO)3 in OA, OM, and ODE.55
NaMF3 (M = Mn, Co, Ni, Mg), LiMAlF6 (M = Ca, Sr), and
NaMgF3:Yb,Er nanoparticles have been prepared by the
cothermolysis of triuoroacetates.56 Recently, Yan et al. have
successfully synthesized Ln3+-based oxysuldes ultrathin nanoplates using lanthanide acetylacetonate and sulfur powder as the
precursors.57 In a similar fashion, monodisperse Ln3+-based
NaLnS2 particles,58 LnSe2 nanosheets,59 and Ln4O4Se3 nanoplates59 have been synthesized. Murray and co-workers
developed the synthesis of high-quality LnF3 nanoplates60
(Figure 1i,j) and NaLnF4 nanoparticles61 with uniform size and
morphology. The LnF3 nanoplates with faceted planar
nanoplates exhibited rich and subtle self-assembly behavior,
while the NaLnF4 nanoparticles exhibited diverse morphologies, including spheres, rods, hexagonal prisms, and plates.
By using Ln3+-based acetylacetonate and benzoylacetonate
complexes as the single-source precursors, Yan et al. have also
synthesized monodisperse Ln2O3 nanoparticles in OA and
ODE.62 Because of the selective adsorption of the capping
ligands on specic cubic faces during the crystal growth, the
morphology of nanoparticles can be modulated, such as
nanopolyhedra, nanoplates, and nanodisks. Uniform CeO2
Also, the nanoparticles synthesized by this method are highly

monodispersed, with uniform morphology and narrow size
distribution.
In 2005, Yan and co-workers reported the rst synthesis of
LaF3 triangular nanoplates (Figure 1a) with the decomposition
of a single-source precursor, La(CF3COO)3, with OA/ODE as
the organic solvents.49 The authors assessed the varieties of
solvents on the synthesis of LaF3 nanoplates. It was found that
the sole use of OA or ODE resulted in less uniform and illshaped nanoparticles, while the use of a mixture of OA and
ODE (molar ratio 1:1) led to uniform LaF3 triangular
nanoplates. The authors then extended the thermolysis of
triuoroacetates to lanthanide uoride and oxyuoride nanoparticles with diverse morphology (truncated-triangular,
hexagonal, quadrilateral, polygonal, and zigzag-shaped nanoplates; nanopolyhedra and nanorods). 50 Monodispersed
luminescent lanthanide oxyuoride nanoparticles (Figure 1b)
were obtained via the decomposition of Ln(CF3COO)3 in OA
and OM.51 Specically, uorophilicity-mediated EuOF nanowires were obtained from the thermolysis of Eu(CF3COO)3 in
OA and OM solutions.52 With La(CCl3COO)3 used as the
single-source precursor, high-quality LaOCl nanoplates (Figure
1c) were synthesized in OM and ODE.53 The uniform LaOCl
nanoplates could align into nanowire-like and rod-like superstructures.
Adopting this synthetic protocol, Yan and co-workers
developed a general synthetic strategy for obtaining NaREF4
(RE = Pr to Lu, Y) and NaYF4:Yb,Er/Tm nanoparticles (cubic/
hexagonal phased nanopolyhedra, nanorods, nanoplates, and
nanospheres) with high qualities (Figure 1df) via the
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Figure 2. TEM images of LaF3 (a), hexagonal phased NaYF4:Eu (b), NaYF4:Tb (c) and NaYF4 (d, scanning electron microscopy image), and CeO2
(e,f) nanoparticles synthesized from solvothermal method. TEM images of LaF3:Yb,Er (g), and CeO2 (h) nanoparticles synthesized from
coprecipitation method. TEM images of hexagonal (i) and cubic (j) phased NaYF4:Yb,Er nanoparticles synthesized from IL- and microwave-assisted
synthetic route. TEM images of YF3 nanoparticles (k) and Pt/CeO2@SiO2 nanocomposites (l) using microemulsion-based procedure. (a) Reprinted
with permission from ref 72. Copyright 2005 Nature Publishing Group. (b,c) Reprinted with permission from ref 73. Copyright 2007 American
Chemical Society. (d) Reprinted with permission from ref 76. Copyright 2007 Wiley-VCH Verlag GmbH & Co. KGaA. (e) Reprinted with
permission from ref 78. Copyright 2005 American Chemical Society. (f) Reprinted with permission from ref 80. Copyright 2006 American Chemical
Society. (g) Reprinted with permission from ref 84. Copyright 2005 Royal Society of Chemistry. (h) Reprinted with permission from ref 88.
Copyright 2009 American Chemical Society. (i) Reprinted with permission from ref 99. Copyright 2009 Royal Society of Chemistry. (j) Reprinted
with permission from ref 102. Copyright 2009 American Chemical Society. (k) Reprinted with permission from ref 104. Copyright 2005 American
Chemical Society. (l) Reprinted with permission from ref 106. Copyright 2010 American Chemical Society.
reaction temperature, and the duration time. On the basis of

the decomposition of Ln(CF3COO)3, Chen and co-workers
synthesized hexagonal phased LaF3 nanoplates,66 and the
amount of sodium oleate and oleylamine was found to be
important for the synthesis. Lin et al. synthesized a series of
LnF3 and NaLnF4 nano-/microparticles using hydrothermal
strategies.6771 Organic additives such as trisodium citrate and
EDTA have an obvious impact on the morphologies of
products.
In 2005, Li and co-workers developed a liquidsolid solution
(LSS)-based hydrothermal synthetic route toward inorganic
nanoparticles.72 This strategy is based on a phase transfer and
separation mechanism occurring at the interfaces of the liquid,
solid, and solution phases. After the phase transfer process of
metal ions from aqueous solution to the solid phase, the metal
ions might react with other anions such as F ions to yield LnF3
nanoparticles (Figure 2a). Alternatively, the metal ions can
dehydrate into oxides and/or composite oxides through
coprecipitation. Using LSS method, lanthanide doped NaYF4
single-crystal nanorods, hexagonal nanoplates, and nanoparticles has also been synthesized (Figure 2b,c).73 The eects
of reaction temperature, duration time, molar ratio of NaF to
Ln(NO3)3, and the reactant content on the size, morphology,
and phase purity of the products have been studied in detail.
Results indicated that the high NaF content and low Ln(NO3)3
content in the reaction mixture, the appropriate reaction
temperature, and long reaction time favor the growth of the
nanoowers were obtained with controlled morphology (cubic,

four-petaled, and starlike) and size, from the decomposition of
(NH4)2Ce(NO3)6 in OA and OM (Figure 1k).63 Recently,
Colvin and co-workers reported the synthesis of CeO2
nanoparticles (Figure 1l) with uniform and tunable size, surface
chemistry, and variable trivalent cerium content via the thermal
decomposition of cerium acetylacetonate hydrate, cerium
oleylamine, and cerium nitrate hexahydrate in ODE.64 The
particle size can be tuned by controlling the molar ratio of
cerium to surfactants as well as the addition of cosurfactants
and water.
2.2. Hydrothermal/Solvothermal Synthesis
The hydrothermal/solvothermal synthesis refers to the

preparation of nanoparticles with the superheated solvents
and the concomitant high pressure in autoclaves. The
crystallinity of the resulting nanoparticles is usually good for
the enhanced solubility and reactivity of reactants under high
pressure. The experimental parameters are exible to be
adjusted. The hydrothermal/solvothermal synthesis method is
eective to obtain high-quality Ln3+-based nanoparticles. In
general, Ln3+-based oxides, chlorides, nitrates, and acetylacetonates are frequently used as precursors.
Qian and co-workers reported Ln3+-doped YF3 nanospindles
synthesized with the hydrothermal method,65 where EDTA was
employed as the modier to control the growth of the
nanospindles. Their morphology and size could be controlled
by varying the concentration of EDTA in the reaction mixture,
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particles, the hydrolysis of Ln3+ is the key process for the

synthesis.
van Veggel and his co-workers reported the synthesis of
lanthanide doped LaF3 nanoparticles with coprecipitation
method in ethanol and water mixed solvents, using Ln(NO3)3
and NaF as precursors.83 During the synthesis, ammonium din-octadecyldithioposhate was added to control the growth of
nanoparticles and adjust the precipitation rate of dierent Ln3+.
As a result, about 10 nm sized LaF3-based nanoparticles were
yielded. In a follow-up study by Yi and co-workers, lanthanide
doped LaF3 nanoparticles were also synthesized using the same
organic surfactants (Figure 2g).84 LnCl3 and NaF were used as
precursors, and the nanoparticles had a mean diameter of 5.4
nm and narrow size distribution. Haase and co-workers
developed a coprecipitation method to synthesize lanthanide
doped NaYF4 nanoparticles.85 Sodium alkoxide, LnCl3, and
NH4F were chosen as precursors and reacted in high-boilingpoint organic solvent N-(2-hydroxyethey)ethylendiamine. The
preparation was also obtained with Ln3+-based EDTA
complexes with a vigorously stirred NaF solution.86 The
average particle size can be tuned from 37 to 166 nm by
adjusting the molar ratio of EDTA to total lanthanides. EDTA
prevented the particle coagulation by shielding the Ln3+ ions,
which is necessary for the preparation of monodispersed
nanoparticles.
Perez and co-workers reported the alkaline-based precipitation of cerium oxide nanoparticles from a solution containing
cerium nitrate and dextran under continuous stirring.87 During
the formation of cerium oxide nanoparticles, dextran molecules
could prevent further growth of the nanoparticles. Karakoti and
co-workers synthesized CeO2 nanoparticles by dissolving
cerium nitrate in PEG solution (Figure 2h).88 The pH value
of the solution was adjusted by the addition of nitric acid. The
solution then was oxidized using hydrogen peroxide to produce
CeO2 nanoparticles. The nal products were obtained after 1
month of aging. Kar and co-workers employed ethylenediamine
as the catalyst as well as capping agent to synthesize CeO2
nanoparticles.89 Ultrasmall CeO2 nanoparticles were synthesized at room temperature by dissolving cerium nitrate in
ethylenediamine with continuous stirring.
2.3.2. Precipitation/Coprecipitation in Organic Solution. In precipitation/coprecipitation in organic solution,
Ln3+-based oleates, acetates, chlorides, and nitrates can be
employed for providing Ln3+ cations, while NaF, NaOH, or
NH4F are used to provide anions, and methoal is also used as
the solvent to assist the synthsis. In 2008, Zhang and coworkers reported the synthesis of hexagonal phased NaYF4:Yb,Er/Tm nanoparticles with controllable morphology with
this method.90 Ln3+-based chlorides, NaOH, and NH4F were
chosen as precursors for Ln3+, Na+, and F ions. The uoride
nucleated at room temperature further evolved into nanoparticles with elevated temperature. Nanoplate, nanosphere,
and nanoellipse shaped NaYF4:Yb,Er/Tm nanoparticles can be
produced by changing the surfactant concentration.
Chen et al. employed Ln3+-based oleates and NaF to
synthesize NaGdF4-based nanoparticles in OA and ODE.91 It
was evident that higher temperatures favored the formation of
hexagonal phased NaGdF4 nanoparticles, while lower temperatures and the presence of OM in the reaction system tend to
lead cubic phase nanoparticles. This is the same for NaYF4
nanoparticles.92 This research is further extened,93 and the
composition of nanoparticles was found to depend on the
lanthanide elements. LaPr would form hexagonal LnF3
nanoparticles. The authors also prepared lanthanides doped

Na(Y1.5Na0.5)F6 single-crystal nanorods,74 and the aspect ratios
of the nanorods were controlled with reaction temperature.
With the LSS solvothermal method, Liu and co-workers
investigated the phase and size control of NaYF4 nanorods
through lanthanide doping.75 It was found that the size of
nanorods decreased with elevated doping concentration of
Gd3+. Meanwhile, the phase structure of products transferred
from cubic to hexagonal. Zhao and co-workers developed a
modied LSS solvothermal route to obtained well-dened
nanoarrays of tubes and rods of lanthanide doped NaYF4.76
Furthermore, through modications of the reaction conditions,
ower-patterned lanthanide doped NaYF4 nanodisks were
obtained (Figure 2d).
Ln(OH)3 nanowires, with Ln(NO3)3 and KOH as the
reagents, were obtained with the hydrothermal method.77 The
amorphous Ln(OH)3 suspensions that formed at room
temperature were transferred into the autoclave for further
evolution. Yan and co-workers reported the shape-selective
synthesis of CeO2 nanopolyhedra, nanorods, and nanocubes by
a hydrothermal method under dierent NaOH concentrations,
using Ce(NO3)3 as the cerium source (Figure 2e).78 The
formation of hexagonal Ce(OH)3 intermediates, and their
transformation into CeO2, as well as the NaOH concentration
were the key factors responsible for the morphology evolution.
Kaneko and co-workers also obtained CeO2 nanoparticles with
Ce(NO 3)3 ,79 and decanoic acid was added to induce
anisotropic growth of the nanoparticles. With the same cerium
source, Gao and co-workers synthesized CeO2 nanocubes
(Figure 2f).80 Moreover, due to the presence of oriented
aggregation-mediated precursor growth, the as-synthesized
CeO2 nanocubes exhibited fascinating structural properties,
which were intriguing for their catalytic applications. Qian and
co-workers developed an improved toluene solvothermal
synthetic route to prepare CeO2 nanoparticles using CeCl3 as
the precursor and hexadecylamine as the surfactant.81 It was
also found that the concentration of surfactants, types of
aliphatic amine, and water content also played important roles
in determining the morphology of nanoparticles. Recently, Yan
and co-workers synthesized lanthanide doped CeO2 nanowires
using CeCl3 as the precursor through hydrothermal synthesis.82
The use of a small amount of NaCl is essential for uniform and
anisotropic growth of Ce(OH)3 intermediate species.
2.3. Precipitation/Coprecipitation
As one of the most classical wet chemical synthetic method,

precipitation/coprecipitation refers to the simultaneous precipitation process of several ions, with the formation of target
nanosized compounds. Despite the easy operation, particular
attention should be paid to the precipitation rate dierence of
various ions. To address the problem, coordinating surfactants
and/or cosolvents are usually added into the reaction system to
mediate the synchronicity of coprecipitation process. Precipitation/coprecipitation synthesis can be performed in aqueous
solution and organic solution.
2.3.1. Precipitation/Coprecipitation in Aqueous Solution. It is noteworthy that the crystallinity of nanoparticles
prepared by precipitation/coprecipitation in aqueous solution is
relatively low, and subsequent heat treatment is often necessary
to improve the crystallinity of products. In general, for Ln3+based uoride nanoparticles, Ln3+-based chlorides and nitrates
are usually adopted to provide Ln3+ ions, while NaF and NH4F
are used to provide F ions. For Ln3+-based oxide nanoF
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Figure 3. Principle of magnetic resonance imaging. (a) Irradiation of resonant RF makes Mz ip away from the z axis to the xy plane. After RF pulse
disappears, the nuclear spins relax to their initial state, in which Mz increases and Mxy decreases. (b) T1 is the time required for Mz to recover to 63%
of its equilibrium. (c) T2 is the time required for Mxy to drop to 37% of its magnitude in the excited state.
varying the length of alkyl chains and the anionic parts of the
ILs, and the volume of ethanol. Zhang and co-workers
performed ionothermal synthesis to prepare hexagonal phased
lanthanide doped NaYF4 nanoparticles (Figure 2i), using
BmimBF4 as the solvent.99 The [Bmim]+ cations can serve as
in situ capping reagent to prevent the nucleation centers from
growing up, and the [BF4] anions can act as uorine source
according to partial hydrolysis. In a similar way, Guo and coworkers prepared 60 nm LnF3 nanoparticles.100
Beneting from the high polarity, ILs are also excellent
microwave absorbents. Yan and co-workers developed an ILsbased route to prepare spherical lanthanide doped NaYF4
nanoclusters with the assistance of microwave radiation.101
Na(CF3COO), Ln(CF3COO)3 were used as precursors. The
as-prepared NaYF4 nanoclusters had a diameter ranging from
200 to 430 nm, and were formed by the self-assembly of small
nanoparticles. It was found that the particle size of products can
be easily tuned by changing the amount of precursors, and the
ILs were the major uorine sources for the formation of the
NaYF4 nanoparticles. Nann and co-workers synthesized a series
of monodisperse cubic NaYF4-based nanoparticles by microwave-assisted synthesis (Figure 2j).102 In their synthesis,
Na(CF3COO), Ln(CF3COO)3 were used as precursors to
undergo thermal decomposition in OA and ODE. The
reactants and solvents were transferred into a microwave
reactor by 300 W of microwave irradiation. Xu and co-workers
prepared lanthanide doped LaF3 nanoparticles with the
microwave-assisted synthesis.103 Ln3+-based chlorides, nitrates,
and NaF were used as precursors, and ethylene glycol was used
as solvents. Polyethylenimine (PEI) molecules were added as
the capping agents to control the growth of nanoparticles. As a
result, about 12 nm hexagonal phased LaF3 nanoparticles were
obtained.
Fabrication of nanoparticles within the reverse microemulsion is convenient to yield nanoparticles with controllable
size. Ritcey and co-workers reported the synthesis of LnF3
nanoparticles (Figure 2k) with diverse morphology and size in
reverse microemulsions of water in cyclohexane stabilized with
Igepal CO-520.104 When mixing two microemulsions containing LnCl3 and NH4HF2, monodisperse amorphous LnF3
nanospheres were obtained. By contrast, nanoparticles
nanoplates, while SmEr and TmLu would form hexagonal

NaLnF4 and cubic Na5Ln9F32 nanoparticles, respectively. When
using LaCl3, NaOH, and NH4F as the starting reagents,
hexagonal LaF3 nanoplates formed in OA and ODE.94 The
morphology of LaF3 nanoparticles can also be manipulated into
nanorods and polyhedrons by adjusting the reaction conditions.
Recently, Huang and co-workers have synthesized lanthanide
doped NaxScF3+x-based nanoparticles with chlorides, NaOH,
and NH4F in OA and ODE.95 By controlling the molar ratio of
OA and ODE, the phase structure, morphology, and
composition of NaxScF3+x could be tuned. In a follow-up
study by Zhu and co-workers, orthorhombic KSc2F7:Yb,Er
nanorods can be obtained using chlorides, KOH, and NH4F in
OA and ODE.96 The F content and reaction temperature
played important roles in determining the size of KSc2F7:Yb,Er
nanorods. High concentration of F and high temperature
favored large sized nanorods.
2.4. Other Synthetic Procedures
In addition to the aforementioned well-developed synthetic

procedures, many other novel methods have been developed to
synthesize Ln3+-based nanoparticles, including ionic liquidbased synthesis, microwave-assisted, and microemulsion-based
synthetic methods. In the following part, several typical studies
on the synthesis of Ln3+-based nanoparticles using these novel
routes will be discussed.
Ionic liquids (ILs) have aroused extensive attention due to
their negligible vapor pressure, wide electrochemical windows,
high ionic conductivity, etc.97 Moreover, the ILs can also serve
as solvents, reaction agents, and templates during the synthesis.
Therefore, the ILs have been recognized as one of the most
promising media for the fabrication of inorganic nanoparticles.
Chen and co-workers reported ILs-based synthesis of LnF3
nanoparticles in 2008.98 In these reaction systems, three types
of ILs (OmimPF6, OmimBF4, and BmimPF6) were chosen to
act as solvents and templates, as well as the uorine sources.
Ln3+-based nitrates were used to provide Ln3+. Uniform and
novel LnF3-based nanodisks and donut-shaped nanostructures
(resulting from the self-assembly of little nanoparticles) were
obtained with a large scale. The morphologies, sizes, and
dispersibility of the as-prepared nanoparticles can be tuned by
G
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Table 1. Ground State, g Values, and Calculated and Experimental Room Temperature T Values for Ln3+
Ln3+
conguration
3+
Ce
Pr3+
Nd3+
Pm3+
Sm3+
Eu3+
Gd3+
Tb3+
Dy3+
Ho3+
Er3+
Tm3+
Yb3+
a
f
f2
f3
f4
f5
f6
f7
f8
f9
f10
f11
f12
f13
gJ
Tcala (emu mol1 K)
Texp (emu mol1 K)
6/7
4/5
8/11
3/5
2/7
0
2
3/2
4/3
5/4
6/5
7/6
8/7
0.8
1.6
1.64
0.9
0.09
0
7.88
11.82
14.17
14.07
11.48
7.15
2.57
0.660.78
1.451.62
1.451.53
1.05
0.32
1.53
7.617.8
11.7612.01
13.0114.05
13.2613.78
11.0511.28
7.03
2.53
ground state
2
F5/2
H4
4
I9/2
5
I4
6
H5/2
7
F0
8
S7/2
7
F6
6
H15/2
5
I8
4
I15/2
3
H6
2
F7/2
3
Tcal = (1/8)gJ2[J(J + 1)].
maintain in the excited state and will return to the initial state,
which is called relaxation. There are two independent relaxation
processes: longitudinal (or T1) relaxation and transverse (or
T2) relaxation. The former refers to the recovering of Mz to the
initial state, which is also known as spinlattice relaxation
because the change in Mz is due to the energy transfer from
nuclei to the environment; while the latter refers to the
disappearing of induced magnetization on the perpendicular
plane (Mxy), which is also known as spinspin relaxation
because the change in Mxy is due to spin dephasing. In the
relaxation process, T1 is dened as the time required for the Mz
to recover to 63% of its equilibrium, while T2 is dened as the
time required for the Mxy to drop to 37% of its magnitude in
the excited state.
The image contrast in MRI actually comes from the
dierences in the signal intensity of each pixel or voxel. In
general, the signal intensity is determined by local proton
density and relaxation time of protons, as well as pulse
sequences.111 The relaxation time of protons is dependent on
their forms (e.g., mobile or bound), which are quite dierent
for various biological tissues, bringing intrinsic contrast.
However, the sensitivity of MRI is relatively low. As in early
stage diagnosis, the dierence between normal and abnormal
regions is usually subtle, and additional contrast is required to
highlight the abnormal region.112 MRI CAs refer to exogenous
substances, which could shorten relaxation time of protons.
The ability of a CA to change relaxation time is represented
quantitatively by longitudinal relaxivity (r1) and transverse
relaxivity (r2), which are the change in relaxation rate (1/T1 and
1/T2) normalized to the concentration of metal ions.
CAs with higher relaxivities can bring adequate image
contrast at a lower dose, or greater contrast at an equivalent
dose. From the viewpoint of clinical applications, the MRI CAs
can be classied into two groups on the basis of their r2 to r1
ratio (r2/r1) values. T1 CAs refer to those with r2/r1 values close
to 1, while T2 CAs refer to those with high r2/r1 values. T1 CAs,
also known as positive CAs, have a dominant T1 shortening
eect, causing an increase in signal intensity. T2 CAs, also
known as negative CAs, have a more dominant T2 shortening
eect, causing a reduction in signal intensity.
synthesized by the single microemulsion method, direct

addition of a solution of NH4HF2 to a microemulsion
containing LnCl3, were found to be monocrystalline, with
well-dened morphology. Seal and co-workers synthesized
monodisperse, nonagglomerated nanocrystalline CeO2 nanoparticles in the range of 5 nm in the microemulsions of water
and toluene.105 Cerium nitrate and NH4OH were used as
precursors, and sodium bis(2-ethylhexyl) sulfosuccinate was
used as surfactant to control the size of the CeO2 nanoparticles.
Yan and co-workers developed thermally stable Pt/CeO2@SiO2
nanocomposites using the microemulsion-based procedure
(Figure 2l).106 In a typical synthesis, the cyclohexane solution,
Igepal CO-520, and aqueous solution formed the microemulsion system, where the hydrophobic ceria nanoparticles
and Pt precursors could be blended in the microemulsion
droplets. After the addition of NH4OH aqueous solution and
tetraethyl orthosilicate, uniform Pt/CeO2@SiO2 nanocomposites were obtained.
3. LANTHANIDE NANOPARTICLES AS MRI CONTRAST

AGENTS
3.1. Introduction of MRI and MRI Contrast Agents
Nuclear magnetic resonance (NMR) spectroscopy was rst

exploited for imaging by Lauterbur and co-workers in 1973.107
Since then, MRI has become one of the most powerful imaging
techniques for bioimaging because it could provide anatomical
and functional images with high spatial and temporal
resolution.108,109 MRI, as a noninvasive imaging technique,
has extremely high tissue penetration depth. Moreover, MRI
does not employ radioactive agents or high-energy electromagnetic waves, as in the case of positron emission tomography
(PET), SPECT, and CT.110 The generation of MRI signal is
based on the resonance and relaxation properties of atom nuclei
under magnetic eld. Among all of the atoms with a net nuclear
spin (such as 1H, 3He, 13C, 19F, 17O, 23Na, and 31P), 1H is the
most widely employed atom because it is abundant in biological
tissues, and also is the second most sensitive nucleus. When
exposed to an external magnetic eld, the magnetic moments of
precessing hydrogen nuclei align either parallel or antiparallel to
the magnetic eld, producing a net magnetization in
longitudinal z axis (Mz), as presented in Figure 3. When
irradiated with a specic radio frequency (RF) pulse, the net
magnetization will be excited and ipped away from its original
axis. After the RF pulse disappears, the nuclei are not able to
3.2. Lanthanide-Based Nanoparticles for T1-Weighted MRI
3.2.1. Gd-Based Nanoparticles for T1-Weighted MRI.

Gd3+ has an isotropic electronic ground state (8S7/2), and nearly
no net orbital momentum, resulting in a negligible spinorbit
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coupling (Table 1). As a result, Gd3+ has a relatively long

electronic relaxation time, around 45 orders of magnitude
longer than that of other Ln3+.3,113 Moreover, Gd3+ has the
highest number of unpaired electrons in the periodic table.
These characteristics make Gd3+ the most ideal ion for T1
relaxation enhancement, while other Ln3+ ions are less ecient.
Because free Gd3+ is toxic, the chelating agents were commonly
used to stabilize Gd3+. As an alternative, inorganic nanostructures can also be used to conne Gd3+ ions, through either
doping Gd3+ ions into inorganic nanostructures or directly
utilizing Gd-based compounds as the host matrixes. To date, a
large amount of inorganic nanostructures have been investigated for doping Gd3+ ions, including silica,114 CaF2,115
hydroxyapatite,116,117 carbon nanomaterials (such as carbon
nanotube118 and carbon nanodot119), semiconductor nanocrystals (such as TiO2,120 ZnS,121 ZnO,122 CdSe,123 and
CdTe124), and other Ln3+-based nanoparticles. Because Gddoped nanostructures are various and dicult to classify, here
we only focus on Gd-based inorganic nanoparticulate T1 CAs,
which is more helpful to reveal the relaxation mechanism and
relevant factors.
3.2.1.1. Gadolinium Oxides. Nanosized gadolinium oxides
were rst evaluated for their physicochemical and NMR
properties by McDonald and co-workers in 2003,125 which
started the eld of Gd-based inorganic nanoparticulate T1 CAs.
Those Gd2O3 nanoparticles (2040 nm in diameter) showed
relatively small r1 (0.2 mM1 s1) and r2 (6.8 mM1 s1). From
then on, Gd2O3 became the prototype of Gd-based inorganic
nanoparticulate T1 CAs, and the relevant studies were
expanding. One facile method for preparing Gd2O3 nanoparticles is through the polyol route,126137 in which polyol
agents are utilized as solvents and capping agents. Kondo and
co-workers synthesized Gd2O3 nanoparticles via a polyol
method, and gelatin was used to form protective colloids.138
The obtained nanoparticles could be used for photoacoustic
and MR imaging. The polyol route has been extensively
studied; however, the yield of the polyol synthesis is rather low,
and lengthy dialysis time is necessary to purify the nanoparticle
solutions from free Gd3+ ions. Uvdal and co-workers reported a
polyol-free way of synthesizing 45 nm-sized Gd2O3 nanoparticles at room temperature, and the obtained nanoparticles
were capped with acetate and carbonate groups, showing
ecient MRI contrast enhancement properties (r1 = 6.9 mM1
s1 and r2 = 7.9 mM1 s1).139
Zhao and co-workers reported a two-step method to
synthesize Ln3+-doped Gd2O3 nanoparticles.140 Size-tunable
Gd2O(CO3)2H2O nanoparticles were prepared rst via a
hydrothermal method using glycerol as a size-controlling agent,
and then calcined to form Gd2O3 nanoparticles. Another route
for preparing Gd2O3 nanoparticles is the thermal decomposition method, typically using oleic acid and/or oleyamine as
solvents.141,142 However, subsequent treatments are commonly
required for water-solubility. Colvin and co-workers prepared
Gd2O3 nanoplates via the thermal decomposition method, with
a core diameter varying from 2 to 22 nm.143 The nanoplates
were then coated with an oleic acid bilayer or an octylaminemodied poly(acrylic acid) (PAA) polymer layer. These
nanoparticles exhibited ecient MRI contrast enhancement,
reaching up to 47.2 mM1 s1 at 1.41 T. As compared to
traditional precipitation routes or decomposition methods, a
top-down method, laser ablation in liquid (LAL) method,
generates products with higher purity and nearly no waste, and
has been applied for synthesizing a variety of nanomaterials.144
With this method, Li and co-workers synthesized ligand-free

monoclinic Gd2O3 nanoparticles with a mean diameter of 7.1
nm.145 The purity of Gd2O3 was suggested to contribute to the
relatively high r1 (5.53 mM1 s1).
Template-directed methods were often used for the synthesis
of Gd2O3 with specic structures.146 Yeh and co-workers
introduced biological gelation particles as shape and structure
templates to synthesize hollow and porous Gd2O3 nanospheres,
involving solgel processes and precursor deposition, respectively.147 Zhao and co-workers prepared Ln3+-doped Gd2O3
hollow nanospheres via a template-directed method using
hydrothermal carbon spheres as sacricial templates.148 The
hollow spheres have mesoporous shells, which are composed of
uniform nanoparticles, and can be used as drug delivery host
carriers in addition to imaging applications. Li and co-workers
reported the one-step synthesis of Gd2O3-encapsulated
mesoporous silica nanoparticles (Gd2O3@MCM-41), which
are of monodispersed spheres around 100 nm in diameter.114,149
Target specicity is a crucial requirement for diagnosis,
leading to reduced dose and minimized damage to normal
tissues. Ye and co-workers prepared oleate-coated Gd2O3
nanoparticles by the decomposition of gadolinium acetylacetonate in an organic medium. 150 Glioma-specic Gd2 O3
nanoparticles were then obtained by surface ligand exchange
with PEG and chlorotoxin conjugation. Wu and co-workers
encapsulated Gd2O3 nanoparticles into albumin, which were
cross-linked with glutaraldehyde and found to exhibit
autouorescence.134 Folic acid was then conjugated onto the
surface, and cancer cell targeting was realized.
Some Ln3+ (such as Eu3+,151156 Tb3+,153,157,158 Tm3+,153 and
Er3+159) exhibit intense narrow-band intra-4f luminescence, and
thus by doping with these emissive ions, Gd2O3 nanoparticles
can become optical imaging agents in addition to MRI CAs.
Besides the doping strategy, multifunctional applications could
also be realized through combining Gd2O3 nanoparticles with
other functional species, such as uorescent molecules,133
mesoporous silica,151 and noble metal clusters.160,161 Roux and
co-workers encapsulated Gd2O3 nanoparticles within a
polysiloxane shell, which carries organic uorophores, enabling
MRI and uorescence dual-mode imaging (Figure 4).162 Yeh
and co-workers prepared a shell-like carbon-coated Gd2O3
hybrid nanocomposite for T1-weighted MRI and NIR photothermal therapy, because the graphite carbon had a large
extinction coecient at 808 nm.163 Sharma and co-workers
prepared mesoporous silica nanoparticles coencapsulating
Gd2O3 and horseradish peroxidase, with an average diameter
around 25 nm.164 The entrapped enzyme could convert a
benign prodrug, indole-3-acetic acid, into a toxic oxidized
product, which can be used to kill cancer cells. Mohapatra and
co-workers encapsulated Gd2O3 nanoparticles within phospholipid micelles as vehicles for small molecules delivery, in
addition to T1 MRI CAs.165 Anker and co-workers reported a
coreshell nanocomposite containing Gd2O3 and -Fe2O3,
where the latter brought a magnetic property enabling the
nanocomposite to be guided, oriented, and heated using
external magnetic elds.166
Similar to oxides, gadolinium sulde can also be used as T1
CAs. Park and co-workers synthesized Eu3+-doped GdS
nanoparticles (8 nm) via the sonochemistry method (Figure
5).167 The nanoparticles could be used as a dual-mode imaging
agent for photoluminescence and T1-weighted MRI, with high
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suitable as host matrixes for luminescent centers, and, as a

result, lanthanide uorides have attracted much attention.
Mimun and co-workers synthesized Nd-doped GdF3 nanoparticles (5.52 2.24 nm) via thermal decomposition method
by employing triuoroacetates as precursors.168 After being
coated with poly(maleic anhydride-alt-1-octadicene), the nanoparticles showed excellent stability in water, combining ecient
NIR to NIR downshifting luminescence and T1 relaxation
enhancement properties. Chen and co-workers synthesized
Ln3+-doped GdF3 nanoparticles through one-step solvothermal
route by employing PAA as capping agents.169 These
nanoparticles can be used for time-resolved photoluminescent
biodetection and T 1 -weighted MRI. As compared to
solvothermal treatment and thermolysis, coprecipitation
method requires milder reaction conditions. With this method,
Prosser and co-workers synthesized citrate-coated GdF3
nanoparticles and a 2-aminoethyl phosphate-coated mixture
of GdF3 and LaF3 nanoparticles, and investigated their NMR
relaxation properties.170 Similarly, Botta and co-workers
synthesized GdF3 nanoparticles with diameter in 2.22.3 nm,
in which citrate was induced to limit particle size during the
synthesis and improve water-dispersibility and chemical
stability.171 The 1H and 17O relaxometric behaviors in aqueous
solution of GdF3 nanoparticles highlighted the dominant role of
Gd3+ ions exposed on the surface. Jin and co-workers reported
the synthesis of monodispersed ultrathin GdF3 nanowires
(lengths of 2040 nm and diameters of ca. 2 nm) with a
solvothermal method.172 After being modied with the
surfactant Pluronic F127, the GdF3 nanowires showed high r1
of 15.0 mM1 s1 at 7 T.
NaGdF4 has also been widely studied as MRI CAs. Prosser
and co-workers prepared PAA-coated NaGdF4 nanoparticle
aggregates and studied both their X-ray absorption and NMR
properties.173 van Veggel and co-workers reported size-tunable
synthesis of ultrasmall NaGdF4 nanoparticles below 10 nm, and
deeply discussed the size-dependent T1 relaxation enhancement
eect.174 Shi and co-workers fabricated ultrasmall NaGdF4
nanoparticles (about 2 nm in diameter) with PEG modication
and chelating molecule grafting to capture the potentially
released Gd3+ ions.175 These nanoparticles were more ecient
than commercially used T1 CAs in MR angiography, and even
capillary vessels and atherosclerotic plaques could be clearly
delineated (Figure 6). Furthermore, the nanoparticles could be
excreted through urine, indicating a negligible toxic eect. After
modication with functional groups on the surface of NaGdF4
nanoparticles, tumor-specic targeted MRI could be realized.176,177 Also, the NaGdF4 nanoparticles could be used for
both optical bioimaging and MRI applications through doping
with uorescent Ln3+ ions.178,179 Amine-functionalized Ln3+doped KGdF4 nanoparticles were synthesized by Chen and coworkers via one-step solvothermal route by employing
polyethylenimine (PEI) as the surfactant and capping ligand.180
These nanoparticles were demonstrated to be sensitive timeresolved FRET bioprobes, in addition to potential T1 CAs (5.86
mM1 s1 at 9.4 T).
3.2.1.3. Gadolinium Oxysalts. Through the hydrothermal
synthesis method, Suzuki and co-workers synthesized dextrancoated rod-like GdPO4 nanoparticles, with 2030 nm in the
major axis and 615 nm in the minor axis.17 The nanoparticles
showed high r1 and r2 values of 13.9 and 15.0 mM1 s1,
respectively, and 1.1 as the r2/r1 value at 0.47 T. The tumors in
rabbit could be eectively visualized with only 1/10 of the dose
applied for clinically used Gd-DTPA, resulting from relatively
Figure 4. (a) Size distribution determined by photon correlation

spectroscopy and high-resolution TEM image of Gd2O3 NPs. (b) T1weighted image of rat 1 h after injection of nanoprobes. (c)
Fluorescence reectance imaging of a nude mouse 3 h after injection
of nanoprobes. The nanoprobes were 2.2 nm-sized Gd2O3 NPs core
embedded in a polysiloxane shell whose inner part is functionalized by
Cy5 and the outer part by PEG (K, kidney; B, bladder). Reprinted
with permission from ref 162. Copyright 2007 American Chemical
Society.
Figure 5. (a) Confocal and phase contrast image (inset) of GdS:Eu3+

NPs internalized into SK-BR-3 cells. (Scale bar: 20 m). (b) T1weighted MR images of SK-BR-3 cell pellets with NPs. (c) T1weighted MR images of mice after injection of the GdS:Eu3+ NPs.
Enhanced signals from blood vessels were indicated by arrows and
numbers. Reprinted with permission from ref 167. Copyright 2012
Elsevier B.V.
r1 and r2 values at 4.7 T (13.48 and 24.53 mM1 s1,

respectively).
3.2.1.2. Gadolinium Fluorides. As compared to oxides,
uorides usually have lower phonon energy and are more
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lized Gd2 (CO3 ) 3:Tb nanoparticles with a narrow size

distribution in the range of 812 nm shaped as a quasisphere.194 The nanoparticles were subsequently coated with a
thin layer of silica shell, and the r1 value was determined to be
1.625 mM1 s1 at 0.5 T. Kong and co-workers synthesized
PAA-coated Gd(OH)CO32H2O nanoparticles (2.3 0.1 nm)
as T1 CAs, showing a high r1 of 34.8 mM1 s1 and a low r2/r1
ratio of 1.17.195 Yeh and co-workers fabricated Gd2O(CO3)2
H2O/silica/Au hybrid nanoparticles for T1-weighted MRI and
photothermal destruction of cancer cells.196 Zhao and coworkers synthesized Gd2O(CO3)2H2O nanoparticles with
diameters varying from 10 to 280 nm, which were further
coated with silica containing uorescein isothiocyanate.197
These nanoparticles showed size-dependent MRI properties.
3.2.1.4. Gadolinium Hydroxides. NMR relaxometric properties of rod-like Gd(OH)3 nanoparticles with the length of 150
nm were studied by Gossuin and co-workers, showing r1 and r2
of 4.03 and 8.0 mM1 s1, respectively, at 1.5 T.198 Yuan and
co-workers reported a hydrothermal method for synthesizing
Gd(OH)3 hexagonal nanorods with an average length of 100
nm and an average diameter of 15 nm.199 The Gd(OH)3
nanorods showed a high r1 of 12.3 mM1 s1.
Layered rare-earth hydroxides with a general composition of
RE2(OH)5XnH2O (RE = rare-earth, X = anions) are a class of
anionic clays that are composed of positively charged hydroxide
layers of trivalent rare-earth ions. Ghanotakis and co-workers
synthesized Gd2(OH)5NO3 nanosheets with an average size of
80 nm by the aqueous coprecipitation method.200 In addition
to MRI contrast enhancement, by modication with rose
bengal, the nanosheets could also be used for photodynamic
therapy. Byeon and co-workers synthesized a layered
gadolinium hydroxychloride, [Gd2(OH)5(H2O)x]Cl.201 The
ultrathin nanosheets had irregular shapes and lateral sizes of
120 30 nm, and the relaxivities are of 2.20 and 6.92 mM1 s1
for r1 and r2, respectively. They also developed surface
modication method of exfoliated layered gadolinium hydroxide.202 In this method, oleate anions were utilized to exchange
with nitrate ions of Gd2(OH)5NO3nH2O, and the delaminated
layers were modied with phospholipids with PEG tail groups.
With the incorporation of uorescein, the layered gadolinium
hydroxide exhibited uorescence and MRI relaxation enhancement properties simultaneously.
3.2.2. Factors That Determine Relaxivity. For rational
design of T1 CAs with superior performance, it is essential to
understand the factors controlling longitudinal relaxivity. The
SolomonBloembergenMorgan (SBM) equations are commonly used to analyze the parameters in the relaxation
process.4,203206 Because many previous reviews have already
discussed these equations in detail, only basic conclusions will
be presented here. The contributions of paramagnetic species
to longitudinal relaxivity come from three distinct types of
interactions with water molecules: direct coordination to metal
ions, hydrogen bond with ligand, and translational diusion
past the chelates or nanoparticles, which are termed as inner(IS), second- (SS), and outer-sphere (OS) contributions,
respectively.
Figure 6. MR angiography of rabbits within 3 min after being injected

with the NaGdF4 nanodots or Magnevist at the same dosage (13 mg
Gd/kg): abdominal aorta (AA) and inferior vena cava (IVC).
Reprinted with permission from ref 175. Copyright 2014 WileyVCH Verlag GmbH & Co. KGaA.
high r1, signicantly long plasma half-life, and high biocompatibility.181 Downconversion luminescence or upconversion
luminescence can be observed after doping emissive Ln3+
ions into GdPO4 matrix.182186
Li and co-workers synthesized Ln3+-doped GdVO4 tetragonal
nanosheets (with a thickness of 5 nm and a width of 150
nm) via solvothermal reaction.186 The surface oleates were
exchanged with PAA, and the hydrophilic nanosheets exhibited
strong uorescence and high r1 (37.8 mM1 s1) at 0.5 T. On
the basis of the uorescent property, quantitative detection of
streptavidin and imaging of integrin 21 expression in human
prostate cancer can be realized. If further modied by64Cu and
peptide, the nanoparticles can be used for targeted PET
imaging as well.187 Hollow and porous structured GdVO4:Dy
nanospheres were fabricated by Lin and co-workers using
Gd(OH)CO3:Dy as sacricial template.188 In addition to
uorescence and T1 relaxation enhancement properties, the
nanoparticles can be used to encapsulate drugs and
biomolecules as a drug delivery tool. Except Dy, Eu ions can
also be doped into GdVO4 nanoparticles to realize multifunction applications.189191 Alexandrou and co-workers
synthesized Eu-doped GdVO4 nanoparticles, which are
luminescent probes, oxidant sensors, and T1 CAs in MRI.192
Time- and space-resolved optical oxidant detection was feasible
due to the reversible photoreduction of Eu3+ to Eu2+.
The MRI contrast enhancement abilities of other gadolinium
oxysalts have been investigated as well. Lee and co-workers
synthesized D-glucuronic acid coated Gd(IO3)32H2O nanomaterials by one-pot precipitation method.193 These nanomaterials exhibited relatively high r1 and r2 (52.3 and 63.4 mM1 s1,
respectively) at 1.5 T, and X-ray attenuation properties due to
the existence of gadolinium and iodine. Li and co-workers
presented a reverse microemulsion method to synthesize the
monodispersed hexadecyl trimethylammonium bromide-stabi-
r1total = r1IS + r1SS + r1OS
(1)
IS
The inner sphere contribution rIS
1 can be expressed as r1 = qPm/
(T1m + m), where Pm is the molar ratio of metal ions and water,
q is the number of bound water per metal ion, and m is the
mean residence time of bound water. T1m is the longitudinal
relaxation time of bound water, which depends on the
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Figure 7. (a) TEM images of oleat-stabilized NaGdF4 NPs with sizes of (A) 2.5, (B) 4.0, (C) 6.5, and (D) 8.0 nm. (b) T1 ionic relaxivity plot for
NaGdF4 NPs of dierent sizes in water (1.5 T). (c) NP size-dependent plots of (A) the surface-to-volume (S/V) ratio, (B) the ionic relaxivity, (C)
the per-nanoparticle relaxivity, and (D) the relaxivity per square meter of surface area. Reprinted with permission from ref 174. Copyright 2011
Gd3+ ions has a reciprocal relationship to the six powers of

distance between Gd3+ and the surface-bound water protons,4
which implies that the innermost Gd3+ ions have the least
contribution. To make a simplied conclusion, for nanoparticles with the same amount of Gd3+ ions, a higher surface to
volume ratio (S/V) brings more Gd3+-bound water molecules
and thus a larger r1 when other parameters are xed.
The relationship between particle size and relaxivity has been
widely investigated. van Veggel and co-workers synthesized
NaGdF4 nanoparticles with four dierent sizes (below 10 nm),
and the r1 value increased while the particle size decreases
(Figure 7).174 Talham and co-workers synthesized three
dierent sizes of Eu0.2Gd0.8PO4H2O nanoparticles and found
that r1 increased for smaller particles.185 Rahman and coworkers synthesized Gd2O3 nanoparticles with the size varying
from 1.5 to 194.0 nm. The nanoparticles with size of 2.3 nm
showed the highest r1, while r1 drastically decreased for other
nanoparticles with smaller and larger sizes, indicating there is an
optimum Gd2O3 nanoparticle size of 2.3 nm.210 Lee and coworkers reported the synthesis of Gd2O3 nanoparticles with
diamters of 1 nm, which showed a large r1 of 9.9 mM1 s1.211
They proposed that surface Gd3+ ions will cooperatively
accelerate the longitudinal relaxation of water protons. Taking
both S/V and the cooperation eect into account, the optimal
range of diameter for the maximal r1 is suggested to be 12.5
nm. Gao and co-workers synthesized NaGdF4 nanoparticles
with three dierent sizes (5, 15, and 20 nm).176 With the same
surface modication, both 5 nm- and 20 nm-sized nanoparticles
showed higher r1 than that of 15 nm-sized nanoparticles. For
nanoparticles with similar shapes, S/V is strongly dependent on
particle size, and the smaller size brings higher S/V. However,
R increases with the nanoparticle size, and slowing the
tumbling of nanoparticles is in favor of higher r1, which is
detrimental for relaxation enhancement (Figure 8). Combining
the negative correlation between S/V and R, a nonmonotonic
longitudinal electron spin relaxation time (T1e) and the rotation

correlation time (R) of chelates. The T1e and m are eld
strength-dependent, and R can be estimated as R = 4a3/3kT
for spherical molecules, where a, , k, and T are radius,
viscosity, Boltzmann constant, and temperature, respectively.4
Dierent from inner-sphere contribution, the second- and
outer-sphere contributions are rather complex and dicult to
precisely analyze, because the relevant parameters are
commonly dicult to quantify.207 It should be noted that,
although these equations are applied to chelates initially, it is
reasonable to qualitatively apply them to nanoparticles, as
reported in the literature.145,171,172,174,185,208 From the viewpoint of chemical design, the nanoparticles are mainly
composed of an inorganic core and water-dispersible layer,
while bioactive groups could be selectively anchored onto the
surface for specic purposes.
3.2.2.1. Inorganic Core. The inner-sphere contribution
mainly originates from the inorganic core, while second- and
outer-sphere contributions are signicantly correlated with
water-dispersible layer. As we illustrated above, both q and R
are tunable parameters and have a great impact on relaxivity.
Increasing the number of water molecules directly bound to
Gd3+ ions (q) will result in an increase of rIS
1 . However, in
contrast to Gd-based chelates, the Gd3+ ions in nanoparticles
do not share the same chemical environment. Obviously, only
Gd3+ ions exposed on the surface of nanoparticles can be
coordinated, and inner Gd3+ ions have no chance to interact
with water molecules through chemical bonds. Although inner
Gd3+ ions still could enhance the water proton relaxation by
dipolar interaction (through space), their contributions are
insignicant.174 Shi and co-workers clearly elaborated the
dierence between surface and inner Gd3+ ions located in the
crystal lattice.209 When Gd3+ ions were buried deeply within
crystal lattices (>4 nm), a nearly 100% loss of r1 was observed,
and the surface coating of a new Gd-containing layer resulted in
the recovery of r1. Moreover, the dipolar contribution of inner
L
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GdF3 nanowires was attributed to the assembly of GdF3

nanocrystals.172 The surface capping ligands selectively
anchored to some specic GdF3 surfaces, and thus facilitated
the oriented attachment along the no (or less) capped crystal
planes. As compared to 0D shapes, the benets of anisotropic
shapes are reected in that simultaneously improving S/V and
R is possible to realize through rational design.
3.2.2.2. Surface Coating Layer. With respect to dierent
synthetic procedures and applications, various capping
strategies have been studied, and hundreds of capping agents
are utilized. The water-dispersible layer not only decides the
water-solubility and biocompatibility, but also contributes to
relaxivity via second- and outer-sphere interactions.129 Moreover, surface ligands will also inuence the interaction between
water molecules and surface Gd3+ ions. Li and co-workers
studied the relaxation properties of ligand-free Gd2O3 nanoparticles, the surface of which was not blocked by any chemical
ligands.145 They believed that water protons get fairly close to
the surface Gd3+ of the ligand-free Gd2O3 nanoparticles as
compared to ligand-coated nanoparticles, resulting in the
increase of r1 values. Ding and co-workers synthesized
monodispersed ultrasmall Gd2O3 nanoparticles capped with
hydrophobic oleic acid, and then modied the surface by two
methods: ligand exchange with polyvinylpyrrolidone and
bilayer coating with hexadecyl trimethylammonium bromide.213
The polyvinylpyrrolidone coated nanoparticles showed higher
relaxivities (r1 = 12.1 mM1 s1, r2 = 33.2 mM1 s1) than that
of bilayer coated nanoparticles (r1 = 0.54 mM1 s1, r2 = 11.9
mM1 s1). The low r1 of bilayer coated nanoparticles was
ascribed to the long hydrophobic chains, which prevented the
water molecules from approaching the surface Gd3+. Lee and
co-workers studied the ligand-size dependence of water protons
relaxivities.214 Three ligands including D-glucuronic acid,
polyethylene glycol diacid-250, and polyethylene glycol
behavior accompanied by size changing possibly exists (Figure

8).
Figure 8. Scheme of size dependence of two parameters (R and S/V)

for spherical particles. When size increases, the R increases and S/V
decreases, which are counteracting for relaxation enhancement.
Nanoparticle shape is another important parameter related to

S/V, and also has great impact on relaxivity. Generally, the
nanoparticles can be divided into three categories according to
their shapes: 0D nanoparticles (sphere and polyhydron), 1D
nanoparticles (nanowire172 and nanorod141,155,182,185,199), and
2D nanoparticles (nanoplate142,143,212 and nanosheet186,187,200).
The 0D nanoparticles are very common; for example, most of
the Gd2O3 nanoparticles we mentioned above have sphere-like
shapes. The anisotropic 1D and 2D shape can be regarded as
the elongation of 0D nanoparticles in one or two dimensions,
which usually resulted from the crystal structures and selective
adsorption of capping agents toward crystal planes exposed on
surface. As reported by Jin and co-workers, the formation of
Figure 9. (a) The most probable surface coating structure of D-glucuronic acid, PEGD-250, and PEGD-600 on the ultrasmall Gd2O3 NPs. (b) Plots
of r1 and r1 values as a function of ligand species (i.e., ligand size). (c) Schematic diagram of the phase transfer of the Gd2O3 NPs using an oleic acid
bilayer and poly(acrylic acid) (PAA)-octylamine (OA) (PAA-OA) polymer. (d and e) Plots of r1 and r2 values of the oleic acid bilayer and PAA-OA
coated Gd2O3 NPs as a function of the core diameters from 2 to 22 nm, respectively. (a,b) Reprinted with permission from ref 214. Copyright 2014
Royal Society of Chemistry. (ce) Reprinted with permission from ref 143. Copyright 2014 Royal Society of Chemistry.
M
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appeared to be 70 nm at 7 T (r2 190 mM1 s1) and 60 nm

at 17.6 T (r2 675 mM1 s1).20 Similar eld strengthdependence of r2 was observed by Gossuin and co-workers.198,220 They studied the NMR relaxometries of Ln3+-based
nanoparticles, and found that the transverse relaxivity of
Gd(OH)3 nanoparticles increased linearly with the magnetic
eld for Gd(OH)3 nanoparticles, because their transverse
relaxation was due to a proton exchange between the surface of
nanoparticles and bulk water. By contrast, a quadratic increase
was observed for Dy2O3, Tb4O7, Er4O(OH)9NO3, and
Ho4O(OH)9NO3 nanoparticles. Lee and co-workers reported
the synthesis of D-glucuronic acid-coated ultrasmall Ln2O3
nanoparticles (Ln = Eu, Gd, Dy, Ho, and Er), and investigated
their potential as T2 CAs.216 The Ln2O3 nanoparticles mixed
with Tb3+ and Eu3+ for T2-weighted MRI and uorescence
imaging, in which the Tb3+ and Eu3+ provided the strong
uorescence emissions in the visible region, as well as those
mixed with transition metal (Mn 2+ ) have also been
studied.221,222 The strategy to combine MRI and optical
imaging through uorescent lanthanide ions doping was also
utilized by Tan and co-workers.223 They synthesized ultrasmall
Tb-doped Dy2O3 nanoparticles (3 nm) for optical imaging
and high eld MRI, and the nanoparticles showed small r2 (2.17
mM1 s1) at 7 T. Ln2O3 nanoparticles prepared with
hydrothermal and solgel methods generally yield small
spherical nanoparticles. Helms and co-workers reported the
synthesis of Ln2O3 (Ln = Gd, Dy, and Yb) nanodiscs via
thermal decomposition method.224 The nanodiscs were of
1014 nm in diameter with a thickness of a single unit cell.
For Dy2O3 nanodiscs, their r2 values were 1.61.7-fold higher
over Gd-DTPA when passivated with poly(acrylic acid)methoxy-terminated poly(ethylene oxide)s at 1.41 T. As
compared to Gd2O3 and Dy2O3, the Yb2O3 nanodiscs exhibited
quite poor contrast enhancement due to their weak paramagnetic properties.
The lanthanide uoride nanoparticles have been exploited as
T2 CAs as well. van Veggel and co-workers synthesized NaDyF4 nanoparticles with the size in the range of 520 nm,
and systematically studied their T2 relaxation enhancement
properties, which increased with an increase in nanoparticle size
and eld strength (Figure 10).225 Zeng and co-workers
reported the synthesis of NaErF4 with dierent shapes and
discussed the shape eect on magnetic properties.226 The rodlike nanoparticles had the highest magnetization, which was
attributed to their highest shape anisotropy. When doped with
Yb3+, multifunctional NaErF4 nanorods were obtained combining upconversion emission, X-ray absorption, and T2 relaxation
enhancement properties.227 Tan and co-workers reported the
Tb-doped NaDyF4 nanoparticles for luminescence and T2weighted MR imaging. The nanoparticles showed the r2 of
22.325 mM1 s1 at 7 T.228
3.3.3. Factors That Determine Relaxivity. In principle,
the transverse relaxation enhancement induced by a paramagnetic compound results from the dephasing of the magnetic
moments in an inhomogeneous eld created by the small
magnetized particles. The diusion of water protons in
inhomogeneous eld reduces their phase coherence, causing
T2 shortening. The major relaxation mechanism accounting for
this process is the dipolar outer-sphere interaction between the
magnetic moment of the nanoparticles and the water proton
spins, as shown in the following equation:16,229,230
diacid-600 in the order of increasing ligand size were used to

coat ultrasmall Gd2O3 nanoparticles, and both r1 and r2 values
decreased with increasing ligand size (Figure 9). They
attributed this phenomenon to ligand size eect on water
accessability to surface Gd3+; that is, smaller ligands will allow
more water molecules to access the surface Gd3+. In fact, the
ligand size will also inuence the R, and the longer ligand chain
will slow the rotation of nanoparticles. In summary, a carefully
designed water-dispersible layer is crucial for nanoparticulate T1
CAs.
3.3. Lanthanide Nanoparticles for T2-Weighted MRI
3.3.1. Gd-Based Nanoparticles for T2-Weighted MRI.

Generally, all of the CAs will show both T1 and T2 relaxation
enhancement eect but, respectively, to a dierent extent. For
example, several Gd-based nanoparticles had a large r2/r1 ratio
in contrast to aforementioned ones, showing a dominant T2
relaxation enhancement. Ocana and co-workers reported the
synthesis of mesoporous Eu-doped GdF3 nanoparticles (85
nm) with quasi-spherical shape based on homogeneous
precipitation reactions using an ionic liquid as uoride
source. 215 The nanoparticles were functionalized with
aspartic-dextran polymers, showing a high r2/r1 ratio of 5 at
1.5 T (r1 = 1.22 mM1 s1 and r2 = 6.08 mM1 s1). Lee and
co-workers synthesized D-glucuronic acid-coated ultrasmall
Gd2O3 nanoparticles, which showed a high r2/r1 ratio of 6.4
at 1.5 T (r1 = 4.25 mM1 s1 and r2 = 27.11 mM1 s1).216
Prasad and co-workers reported Gd-doped upconversion
nanophosphors, showing the r2/r1 ratio of 62 at 9.4 T.217
Murray and co-workers reported the Gd2O3 tripodal nanoplates
with r2/r1 ratios of 99.3 and 217, at 9.4 and 14.1 T,
respectively.218 Speghini and co-workers synthesized PEGcapped GdF3 nanoparticles, and both Yb3+/Er3+ and Yb3+/
Tm3+ codoped nanoparticles showed substantially low r1 and
thus large r2/r1 ratios (452 and 790, respectively). However,
Gd3+ itself is not the rst choice for T2 relaxation, because its
magnetic moment is not the highest among trivalent lanthanide
ions.
3.3.2. Other Ln 3+ -Based Nanoparticles for T 2 Weighted MRI. All Ln3+ ions, with the exception of La3+
and Lu3+, have unpaired electrons and thus are paramagnetic.
However, dierent from their chemical behaviors, their
magnetic properties are determined by electron congurations
and dier dramatically along the series. The unpaired electrons
in paramagnetic Ln3+ ions other than Gd3+ inevitably populate
the f orbitals anisotropically, which gives rise to a strong
magnetic anisotropy and very short electronic relaxation time
(on the order of 1013 s).2 As a result, these Ln3+ ions usually
have small T1 relaxation enhancement, but they can have a
signicant eect on T2 relaxation. For example, Peters and coworkers studied the NMR properties of lanthanide (Nd, Gd,
Dy, Er, and Yb) oxide nanoparticles.124 The Ln2O3 nanoparticles had nearly no eect on T1 relaxation times except
Gd2O3. By contrast, their eects on the T2 relaxation times
were substantial. They observed the line widths of 1H water
resonance of Ln2O3 were larger than those of diamagnetic
La2O3, and the line broadenings can be ascribed to the eld
inhomogeneities created by the magnetized particles. They also
found that the r2 value was proportional to the eld strength
and the square of eective magnetic moment (eff), and the
cooperative eect between the individual ions of a particle did
not occur.219 Moreover, they reported the size-dependence of
r2 of Dy2O3 nanoparticles, and found that the optimal size
N
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not comparable with SPIO for T2 relaxation enhancement at a

weak external magnetic eld, they will show great advantages
with increasing eld strength. Thus, the paramagnetic Ln3+based nanoparticles hold great potential for high eld T2 MRI.
3.4. Lanthanide Nanoparticles for T1 and T2 Dual-Mode MRI
Considering the dierences of various imaging modalities in

penetration depth, resolution, and sensitivity, the combination
of multiple imaging modalities could provide complementary
diagnostic information over single modality.112,245,246 The T1
and T2 dual-mode MRI has attracted much attention, by which
valid reconstruction and visualization is guaranteed due to the
elimination of artifacts and the dierentiation of signals induced
by T2 CAs from low-level background.247,248 However, the
development of T1 and T2 dual mode CAs with both large T1
and T2 relaxation enhancement eects is challenging. In fact, all
of the CAs intrinsically show both T1 and T2 relaxation
enhancement eects. For instance, the SPIO shows a
predominant T2 eect. Further decrease of their sizes leads to
the improvement of the T1 eect, but, unfortunately, their T2
eects are reduced as well.249 Although FeCo alloy nanoparticles exhibit both high r1 and r2 values, the mechanism
underlying remains unclear.250 As we discussed above, the
paramagnetic Ln3+-based nanoparticles have been extensively
studied for their T1 and T2 eects, but simultaneously achieving
high r1 and r2 is dicult, due to the relatively small magnetic
moment of Gd3+ and poor T1 eect of other Ln3+.
The association of regular T1 and T2 CAs has become a
promising strategy for fabrication of T1 and T2 dual-mode CAs.
For example, Yang and co-workers synthesized T1 and T2 dualmode CAs by modifying Gd-chelates on the surface of magnetic
iron oxide nanoparticles.251 Liao and co-workers reported the
Gd-complex and phosphorescent probe-modied NaDyF4
nanorods for multimodality imaging.252 The construction of
coreshell structure is another way to combine T1 and T2 CAs.
Lee and co-workers synthesized MnO-coated Gd2O3 nanoparticles (12 nm), with the r1 and r2 of 12.8 and 26.6 mM1
s1 at 3 T, respectively.253 A smart theranostic NaDyF4:Yb@
NaGdF4:Yb,Er nanoprobe was reported by Tan and coworkers, which oered not only excellent dark T2-weighted
contrast but also tunable bright and dark T1-weighted
contrast.254 A similar Fe3O4@NaGdF4 structure was reported
by Anker and co-workers.255 However, the main problem is
that when T1 and T2 contrast materials are in direct contact, the
magnetic eld induced by T2 CAs will interfere with the
relaxation progress of paramagnetic T1 CAs, resulting in
undesired quenching of T1 eect.256,257 On the basis of this
consideration, Cheon and co-workers proposed a magnetically
decoupled coreshell design concept to develop a dual-mode
nanoparticulate contrast agent (Figure 11).248 The T2 contrast
material, MnFe2O4 (with diameter of 15 nm), and T1 contrast
material, Gd2O(CO3)2 (with a thickness of ca. 1.5 nm), were
used as core and shell, respectively, and separated by a layer of
SiO2 with thickness of 4, 8, 12, 16, and 20 nm. The degree of T1
and T2 eect can be tuned by controlling the thickness of the
separating layer, which makes it possible to create new T1/T2
CAs with maximized T1 and T2 eects. This concept of design
was extended by changing the compositions of core and shell,
and the ability to perform the AND logic gate algorithm to
enhance the accuracy of the raw MR images was
demonstrated.258 A similar structure (Fe3O4@SiO2@Gd2O(CO3)2) was reported by Luo and co-workers.259 The eect of
induced magnetic eld on T1 relaxation progress depends on
Figure 10. TEM images of the synthesized -NaDyF4 NPs, with the
sizes of (a) 5.4 0.3 nm, (b) 9.8 1.1 nm, and (c) 20.3 1.7 nm.
The inset shows the size analysis of the nanoparticles of at least 50
nanoparticles in each histogram. The scale bar is 50 nm for all three
images. (d) Longitudinal (r1) and (e) transverse (r2) relaxivity
obtained for the three sizes of -NaDyF4 NPs at 3 and 9.4 T. (f)
Comparison of r2/r1 values among the commercial T2 CAs and the
20.3 nm -NaDyF4 NPs. Reprinted with permission from ref 225.
Copyright 2012 American Chemical Society.
R2 =
1
a 2 2
=
Cj( , D)
T2
dD
(2)
where a is a constant, d is the diameter of the nanoparticle, D is

the diusion coecient, is the gyromagnetic ratio of the water
proton, is the magnetic moment of the nanoparticle, C is the
concentration of the nanoparticle, and j (, D) is the spectral
density function. The magnetic moment of Ln3+-based
paramagnetic nanoparticles depends on the total number of
Ln3+ ions per particle, the magnitude of the magnetic moment
of the individual ion, and the potential cooperative eect or
spin canting eect.20,231 Among all of the Ln3+, Dy3+ (10.63
B) and Ho3+ (10.60 B) have the largest eective magnetic
moments (eff), followed by Tb3+ (9.72 B) and Er3+ (9.59 B).
Thus, the Ln3+-based T2 CAs are mainly focused on the
paramagnetic ions with large magnetic moment (especially
Dy3+ and Ho3+). Although the magnetism is an intrinsic
property of bulk materials, the magnetic properties of
nanoparticles are signicantly aected by their size, shape,
and surface properties.232235 Hence, to design ecient T2
CAs, careful modulation of magnetization properties of
nanoparticles is required.
3.3.4. Field Strength Eect on Relaxivity. The trend of
MRI development is toward higher magnetic elds (>3 T),
which can give rise to higher signal-to-noise ratio, and better
spatial and temporal resolution.235238 However, the present
clinically used T1 and T2 CAs showed discounted ecacies in
ultrahigh eld. The optimal eld strength of Gd-based chelates
is below 1 T, and as much as one-third of r1 was reduced at 3
T.236,239242 The SPIO, clinically used T2 CAs, are known to
achieve magnetization saturation at around 1.5 T, and further
increase of eld strength will not lead to the increase of the T2
relaxation enhancement eect.19,198,243,244 In contrast, Ln3+based nanoparticles are far from saturated at clinic eld
strength. 3,198 For example, the magnetization of Dy2O3
nanoparticles does not saturate at up to 30 T.20 As we
mentioned above, the magnetic moment of paramagnetic Ln3+based nanoparticles increased with the eld strength before
saturation, which means their transverse relaxivities will keep
evolving at higher eld. Although Ln3+-based nanoparticles are
O
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modication process can be achieved by ligand exchange,266

ligand oxidation,267 silica coating,268 intercalation with
amphiphilic polymers,269 and so forth, after which UCNPs
are ready to be employed into extensive optical applications.
Despite these features, two aspects of UCNPs concerning
spectral modulation and extensive bioapplications are still of
great concern. On the one hand, the energy transfer pathways
play a crucial role in the upconversion process, which
determines the emission and excitation for promising
bioapplications. On the other hand, deepening the existing
bioapplications and developing novel biological models are also
essential for the potential applications of UCNPs. In this
section, we will present a comprehensive discussion regarding
the biosensing, bioimaging, and therapeutic applications of
Ln3+-based UCNPs. The basic mechanisms and very typical
spectral modulations will also be briey discussed; readers may
refer to the recently published reviews, which focus on the
upconversion energy transfer modulations for deeper understanding.270272
4.1. Mechanisms of Ln3+ Upconversion Emissions
With abundant energy levels of 4f electron congurations, Ln3+

can undergo various upconversion processes, and the
upconversion eciency also diers. In general, Ln3+ related
upconversion emissions can be derived from the following
types of energy transfer pathways: excited-state absorption
(ESA, Figure 13a), energy transfer upconversion (ETU, Figure
13be), cooperative energy transfer (CET, Figure 13f), and
energy migration-mediated upconversion (EMU, Figure 13g).
Photon avalanche (PA) is scarcely found in nanomaterials; thus
PA mechanized upconversion emissions would not be discussed
in detail here.
The ESA process refers to the sequential absorption of two
or more low-energy photons in one single type of Ln3+ with
long-lived intermediate energy states. The high-lying excited
state of Ln3+ can be populated by electrons via successive
upward transitions and then yield upconversion emissions. For
ETU processes, two types of luminescent centers, sensitizer and
activator, are involved. Energy transfer from sensitizer to
activator can be triggered upon excitation with pump photons.
Upconversion emission then can be observed from the
activator. The major dierence between ETU and CET lies
in the absence of a long-lived intermediate energy state of the
activator, and thus the ecienty is very low. In 2011, Liu and
co-workers developed the EMU process with the core/shell
nanostructure.273 Four types of luminescent centers, sensitizer,
accumulator, migrator, and activator, are incorporated into
dierent parts with precisely dened concentration. The energy
is nally trapped by the activator via sequential energy transfer
through the core/shell interface.
In Yb3+Ln3+ codoped ETU-based UCNPs, Yb3+ absorbs
NIR light (2F7/2 2F5/2) and then donates the obtained energy
to adjacent Ln3+. In Yb3+Er3+ codoped UCNPs (Figure 13c),
the energy is transferred to Er3+ via upward transitions to the
2
H9/2, 2H11/2, 4S3/2, and 4F9/2 states, generating three-photon
violet (415 nm, 2H9/2 4I15/2), two-photon green (525 nm,
2
H11/2 4I15/2; 545 nm, 4S3/2 4I15/2), and red (655 nm, 4F9/2
4I15/2) emissions. In Yb3+Ho3+ codoped UCNPs, twophoton upconversion can also occur to produce green (545 nm,
5
F4, 5S2 5I8) and red (650 nm, 5F5 5I8) emissions, while
the three-photon process generates blue (485 nm, 5F3 5I8)
emission (Figure 13d). It is worth noting that the matching
degree in energy state diagram of Yb3+Ho3+ pairs is inferior to
Figure 11. (a) Schematic and TEM image of coreshell type DMCA
(MnFe2O4@SiO2@Gd2O(CO3)2). (b) T1- and (c) T2-weighted MR
images and their color coded images of DMCA with varying SiO2
thickness by using 4.7 T MRI. Contrast agents: 200 M (Gd) for T1
image, 100 M (Mn + Fe) for T2 images. The images of Gd-DTPA
and Feridex were taken together for the purpose of comparison. (d)
Graph of r1 vs SiO2 thickness. (e) Graph of T1 quenching vs SiO2
thickness. (f) Graph of r2 vs SiO2 thickness. Reprinted with permission
from ref 248. Copyright 2010 American Chemical Society.
the location of the T1 contrast material. As reported by Gao and

co-workers, the inside T1 contrast materials were actually
exposed in an increased eld, and nally showed an enhanced
T1 eect (Figure 12).260 Meanwhile, the collection and
cooperation of Gd3+ spin order signicantly increased the
local magnetic eld of T2 contrast material, and thus synergistic
enhancement of T1 and T2 eect was observed. These Gdembedded iron oxide nanoparticles also provided a platform for
gene delivery with MRI monitoring.261 Therefore, doping Gd3+
into iron oxide nanoparticles is an eective route for the design
of T1 and T2 CAs, which was further veried by Ye and coworkers.262 They synthesized PEGylated Gd-doped iron oxide
nanoparticles via the polyol route, with r1 and r2 of 65.9 and
73.9 mM1 s1, respectively.
4. LANTHANIDE UPCONVERSION NANOPARTICLES

FOR BIOSENSING, BIOIMAGING, AND THERAPY
The upconversion process was rst proposed by N.
Bloembergen in a conceptual device named infrared quantum
counter in 1959.263 Since then, numerous eorts were made to
enrich the upconversion family, and Ln3+ activated bulk
materials have found application in temperature sensing264
and compact solid-state lasers.265 With the large surface-tovolume ratio, these nanoparticles can be easily decorated with
various functional groups for target applications. The surface
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Figure 12. (a) Two spin phenomena between T2 and T1 contrast materials with dierent locations. Left: The local magnetic eld intensity of T1
contrast materials is reduced when located outside of the T2 contrast materials. Right: The local magnetic eld strengths of T1 and T2 contrast
materials are enhanced simultaneously when T1 contrast materials are located inside the T2 contrast materials. T1- and T2-weighted MR images of (b)
Gd2O3-embedded iron oxide (GdIO) NPs, (c) magnetic NPs, and (d) Gd2O3 NPs at dierent metal concentrations in water (containing 1% agarose
gel). (e and f) The analysis of relaxation rate vs metal concentration for NPs in water. The phantom study was performed on a 0.5 T MRI scanner.
(g) T1- and (h) T2-weighted in vivo MR images of BALB/c mice (top, coronal plane; bottom, transverse plane) before and after intravenous
injection of GdIO NPs with a dose of 2.0 mg/kg. The region of liver in the coronal planes was circled by dash lines. (i) T1- and (j) T2-weighted in
vivo MR images of nude mice orthotopically inoculated with HepG2 liver cancer cells (sagittal plane) before and after intravenous injection of GdIO
nanoparticles with a dose of 2.0 mg Fe/kg. Gray arrows, gallbladder; black arrows, liver; white dotted circles and white arrows, liver tumor. Reprinted
with permission from ref 260. Copyright 2012 Wiley-VCH Verlag GmbH & Co. KGaA.
that of Yb3+Er3+ pairs; thus the upconversion eciency in

Yb3+Ho3+ pairs is lower than that in Yb3+Er3+ pairs. By
contrast, multiphoton upconversion emissions can be detected
in blue and UV regions from Yb3+Tm3+ codoped UCNPs
(Figure 13e). This should be attributed to the simple and
discretely arranged energy states of Tm3+, which minimizes
nonradiative relaxations and multiphoton cross relaxations
within activators. With the energy transferred from Yb3+, Tm3+
can release two-photon NIR (800 nm, 3H4 3H6) and red
(695 nm, 3F3 3H6) emissions, three-photon red (645 nm,
1
G4 3F4) and blue (475 nm, 1G4 3H6) emissions, fourphoton blue (450 nm, 1D2 3F4) and UV (365 nm, 1D2
3
H6) emissions, and ve-photon UV (345 nm, 1I6 3F4; 290
nm, 1I6 3H6) emissions.
can be divided into four categories: (a) controlling Ln3+ doping

concentration, (b) incorporating multiple activators, (c)
screening host matrixes, and (d) luminescence resonance
energy transfer.
4.2.1. Controlling Ln3+ Doping Concentration. The
doping concentration of Ln3+ aects the upconversion emission
behaviors by determining the energy transfer distance, which is
crucial for energy transfer eciency and energy transfer
pathways such as multiphoton cross-relaxations. From previous
investigations, independently altering the concentration of both
sensitizer and activator can lead to distinctive spectral proles,
and some regularities can be found.
In Yb3+Er3+ codoped UCNPs, it has been found that the
red to green emission ratio of Er3+ enhances with the increase
of the doping concentration of Yb3+ and Er3+. Yan and coworkers carefully studied the upconversion emission behaviors
of hexagonal phased NaYF4:Yb,Er nanoparticles with dierent
doping concentrations of Yb3+ and Er3+.275 A similar
phenomenon was found that the red to green emission ratio
of Er3+ increased monotonically with elevated content of Yb3+
and Er3+. Moreover, such regularity was suitable for both large
(185 nm) and small (20.2 nm) nanoparticles. In a very recent
study, Tan and co-workers investigated the upconversion
emissions from nanoparticles with heavy activator doping.276
With the increasing doping concentration of Er3+ from 1% to
50%, the red to green emission ratio of Er3+ greatly enhanced,
with the color output shifting from green to red (Figure 14a).
Generally, the enhanced red to green emission ratio of Er3+ was
attributed to the phonon assisted nonradiative relaxation and
4.2. Multicolor Modulation of Upconversion Emissions
The upconversion emission behaviors are unique in bioapplications, such as the ecacy of bioimaging, therapy,
sensing, and detection. Therefore, modulation of upconversion
emissions has always been a great concern. Only a few dopant
pairs including Yb3+Ln3+ (Ln = Er, Tm, and Ho) are ecient
for upconversion transitions. Moreover, spectral overlap can be
found in these luminescent centers. The progress of UCNPs for
multicolor imaging and multiplexed detection applications is
thus limited.271 Modulation of upconversion emission ratio and
the combination of independent emissions from dierent
activators are the main concerns for producing multicolor
UCNPs.274 To date, many approaches have been developed to
endow Ln3+ doped UCNPs with multicolor emissions, which
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Figure 13. Principal mechanisms for Ln3+ related upconversion emissions: (a) ESA, (b) ETU, and upconversion energy transfer diagrams in (c)
Yb3+Er3+, (d) Yb3+Ho3+, and (e) Yb3+Tm3+ pairs, (f) CET, (g) EMU. Note that dierent regions are highlighted with dierent background
colors in the EMU process.
Figure 14. Modulating multicolor upconversion emissions by controlling the doping concentration of activators. The digital luminescence
photographs and upcoversion emission spectra of NaYbF4:Er (a) and NaYbF4:Tm UCNPs with the concentration of activator varying from low to
high. Specically, the concentration of Er3+ was tuned from 1% to 100%, while that of Tm3+ was tuned from 1% to 20%. Reprinted with permission
cross-relaxation process within two adjacent Er3+ ions: 4F7/2 +

4
I11/2 4F9/2 + 4F9/2, where the 4F9/2 state is responsible for
red emission. The cross-relaxation between Er3+ and Yb3+ was

also proposed to account for the enhanced red emission by Liu
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Figure 15. Modulating multicolor upconversion emissions by incorporating multiple activators into the same region. (a) Upconversion emission
spectra of NaYbF4:Er,Tm, NaYbF4:Er,Ho and NaYbF4:Tm,Ho UCNPs. Insets are corresponding digital luminescence photographs. (b) Normalized
upconversion emission spectra (top) and color map (bottom) of NaYF4:Er,RE UCNPs. (c) Upconversion emission spectra of KMnF3:Yb,RE
UCNPs. Insets are corresponding digital luminescence photographs. (a) Reprinted with permission from ref 280. Copyright 2009 American
Chemical Society. (b) Reprinted with permission from ref 282. Copyright 2012 American Chemical Society. (c) Reprinted with permission from ref
283. Copyright 2011 Wiley-VCH Verlag GmbH & Co. KGaA.
and co-workers.277 They reasoned that the interatomic distance

between Yb3+ and Er3+ was shortened and consequently
promoted the 4S3/2 (Er3+) + 2F7/2 (Yb3+) 4I13/2 (Er3+) +
2
F5/2 (Yb3+) process, facilitating the population on the 4F9/2
state via 4I11/2 (Er3+) 4I9/2 (Er3+).
Similarly, the doping concentration of Ln3+ also signicantly
inuences the emission ratio from Yb3+Tm3+ codoped
UCNPs. It can be found that the ratio of multiphoton UV
and blue emissions to two-photon NIR emissions enhanced
almost monotonically with the increment of doping concentration of Yb3+,278 and decreased with increasing content of
Tm3+.279 The researchers reasoned that the energy transfer
distance was shortened with increased Yb3+ content, hence the
enhanced energy transfer eciency from Yb3+ to Tm3+, which
facilitated the multiphoton emissions eectively. For example,
Tan and co-workers found that with increasing Tm3+ content
from 1% to 10% in hexagonal phased NaYbF4 lattice, the
multiphoton emissions released from high-lying 1D2 and 1G4
states were completely quenched, while the two-photon NIR
emissions were enhanced (Figure 14b). The cross-relaxation
process between two neighboring Tm3+ ions, 1G4 + 3F4 3H4
+ 3F2, should be responsible.
4.2.2. Incorporating Multiple Activators. When multiple
activators are incorporated into one single type of nanoparticles, it is possible for them to extract energy from
sensitizers simultaneously. Moreover, novel cross-relaxations

may be triggered when multiple activators are incorporated,
which can bring novel upconversion emissions and a distinctive
emission ratio.
Xu and co-workers obtained multicolor emissions, including
orange, yellow, green, cyan, blue, and pink, by codoping two
activators among Er3+, Tm3+, and Ho3+ into a single NaYbF4
nanoparticle (Figure 15a).280 It is worth noting that multiple
activators in the same region would result in nonradiative
multiphoton cross-relaxations within dierent activators. With
the proper assistance of cross-relaxation, the upconversion
emission ratio of the original activator can be aected greatly.
Zhang and co-workers studied the upconversion emission
behavior of Yb3+Ho3+ doped NaYF4 nanoparticles after
incorporating Ce3+.281 With increasing doping concentration
of Ce3+ from 0% to 15%, the red to green emission ratio of
Ho3+ increased signicantly, with the color output from green
to red. Chan and co-workers performed combinatorial
discovery of upconversion emissions from nanoparticles with
dual activators (Figure 15b).282 Spectral proles indicated that
pronounced green emission of Er3+ can be generated from
Er3+Pr3+ and Er3+Sm3+ codoped nanoparticles, while the
prominent red emission of Er3+ can be released from Er3+
Ho3+ and Er3+Tm3+ codoped nanoparticles. For Er3+Sm3+
codoped nanoparticles, selective quenching of the red emission
is responsible for the pronounced green emission. For Er3+
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Figure 16. Modulating multicolor upconversion emissions by LRET process. (a) Schematic design of LRET-based multicolor NaYF4:Yb,Er/Tm@
SiO2 UCNPs. (b)Upconversion emission spectra of NaYF4:Yb,Tm@SiO2 UCNPs and FITC-, QD605-encapsulated NaYF4:Yb,Tm@SiO2 UCNPs.
(c) Upconversion emission spectra of NaYF4:Yb,Er@SiO2 UCNPs and TRITC-encapsulated NaYF4:Yb,Er@SiO2 UCNPs. (d) Upconversion
emission spectra of TRITC-encapsulated NaYF4:Yb,Er@SiO2 UCNPs with dierent amounts of TRITC (10, 20, 30, 40 nmol). Reprinted with
permission from ref 287. Copyright 2008 Wiley-VCH Verlag GmbH & Co. KGaA.
Ho3+ and Er3+Tm3+ codoped nanoparticles, multiphoton

cross-relaxation processes should account for the enhanced red
emission.
Transition metal ions with unique energy states have also
been introduced to mediate the photon upconversion processes
of Ln3+. With the 4T1 state, Mn2+ is frequently used an energy
bridger to mediate the energy transferred from Yb3+ to Ln3+
activators. Liu and co-workers prepared KMnF3:Yb,Er nanoparticles and studied the emission behavior.283 As a result,
nearly spectrally pure red emission can be observed. Because
the 4T1 state of Mn2+ lies lower than the 2H11/2 and 4S3/2 states
of Er3+, cross-relaxation processes between Er3+ and Mn2+ make
the population of the 4F9/2 state, thus yielding prominent red
emission. Moreover, spectrally pure red and NIR emissions
were also achieved in Yb3+Ho3+ and Yb3+Tm3+ doped
KMnF3 nanoparticles, respectively (Figure 15c). Mo6+ was also
proved to be ecient for tuning the upconversion emission
ratio.284 Spectral proles showed that the respective green and
blue emissions of Er3+ and Tm3+ enhanced signicantly as
compared to their red emissions.
4.2.3. Screening Host Matrixes. Dierent host matrixes
possess diverse phonon energy, which is important for the
upconversion emission behavior by aecting the energy transfer
pathways. For example, when Yb3+ and Er3+ are codoped into
NaYF4 lattices, which are adopted as one of the most ecient
host matrixes for upconversion emissions, the emission ratio
diers greatly in the cubic and hexagonal counterparts.275 In
hexagonal NaYF4 nanoparticles, the green emission dominates
the spectral prole, generating green color output. However, in
cubic NaYF4 nanoparticles, the red emission is comparable with
the green emission, yielding yellow color output.
Besides the dierence in phonon energy, the capacity of
preserving excitation energy also diers in various host
matrixes. Very recently, Liu and co-workers discovered
enhanced multiphoton violet upconversion emission of Er3+
through energy clustering at sublattice level in orthorhombic

KYb2F7 nanoparticles.285 As compared to the nanoparticles
featuring high-symmetry unit cells, which promote the
depletion of excitation energy, like cubic NaYF4, NaEuTiO4
and Sr2CeO4, KYb2F7 nanoparticles are superior in facilitating
localized energy exchange interaction and simultaneously
minimizing the delocalization of the excitation energy. The
upconversion emission spectra indicated that the multiphoton
violet emission is comparable to the two-photon green and red
emissions. Moreover, the violet emission was conrmed a fourphoton emission resulting from fast energy transfer within
tetrad Yb3+ clusters.
4.2.4. Luminescence Resonance Energy Transfer. The
luminescence resonance energy transfer (LRET) process refers
to a resonant energy transfer that occurred from an energy
donor to an energy acceptor. For UCNP-based LRET systems,
in general, UCNPs are employed as the energy donor due to
their large anti-Stokes shifts and sharp-band emissions, while
organic dyes, quantum dots, noble metals, and some other
entities are used as energy acceptor for their excellent
absorption capacity. In most cases, the energy acceptor is
designed to extract one of the multiple upconversion emissions
from UCNPs, leading to a signicant quenching, and thus the
emission ratio can be eectively modulated. To achieve a highly
ecient LRET process, two key factors should be considered,
the spectral overlap between the upconversion emission of
UCNPs and absorption of energy acceptors as well as a proper
spatial distance (<10 nm).
Yan and co-workers employed tetrametrylrhodarnine isothiocyante (TRITC) molecules, which had an absorption peak
in the green region, as a potential energy acceptor to absorb the
green upconversion emission from hexagonal NaYF4:Yb,Er
nanoparticles.286 The green emission of Er3+ was signicantly
quenched, while the concomitant red emission was almost not
aected. Moreover, the typical emission of TRITC was
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triggered by NIR excitation. Moreover, the luminescence

lifetime of UCNPs shortened, while that of TRITC greatly
lengthened. All of these results indicated the LRET process
occurred from UCNPs to TRITC. Zhang and co-workers
encapsulated uorescein isothiocyanate (FITC), QD605, and
TRITC into the silica layer capped over UCNPs (Figure 16).287
Spectral results exhibited that the upconversion emissions from
Tm3+ and Er3+ were eciently quenched after introducing these
energy acceptors. Meanwhile, typical emissions from the
organic dyes and quantum dots can be triggered upon NIR
excitation, and the emission intensity of TRITC was proportional to the amount of TRITC used, indicating the occurrence
of the LRET process.
4.3. Eciency Enhancement of Upconversion Emissions
As is known, the intracongurational transitions of Ln3+ are

parity-forbidden, and thus the absorption cross-section of Ln3+
is rather small, resulting in limited upconversion emission
eciency. Moreover, when the particle size is down to
nanoscale, the upconversion emissions also face a signicant
quenching eect from surface defects, ligands, and solvent
molecules. However, excellent ecacy of bioapplications
requires adequate upconversion emission eciency. On this
basis, eciency enhancement of upconversion emissions is of
vital importance. After nearly a decade of development, several
methods have been proposed and veried to enhance the
upconversion emissions, including (a) tailoring the local
symmetry of luminescent center, (b) surface passivation with
core/shell structure, and (c) plasmonic enhancement with
noble metals.
4.3.1. Tailoring the Local Symmetry of the Luminescent Center. It is the change in point symmetry of Ln3+ that
makes their parity forbidden 4f4f intracongurational
transitions partially allowed when they are embedded in
inorganic lattices. Therefore, further tailoring the local
symmetry of the luminescent center should facilitate the
intracongurational transitions and thus enhance the upconversion emission eciency. The local symmetry tailoring
process is usually achieved by incorporating optically inert
non-Ln3+ ions, whose ionic radii are quite dierent from those
of Ln3+.
Li+ ions, with the much smaller ionic radius than Ln3+ ions,
are expected to eectively tailor the local symmetry of Ln3+
luminescent centers when they are introduced to Ln3+ activated
UCNPs. Zhang and co-workers reported the rst enhancement
of upconversion emissions of Er3+ by incorporating Li+ into
Y2O3:Yb,Er nanoparticles (Figure 17a).288 With increasing
doping concentration of Li+ from 0% to 15%, apparent shifts of
the diraction peaks were observed, indicating the potential
change in the local symmetry of Er3+. Meanwhile, both the
green and the red emissions of Er3+ enhanced signicantly by 2
orders of magnitude with increasing content of Li+ from 0% to
5% and then saturated with further increasing content of Li+.
Moreover, the visible emission intensity of Er 3+ in
Y2O3:Li,Yb,Er nanoparticles, where 5% Li+ ions were tridoped,
reached up to one-half that of their bulk counterparts. On one
hand, lengthened lifetimes in the intermediate 4I11/2 (Er3+) and
2
F5/2 (Yb3+) states indicated the population on the 2H11/2 and
4
S3/2 states of Er3+, leading to enhanced green emission via
2
H11/2/4S3/2 4I15/2 transition. On the other hand, crossrelaxations between two Er3+ ions and between Yb3+ and Er3+
assisted the population on the 4F9/2 state of Er3+, resulting in
more prominent red emission via 4F9/2 4I15/2 transition.
Figure 17. Enhancing upconversion emission eciency by tailoring

the local symmetry of luminescent center. (a) Upconversion emission
spectra of nanocrystalline and bulk Y2O3:Yb,Er and Y2O3:Li,Yb,Er
UCNPs. (b) Upconversion emission spectra of BaTiO3:Yb,Er lm
under bias voltage ranging from 0 to 10 V. Inset is schematic
illustration for the tetragonal lattice of BaTiO3:Yb,Er with an external
electric eld E. (a) Reprinted with permission from ref 288. Copyright
2008 American Chemical Society. (b) Reprinted with permission frm
ref 291. Copyright 2011 Wiley-VCH Verlag GmbH & Co. KGaA.
Apart from Li+, Bi3+ and Mo3+ ions have also been veried to
possess an eective tailoring eect on the local symmetry of
Ln3+ luminescent centers.289,290
Hao and co-workers reported another intriguing manner to
tailor the local symmetry of Ln3+ in ferroelectric BaTiO3:Yb,Er,
where Er3+ ions are noncentrosymmetric in the lattice (Figure
17b).291 When applying an external electric eld along the
direction of spontaneous polarization, the lattice elongated and
promoted the asymmetry of the BaTiO3 host, leading to lower
symmetry around Er3+ ions. As a result, the green emission
enhanced about 2.7 times.
4.3.2. Surface Passivation with Core/Shell Structure.
van Veggel and co-workers assessed the absolute quantum yield
of hexagonal NaYF4:Yb,Er nanoparticles with dierent particle
size.292 With the particle size decreasing from 100 to 10 nm, the
quantum yield sharply decreased from 0.3% to 0.005%.
Moreover, a 95% decrease in quantum yield was observed
when the particle size decreased from 30 to 10 nm. Jin and coworkers analyzed the upconversion emission decay proles in
dierent-sized hexagonal NaYF4:Yb,Er nanoparticles.293 It was
found that both the green and the red emission lifetimes
reduced monotonically when the particle size decreased from
45 to 6 nm. Therefore, the upconversion emission eciency
decreased sharply with decreased particle size. Capobianco and
co-workers observed the dependence of upconversion
emissions on solvent molecules.294 The green emission of
hexagonal NaYF4:Yb,Er nanoparticles was greatly quenched
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Figure 18. Enhancing upconversion emission eciency by surface passivation with core/shell structure. Schematic illustration (a, inset:
concentration analysis of luminescent centers) and upconversion emission spectra (b) for NaYF4:Yb,Er@NaYF4 core/shell UCNPs with dierent
shell thickness. Upconversion emission spectra (c), digital luminescence photographs (d), and luminescence decay proles (e) of NaYF4:Yb,Er@
NaGdF4 core/shell UCNPs with dierent shell thickness. (fh) Upconversion emission spectra of NaYF4:Yb,Er/Tm/Ho@CaF2 UCNPs. Insets are
corresponding digital luminescence photographs. (a,b) Reprinted with permission from ref 295. Copyright 2012 American Chemical Society. (ce)
Reprinted with permission from ref 296. Copyright 2012 American Chemical Society. (fh) Reprinted with permission from ref 297. Copyright
2012 Wiley-VCH Verlag GmbH & Co. KGaA.
compounds should be considered for epitaxial shell growth

process.
The thickness of the shell layer aects the upconversion
emission behavior greatly. van Veggel and co-workers
developed a layer-by-layer epitaxial growth of NaYF4:Yb,Er@
NaYF4 core/shell nanocrystals by Ostwald ripening.295 By
controlling the growth time, the thickness of the shell can be
subtly tuned from 0.7 to 2.1 nm. Meanwhile, the emission
intensity of Er3+ enhanced progressively with the increasing
shell thickness (Figure 18a,b). Zhang and co-workers fabricated
NaYF4:Yb,Er@NaGdF4 core/shell structures and assessed the
dependence of shell thickness on upconversion emission.296 It
was found that the emission intensity enhanced progressively
with increasing thickness (Figure 18c,d). Moreover, the
emission lifetimes lengthened as a result (Figure 18e). Recently,
Yan and co-workers developed an unprecedented category of
NaYF4:Yb,Ln@CaF2 (Ln = Er, Ho, Tm) heterogeneous core/
shell structures.297 The CaF2 shell thickness-dependent
upconversion emission behavior was also studied. When the
shell thickness reached 3 nm, the emission intensity of Er3+ in
when the oleate ligands were removed in H2O. Hydroxyl

(OH) groups generated vibrational modes at 32003600
cm1, which can be ecient as the oscillators to induce the
nonradiative relaxation processes of 2H11/2 4F9/2 and 4I11/2
4I15/2 and then quenched the green emission of Er3+.
An eective way to minimize the quenching eect induced by
surface defects, capped ligands, and solvent molecules is surface
passivation with core/shell structure. The core/shell structure
refers to epitaxial growth of a shell layer over the core
counterpart. After deposition with a shell layer, the excitation
energy can be blocked in the core region, avoiding further
transportation to surface defects. Meanwhile, the quenched
luminescent centers in the core surface can be reactivated by
the protection of shell layer. Moreover, the distance between
the luminescent centers in the core and capped ligands or
solvent molecules is lengthened, and thus nonradiative
relaxation processes induced by stretching vibration modes
can be eectively minimized. Excellent matching in the phase
structure and lattice parameter between the core and shell
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Figure 19. Modulating upconversion excitation pathway by incorporating Nd3+. (a) Schematic design and proposed energy transfer pathways for
Nd3+ sensitized core/shell UCNPs. (b) Typical upconversion emission spectra of NaGdF4:Yb,Er@NaGdF4:Nd,Yb UCNPs upon 980 and 808 nm
excitation. (c) In vivo UCL of a nude mouse subcutaneously injected with NaGdF4:Yb,Er@NaGdF4:Nd,Yb UCNPs upon 980 nm (left) and 808 nm
(right) excitation. (d) In vivo heating eect induced by 980 nm laser irradiation for 50 s and 808 nm laser irradiation for 300 s. Reprinted with
permission from ref 310. Copyright 2013 American Chemical Society.
the blue emissions of Tm3+, resulting in eective coupling.

Specically, a more than 150% increase in emission intensity
was observed for the emissions at 450 and 475 nm, while a 50%
increase was seen for 645 nm emission.
The distance between the UCNPs and noble metal
nanostructures is important for the enhancement eciency.
Kagan and co-workers constructed a three-layered assembly of
UCNPs-Al2O3-Au/Ag, and investigated the upconversion
emission behavior by tuning the thickness of Al2O3 layer
from 2 to 15 nm.303 The thickness of the Al2O3 layer at which
the largest enhancement occurred was 5 nm for Au
nanoparticles and 10 nm for Ag nanoparticles, and was
independent of the composition of UCNPs. Schietinger and
co-workers presented a single particle-based study of plasmonic
enhanced upconversion emissions with a homemade setup
comprising inverted confocal microscope and atomic force
microscope.304 When the two composites were in close vicinity,
strongly enhanced upconversion emissions can be observed.
The enhancement factor was 4.8 and 2.7 for green and red
emissions, respectively. In addition, ne arrays of various noble
metal nanostructures are ecient LSPR supporters, such as Au
nanohole arrays,305 Au surfaces,306 Au nanopillar arrays,307 and
Au pyramid array.308
NaYF4:Yb,Er@CaF2 nanoparticles enhanced about 300 times as

compared to that of Er3+ in naked NaYF4:Yb,Er core
counterparts (Figure 18f), and the emission lifetimes
lengthened from 15 to 102 s. A similar signicant enhancement was also noticed in NaYF4:Yb,Ho@CaF2 (Figure 18g)
and NaYF4:Yb,Tm@CaF2 (Figure 18h) nanoparticles. Another
advantage of such NaYF4:Yb,Ln@CaF2 core/shell structures is
the suppressed leakage of Ln3+ when applied in biological
applications, ensuring the biosafety.
4.3.3. Plasmonic Enhancement with Noble Metals. To
date, various Au and Ag nanostructures have been widely used
to provide localized surface plasmon resonance (LSPR), whose
capacity for enhancing emissions from organic dyes, quantum
dots, and UCNPs has been veried.298300 The enhancement
eect can be ascribed to enhanced local excitation eld and
promoted emission rate. According to these two rules, various
nanocomposites comprising UCNPs and noble metal nanostructures can be exibly designed to enhance the upconversion
emissions.
Duan and co-workers observed highly spectral-dependent
enhancement of upcoversion emissions with sputtered gold
island lms.301 The LSPR peak was featured in the NIR region
where the excitation wavelength (980 nm) for UCNPs was
involved. As a result, larger enhancement factors are observed
for emissions with excitation processes that involved more
photons. Thus, they attributed this to the increased excitation
ux due to local eld enhancement. They also noticed
accelerated radiative decay rate dominated enhancement of
upconversion emissions in NaYF4:Yb,Tm@Au nanocomposites.302 The LSPR peak of Au nanoparticles overlapped well
4.4. Upconversion Excitation Modulation
Because of the simple energy state diagram with only one

excited state, Yb3+ ions exhibit one single excitation band
centered at 980 nm (2F7/2 2F5/2). Therefore, exible
excitation ways for upconversion emissions cannot be achieved,
which to a large extent hinders the progress of bioapplications.
For example, water molecules have intense absorption at 980
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4.5. Upconversion Nanoparticles for Biosensing
nm; hence, when 980 nm NIR light is radiated to biological

tissues that contain lots of water molecules, an overheating
eect can be induced.309 To address such problem, energy
transfers from Ln3+ ions and externally modied antenna
ligands have been developed.
4.4.1. Energy Transfer between Lanthanide Ions.
Enlightened by abundant energy states of Ln3+ ions, ecient
energy transfers between various Ln3+ ions are possible.
Because the 4F3/2 excited state of Nd3+ lies higher than the
2
F5/2 excited state of Yb3+, Nd3+ can donate as-absorbed energy
to Yb3+ via an ecient down-shifting process. On this basis, the
excitation pathway for upconversion emissions might be
modulated by incorporating Nd3+ ions into Yb3+ sensitized
nanoparticles. Moreover, beneting from the large absorption
cross-section of Nd3+ (5.8 1020 cm1) around 800 nm,
satisfactory upconversion emission eciency could be obtained
by exciting Nd3+.
Yan and co-workers developed a novel series of Nd3+sensitized NaGdF4:Yb,Ln@NaGdF4:Nd,Yb (Ln = Er, Tm)
core/shell nanoparticles.310 Considering the complicated
energy state diagram of Nd3+ and potential multiphoton
cross-relaxation processes between Nd3+ and Er3+, Nd3+ and
Er3+ ions were incorporated into separate regions (Figure 19a).
The appropriate amount of Yb3+ ions was also introduced to
the shell region to migrate energy from Nd3+ to Er3+ in the
core. Spectral proles exhibited that the upconversion emission
eciency was similar upon 980 and 808 nm excitation (Figure
19b,c). Moreover, the overheating eect induced by long-time
980 nm irradiation can be eectively minimized by 808 nm
irradiation. As depicted in Figure 19d, a notable local heating
eect and signicant rise in temperature (ca. 7 C) were
observed upon 980 nm irradiation for 50 s with the excitation
power density of 130 mW/cm2. By comparison, upon 808 nm
irradiation, only a slight rise in temperature (ca. 1 C) was
detected under the same condition. With proper design of
core/shell structure, Wang and co-workers also noticed ecient
upconversion emissions upon 808 nm excitation.311 To further
eliminate the multiphoton cross-relaxation processes between
Nd3+ and Er3+, Zhao and co-workers introduced an NaYF4:Yb
interlayer between the two layers containing Er3+ and Nd3+,
respectively.312 As a result, about 8 times enhancement was
observed. Aside from that, tridoping with Nd3+ was also
possible to realize upconversion emissions from activators.313315
4.4.2. Introducing Near-Infrared Antenna Ligand.
Dierent from the aforementioned LRET process, here the
NIR antenna ligands serve as energy donors while UCNPs
work as energy acceptors. Spectral match between the emission
of antenna ligands and absorption of UCNPs as well as proper
spatial distance should be considered.
Hummelen and co-workers presented a broadband dyesensitized nanocomposite comprising NIR antenna and
UCNPs.316 In their study, commercial IR-780 molecules were
functionalized with carboxylic acid molecules, leading to a novel
derivative IR-806 whose emission band covered 980 nm. To
achieve close vicinity, IR-806 molecules were decorated on
UCNPs via a ligand exchange procedure. On this basis, ecient
energy transfer from NIR antenna ligands to UCNPs can occur
when the NIR antenna ligands were excited. As a result, the
excitation wavelength was shifted to 800 nm. Moreover, as
compared to oleate capped UCNPs, signicantly enhanced
upconversion emissions can be observed for NIR ligandssensitized nanoparticles with the enhancement factor of 3300.
It is well-known that biosensing plays an important role in

biomedical detection. For example, the real-time monitoring of
the changes of pH, temperature, and other fundamental
parameters in living cells is essential for the systematic studies
on cell activities.317 Ln3+-doped UCNPs have found great
signicance in biomedical detection due to their excellent
optical characteristics and stability. In particular, the excitation
wavelength of NIR oers increased penetration depth in
biological tissue, making UCNPs exceptionally favorable in
biosensing processes. The emission wavelength of UCNPs has
a large anti-Stokes shift from the excitation lines typically at 980
or 808 nm.310 Thereby, both the UCL, and, in some cases, the
emission of the uorescent indicators of the interested substrate
induced by energy transfers from UCNPs can generally be
isolated from the scattering excitation light, and the Stokesshifted autouorescence in biological tissues. The following
paragraphs will focus on a series of in-depth detection
applications utilizing UCNPs for diagnostic purposes.
4.5.1. Upconversion Nanoparticle-Based Thermometers. Temperature is a fundamental parameter in numerous
scientic research studies and applications. Sensing and
mapping temperature in a noninvasive and accurate way is
particularly signicant and necessary for diagnosis and therapy.
In many cases, the precise determination of the temperature of
living cells (especially cancer cells) and accurate real-time
monitoring of cell temperature during in vivo treatments such
as PDT and PTT are required for successful diagnoses and
therapies.
Traditional solid-state thermometers have been found not
suitable for temperature measurements in biological systems
due to their low biocompatibility and the diculties in their
miniaturization. RE-doped UCNPs, on the contrary, are highly
biocompatible and small in size. The NIR light excitation of
UCNPs can also aord deep penetration into biological tissues
with negligible photodamage. Moreover, the relationship
between the optical properties of some UCNPs and temperature has been well-investigated,318 enabling conveniently visual
readout of temperature simply from their luminescent spectra.
Changes in the optical behavior of such UCNP-based
thermometers with temperature involve: (a) the emission
intensities,319 (b) uorescence intensity ratio(s) (FIR, also
called band shape),320 (c) spectral positions,321 (d) bandwidth,322 (e) polarization, and (f) lifetime.323
Taking account of the cost, the response time, and the
insensitivity to environmental interferences, FIR-based thermometry has been recognized as the most promising
temperature sensing technique for biomedical uses, and is
based on uorescent systems consisting of two or more
emissive lines/bands, where the relative intensity of the signals
is strongly dependent on the temperature. Such a change of
spectral shape is generally caused by the change of electronic
population of the thermally coupled energy levels of the
emitting center.284
Figure 20 shows the simplied energy levels diagram for the
FIR temperature sensing technique. The elctrons are pumped
to the higher energy level 3 (labeled process 1), and then
quickly jump to a lower energy level 2 through multiphonon
relaxation (MPR). Because of the small energy gap (about
2002000 cm1) between level 2 and level 1, thermal phonon
coupling distribution can occur between these levels, causing
the redistribution of electrons on these two levels to a new
thermal equilibrium.
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induced death at 45 C, was measured and mapped (shown in

Figure 22). This example indicates that UCNPs provide a
promising platform for temperature sensing of biological
systems.
Figure 20. Simplied diagram showing the energy levels and

transitions of interest in the uorescence intensity ratio (FIR)-based
thermometry. Nonradiative decay is depicted as red dashed lines, and
the luminescent transitions for FIR measurements are shown as green
arrows, labeled I2i and I1i.
FIR then can be dened as

I
FIR R = 2 eE / kBT
I1
Figure 22. (Top) Optical transmission images of an individual HeLa

cell at three inner temperatures. Cell death is observed at 45 C.
(Bottom) Temperature of the HeLa cell determined by the Er3+ ion
uorescence in the NaYF4:Er3+,Yb3+ nanoparticles as a function of the
applied voltage. Reprinted with permission from ref 328. Copyright
2010 American Chemical Society.
(3)
where E is the energy gap between emission level 1 and level

2. According to eq 3, the temperature-dependent eect leads to
an increase of the population of level 2 but a decrease of that of
level 1, resulting in a higher FIR value.
Many lanthanide ions including Er3+, Nd3+,324 Eu3+,325 and
Dy3+326 have been reported as spectral thermometers for
selective population of excited states (Figure 21).327 Of all of
the lanthanide-based thermometers, Yb3+Er3+ codoped
UCNPs oer the highest energy transfer eciency, and are
the best choice for nanothermometers. In such systems,
electron redistribution can occur between the 2H11/2 state and
4
S3/2 state of Er3+, leading to the 2H11/2 4I15/2 and 4S3/2
4
I15/2 transitions varying at an elevated temperature.
Vetrone et al. realized the optical sensing of intracellular
temperature for the rst time using PEI-coated UCNPs.328 This
novel thermometer was successfully used for the accurate
determination of the temperature in biological systems. With
incubation of the UCNPs with HeLa cells, the internal
temperature of the living cells, from 25 C to its thermally
Later, Chen et al. developed hydrophilic UCNPs that oer

dual mode physiological range temperature sensing and cell
imaging.329 In this work, the surface of the NCs of NaYF4:Yb,Er
was modied with amphiphilic silanes, and Eu(TTA)3(TPPO)2
complexes, which display down-shifting emissions, were loaded
in this coating layer. Upconversion/down-shifting dual mode
physiological range temperature sensing and dual mode cell
imaging were achieved. The sensitivity of this thermometer in
the physiological range from 26 to 46 C was found to be
0.89% per C for UC detection and 3.48% per C for downshifting detection.
In addition, Wolfbeis et al. reported that NaYF4:Yb,Er
UCNPs of varying size, dopants concentrations, and coreshell
structure enabled a ratiometric temperature readout.330 More-
Figure 21. Energy level diagrams of the trivalent rare earth ions (neodymium, dysprosium, erbium, and europium) used for thermometers. Reprinted
with permission from ref 327. Copyright 2014 Royal Society of Chemistry.
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over, it was found that, as compared to NaYF4:Yb,Er, the

hexagonal core/shell NaYF4:Yb,Er@NaYF4 was more suitable
for temperature sensing due to the higher brightness and high
resolution of less than 0.5 C in the physiological range
between 20 and 45 C.
Although UCNPs-mediated temperature sensing still faces
the problem of low eciency, it is believed that the
development of multifunctional NIR upconversion-based
thermometers can lead to signicant advances in diagnoses
and therapy in the near future.
4.5.2. Upconversion Nanoparticles as Indicators for
Hazardous Substances. The sensitive and selective sensing
of hazardous species in biological environments is necessary for
ecient clinical diagnosis. For instance, heavy metal ions (Hg2+,
Pb2+, etc.) and cyanide ions (CN) are highly poisonous to
humans. Some toxic molecules, such as ammonia and
melamine, can also lead to life-threatening situations.
Obviously, there are needs for alarm systems that give warning
of hazardous substances by accurate quantication of their
concentrations. As compared to conventional sensors based on
dyes or QDs, UCNPs can provide noninvasive sensing in deep
tissues and improved limit of detection (LOD)23 with the
merits of negligible autouorescence interference, good photoand chemical stability, as well as no toxicity.
4.5.2.1. Sensing of Highly Toxic Heavy Metal Ions. In
general, the detection of heavy metal ions by UCNPs is
achieved through an observable change in the intensity of one
UC emission band, and/or the ratio of the intensities of two
UC emission bands from the same Ln3+ activator. It is worth
mentioning that the latter approach based on ratiometric
calculation is a more popular strategy for the accurate
quantication of the concentration of the target species. Such
changes in the upconverted luminescence are caused by energy
transfer from the UCNPs to an antenna species (organic
molecule, nanoparticles, or organometallic complex), which is
highly responsive with the presence of the heavy metal ions. To
be more specic, the interaction between the target ions and
the antenna can result in a change in (a) the optical properties
of the antenna or (b) the distance between the antenna and the
UCNPs.
4.5.2.1.1. Detection of Hg2+ and MeHg+ Ions. Mercury is
recognized as the most toxic nonradioactive metal that could
cause serious environmental and health problems due to its
bioaccumulative nature.331,332 It exists in a variety of dierent
forms including metallic, ionic, and organometallic forms.
Mercuric ion is a stable inorganic form of mercury, and the
safety level in drinking water has been set to be only 10 nM (2
ppb) by the United States Environmental Protection
Agency.333
On the basis of UC-LRET processes, Lis group established
the rst upconverting nanoprobe for selective Hg2+ sensing.
Using chromophoric ruthenium(II) complex conjugated
NaYF4:Yb,Er,Tm nanoparticles, where the absorbance of the
Ru(II) antennas gave a blue shift upon the addition of Hg2+ as a
result of forming an adduct (max abs from 541 to 485 nm), the
detection of Hg2+ in aqueous solution and living cells was
realized by the turned-on green UCL (centered at 541 nm) of
the system under the 980 nm NIR excitation, with the UCL at
801 nm as the internal standard for ratiometric calculation. The
LOD of this nanoprobe in water was 1.95 ppb, and its
selectivity was conrmed by the addition of a series of other
metal cations including Pb2+, Pd2+, Cd2+, Zn2+, Mn2+, Cu2+,
Ni2+, Co2+, Mg2+, Ca2+, Cr3+, Fe3+, Ag+, Na+, and K+.334
A similar approach was developed recently by the same

group for selective Hg2+ sensing in water. Instead of covalently
grafting the Ru(II) antennas to the ligands of the UCNPs, a
dierent Ru(II) ionic complex [Ru(bpy)2(thpy)][PF6] was
assembled in the UCNPs with the same Ln3+ compositions
through the hydrophobichydrophobic interactions between
the Ru complexes and the ligands of the UCNPs. Using the
same ratiometric UCL emission at 541801 nm as the
detection signal, the LOD was found to be 8.2 ppb.335
Other than detecting Hg2+ through the turned-on UCL of
UCNPs, a Rodamine B thiolactone (RBT) incorporated
NaYF4:Yb,Er was developed by Wang and co-workers to give
the turned-o green UCL centered at 541 nm as the indication
of the presence of Hg2+. The mechanism can be described as
follows: under 980 nm NIR excitation, the UC-LRET from the
UCNPs to the RBT derivatives was activated upon the
formation of the RBT-Hg adduct. This upconverting nanoprobe was found ultrasensitive and selective toward Hg2+ among
other cations over a broad pH range, with a LOD of 3.7 nM in
water.336
An even lower experimentally estimated LOD of 0.5 nM in
water was obtained by Liu et al. with a platform combining
graphene oxide (GO) and NaYF4:Yb,Er functionalized by
thymine-rich and Hg2+-specic oligonucleotides. In the absence
of Hg2+, the UCNPs were closely captured on the GO surface
via a strong noncovalent stacking interaction between the
ssDNA ligand of the UCNPs and GO, causing complete
quenching of the UCL. The introduction of Hg2+ led to the
transformation of the Hg2+-responsive ssDNA into its dsDNA
counterpart, resulting in a weaker interaction with GO and the
subsequent departure of the UCNPs from the GO surface. The
detection signal is the restored UCL of Er3+, and thus this
sensing technique is known as the UCL quenching-based turnon assay.337
Hg2+ can be transformed into methylmercury (MeHg+) ion
by microbial biomethylation in aquatic sediments and
accumulate in the human organs through the food chain and
cause severe damage to the central nervous system. Lis group
developed an in vivo detection system for MeHg+ based on
their previous studies on the NaYF4:Yb,Er,Tm UCNPs assisted
sensing of Hg2+. As shown in Figure 23, a cyanine derivative
hCy7 was modied on the surface of the UCNPs via a P-PEG
polymer to act as the MeHg+ responsive group. Instead of
forming an organometallic adduct, the hCy7 molecule lost its
sulfur atom followed by a cyclization reaction to give hCy7
upon the addition of MeHg+. This process induced a signicant
red shift of the absorbance of the cyanine antennas from 670 to
845 nm, causing a decrease of the UCL at 800 nm (3H4 3H6
transition of Tm3+). Thus, the ratiometric UCL at 800 and 660
nm was used as the detection signal, and the LOD of the
sensing nanoplatform was 0.18 ppb MeHg+ in aqueous
solution. The in vivo detection was successfully demonstrated
in the liver of a mouse model exposed to MeHg+ using the
described signal change of the sensing system.338
4.5.2.1.2. Detection of Pb2+ Ions. Apart from mercury, lead
is also a detrimental heavy metal that has been recognized as a
serious threat to the environment and human health. The safety
limit of lead ion (Pb2+) in blood is as low as 480 nM (100
ppb).339,340
Recently, Song et al. developed a novel UCNP-based
biosensor for the selective detection of Pb2+ in human serum
with a low LOD of 80 nM. The UCNPs and the QDs were
assembled together via the electrostatic interaction between the
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Figure 25. Schematic illustration of the Pb2+ sensing process of the Au

nanoparticles-UCNPs hybrid system. Reprinted with permission from
ref 342. Copyright 2014 Royal Society of Chemistry.
In another study on developing UCNP-based biosensors, the

Hg2+-aptamers-modied NaYF4:Yb,Er,Mn and Pb2+-aptamersmodied NaYF4:Yb,Ho UCNPs were combined with Au
nanorods/nanoballs functionalized by the complementary
DNA of the Hg2+/Pb2+-aptamers to give a UC-LRET-based
dual detecting nanoprobe. This is the rst example of a UCNPbased biosensing system including two pairs of UCL energy
donor/acceptor. Also, by adopting UCL quenching-based turnon mechanism, the restoration of the green/red uorescence
can be used as the indicator of the existence of Pb2+/Hg2+. The
LOD of Pb2+ /Hg2+ in water was found as low as 50 pM/150
pM. The high selectivity and sensitivity of this biosensor was
also conrmed by the accurate monitoring of Pb2+ and Hg2+
levels in samples of naturally contaminated sea food and human
serum.343
4.5.2.1.3. Other Heavy Metal Ion Sensing Systems. Our
group has reported in 2009 an Ce4+ sensor based on 2-(4aminophenylethylyl)-5-methoxy-2-(2-pyridyl)thiazole
(MPTEA)-modied NaYF4:Yb,Er nanoparticles. Other than
utilizing UC-LRET process, a dual excitation method was used
in this system: under 350 UV excitation, the MPTEA units gave
uorescence at 430 nm, while their complexation with Pb2+
leads to the formation of nonuorescent complexes that have a
stronger absorption at 545 nm. Thus, the quantication of Ce4+
was realized by the ratiometric uorescent intensity at 430 nm
(350 nm UV excitation) to that at 545 nm (980 nm
excitation).267
A NaYF4:Yb,Er UCNP-based nanoprobe for the trace
detection of Cr6+ in water was prepared by Ren et al. In this
system, the component dipheylcarbazide (DPC) can react
selectively and quantitatively with Cr6+, and the yielding
Cr(III)-DPC complex absorbed the green UCL. This sensing
nanoplatform based on the decrease of the intensity of the
green UCL oers a LOD of 24 nM.344 Later, a UCL quenchingbased turn-on assay of Cr3+ was developed using a similar
UCNPs-Au nanocomposite. The lysine coated UCNPs of
NaYF4:Yb, Er and captosuccinic acid-capped Au nanoparticles
together aord a low LOD of 0.8 nM Cr3+ in water and the
successful determination of Cr3+ in urine, with the restored
green UCL at 542 nm as the detection signal.345
Copper is essential to human as a trace dietary mineral, but
excessive intake of Cu2+ (e.g., due to environmental pollution)
can lead to serious diseases such as organ damage. According to
the United States Environmental Protection Agency, the safety
level of Cu2+ in drinking water should be below 20 M.346
UCNP-based Cu2+ sensing systems, which are based on the
UC-LRET from NaYF4:Yb,Er to the complexation product of
rhodamine B hydroazide (RBH) with Cu2+, were reported.
RBH itself is nonuorescent, but its Cu(II) complex can absorb
Figure 23. Schematic illustration of the MeHg+ sensing process of the

hCy7-UCNPs conjugate. Reprinted with permission from ref 338.
positively charged PEI ligands on the surface of the UCNPs and

the negatively charged TGA ligands on the surface of the QDs,
which enables an ecient UC-LRET process from the UCNPs
to the QDs. Pb2+ can bind with the TGA ligands and thus cause
the quenching of the green uorescence of QDs. Although the
quantication of Pb2+ by this nanoprobe was not based on
ratiometric calculations, a good linear relationship was obtained
from the Pb2+ concentration and the uorescent intensity of the
QDs. Moreover, the self-luminescence of serum under visible
light can also be overcome by the NIR excitation of the
nanoprobe (Figure 24).341
Figure 24. Schematic illustration of the Pb2 sensing process of the

UCNPs-QDs nanocomposites. Reprinted with permission from ref
341. Copyright 2014 Royal Society of Chemistry.
Later, an improved LOD of Pb2+ in water was achieved by Lv

et al. Similarly, the nanocomposite of PEI coated NaYF4:Yb,Tm
UCNPs and MUA (11-mercaptoundecanoic acid) capped gold
(Au) nanoparticles was assembled via the electrostatic
interaction between their oppositely charged ligands. The
UC-LRET process in this system results in the quenching of
the green UCL by the Au nanoparticles. In the presence of
Pb2+, the Au nanoparticles underwent aggregation caused by
the chelation between Pb2+ ions and the MUA ligands, leading
to the detachment of Au nanoparticles and the consequent
restoration of the green UCNPs (Figure 25). This biosensor
was impervious to common metal ions such as Hg2+, Ba2+,
Cd2+, Fe2+/3+, Mn2+, Cu2+, and Ag+.342
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the green UCL and result in uorescence at 578 nm. The red
UCL can be used as the internal reference for the quantication
of Cu2+, and a low LOD of 4.6 ppb in water has been
achieved.347349
Actually, most heavy metal ions on themselves can cause a
noticeable quenching of the luminescence of the UCNPs when
reaching a certain concentration (on the level of 101 mM).
This quenching of UCL by heavy metal ions has been
systematically investigated by Wolfbeis et al.350
4.5.2.2. Sensing of Poisonous Molecules and Anions.
Development of UCNP-based biosensors for the selective and
ecient detection of CN351,352 and ammonia353 before 2013
has been reported and reviewed. Here, some recent studies on
the UCNPs assisted detection of hydrogen sulde, melamine,
and nitrite are discussed.
H2S is recognized as a broad-spectrum poison because it can
damage several body systems and especially the nervous system.
The rst UC-LRET-based H2S sensing system was reported by
Zhang and co-workers. As illustrated in Figure 26, the surface of
as the detection signals to aord a LOD of 9.1 nM in

melamine-containing milk samples.361
The ratiometric uorescence detection of nitrite using
UCNPs was reported by Zhang and co-workers. Nitrite salts
are widely used in food preservation, and are toxic with a lethal
dose in humans of about 22 mg NO2 per kg bodyweight. The
maximum levels of nitrite in drinking water and cured meat
products are set by the United States Environmental Protection
Agency to be 1 and 200 ppm, respectively. The ratiometric
UCL emission of hexagonal NaYF4:Yb,Er UCNPs at 539 to 654
nm was used as the detection signal. Neutral Red dye was used
as the energy acceptor of the green UCL, and this UC-LRET
process was terminated by the NO2-induced detachment of
the amine group of the dye in acidic environments. The red
UCL was used as the internal standard, and a low LOD of 0.2
ppm of NO2 in water was achieved. This detection system was
found independent from other ions including F, Cl, COOH,
NO3, and SO42, and has been successfully used in tap water,
lake water, and cured meat samples.362
4.5.3. UCNPs as Indicators of Health Condition. In this
section, the NIR upconversion-based sensing of ions/molecules
that plays a vital role in human life is discussed. Rather than
functioning as an i that set o on the detection of dangerous
species, UCNPs was utilized to deliver real-time online
information on the presence of a target biomolecule or the
concentration of a specic chemical, which in a certain way
reveals the health condition of the treated organism.23 For
instance, the ecient detection of cancerous biomarkers can
provide early diagnostics, and increase the chance of survival of
the patient. The accurate measurement of the reactive oxygen
species (ROS, e.g., HClO) concentration in human body can
prevent the damage caused by the elevated amount of these
chemicals above a physiological range. Therefore, the ability to
detect the generation of such pathological messengers is critical
to the timely and optimized therapeutic interventions.
4.5.3.1. Monitoring of Vital Chemicals. 4.5.3.1.1. pHi
Sensing. Apart from temperature, the intracellular pH (pHi)
is another important parameter in living cells. An abnormal
value has been found associated with inappropriate cell
function, and observed in some disease types such as cancer
(acidic pHi). UCNPs-mediated pH sensing systems have been
reported,363367 but not until recently have UCNPs been
applied in determining the pHi value in living cells. The
nanocrystals of hexagonal NaYF4:Yb,Er were coated with a thin
layer of aminosilane, where the pH responsive pHrodo Redsuccinimidyl ester was covalently grafted. pHrodo Red is a
commercial available rhodamine dye whose uorescent
intensity signicantly increases upon protonation, while its
absorption prole and emission band position remain
unchanged. Upon 980 nm irradiation, the pHrodo Red dye
absorbed the energy of the green UCL at 550 nm and gave
emission at 590 nm. Thus, the ratiometric emission at 550 to
590 nm was used as the detection signal, and the quantitative
determination of pH inside HeLa cells was successfully
performed. No cytotoxic eects and photobleaching were
observed for this nanoprobe, suggesting the advantages of this
UCNP-based sensing platform.368
4.5.3.1.2. Hypoxia and Hypochlorous Acid Sensing.
Following the O2 sensing upconverting nanoplatform developed by Wolfbeis et al.,369 an in vivo hypoxia sensing model
was established by Shi and co-workers with the aim of the
ecient estimation of the malignant degree of solid tumors for
point-to-care theranostics. In this work, a ruthenium complex as
Figure 26. Schematic illustration of the H2S sensing with -CD (cyclodextrin)-modied UCNPs. Reprinted with permission from ref
354. Copyright 2014 Wiley-VCH Verlag GmbH & Co. KGaA.
-cyclodextrin coated UCNPs of NaYF4:Yb,Er,Tm was

modied with coumarin-hemicyanine (CHC1) dyes, which
had a strong/weak absorption of the green/red UCL itself. The
reaction of CHC1 and H2S led to the formation of CHC1-HS
that is nonuorescent, and thus the LRET process was turned
o, restoring the green UCL. Because the NIR UCL of Tm3+ at
800 nm was unchanged during the reaction, it was used
together with the green UCL of Er3+ at 541 nm as the
ratiometric UCL signals for the detection of H2S. The
estimated LOD of this designed hybrid nanoprobe was
estimated to be 0.13 M, and its selectivity was examined
using a broad range of reactive oxygen/nitrogen/sulde species
and nucleophilic anions. The ratiometric imaging of H2S in
HeLa cells, as well as the measurement of H2S levels in
lipopolysaccharide-induced inammation mouse modals, have
also been successfully carried out using this nanoplatform.354
The rst demonstration of UCNPs-mediated detection of
melamine was reported by Mahalingams research group.
Melamine, a trimer of cyanamide with a high nonprotein
content (67% by mass), has been found illegally used in infant
formula to fabricate the apparent protein content of the
product, which was usually estimated by the measurement of its
nitrogen content.355 Because of the toxic nature of melamine,
which can lead to reproductive damage or kidney/bladder
stones, the UN food standard commission set a new safety level
of melamine in food/infant formula as 2.5 ppm/1 ppm.356360
In this detection system, the UCNPs of NaYF4:Yb,Er was
coated with 3,5-dinitrobenzoic acid, whose electron-decient
aryl center was used to selectively bind with melamine. The
UC-LRET process activated by 980 nm NIR excitation in the
presence of melamine resulted in the quenching of both the
green (550 nm) and the red (650 nm) UCL, which were used
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was found to aord good accuracy in quantifying the

physiological range of glucose concentration levels in blood.373
4.5.3.2. Bioassays. Because of the ideal photostability and
biocompatibility of Ln3+ doped UCNPs, as well as their
tolerance to various test conditions and the negligible
background luminescence, UCNPs are considered excellent
candidates for the sensing of biomolecules and have been
widely used in biomedical applications.374381 With the aim of
in-time and personalized treatments, intensive studies on the
design of new upconverting nanoplatforms for the detection of
target cholesterol, oligonucleotides, and enzymes have been
reported in 2014 and early 2015. These studies are briey
summarized here.
4.5.3.2.1. Oligonucleotides Detection. Developments of
paper-based oligonucleotide assay on the basis of UC-LRET
processes have been reported by Krulls group for the selective
and sensitive detection of dierent DNA fragments. Cellulose
paper was used as the immobilization matrix for the DNA
indicators (probe DNA)-modied UCNPs in these investigations for rapid diagnostic applications.
In the rst demonstration, the biotinylated SMN1 DNA
probe was linked on streptavidin coated UCNPs of hexagonal
NaYF4:Yb,Er@NaYF4. The hybridization of the Cy3-labeled
target SMN1 DNA with the probe DNA resulted in an ecient
UC-LRET process when excited by 980 nm NIR light, where
Cy3 gave emission upon absorbing the green UCL. The
emission from Cy3 was used as the detection signal, and the
hybridization was observed to be rapid and of high
selectivity.382 This nanosensor was then modied with an
additional probe DNA to possess dual SMN1 DNA/uidA DNA
detection functions (Figure 28), with the Cy3 labeled SMN1
the oxygen probe was loaded in the hollow cavity of

mesoporous silica shell of the NaYF4:Yb,Tm@NaYF4 core.
When exposed to 980 nm NIR light, the complex absorbed the
UV/blue UCL and gave red uorescence, which can be
quenched by O2. Thus, this turn-on of red uorescence in
hypoxic conditions was used to indicate the O2 level in living
U87MG cells and the cerebral anoxia in living zebrash
embryos induced by 2,3-butanedione.370
Other than O2, reactive oxygen species also play a key part in
human systems. For example, hypochlorous acid (HClO)
generated in human body can react with a broad range of
biomolecules including proteins, nucleotides, and cholesterol.
However, the excessive intake or the abnormal internal
production of HClO can cause serious diseases including
cancer. Recently, the rst UC-LRET-based HClO sensing
system was established by Zhang et al. As shown in Figure 27,
Figure 27. (a) Schematic illustration of the HClO sensing by PAAmodied UCNPs and RBH1. (b) The overlaid uorescent spectra of
the sensing system with dierent concentration of HClO. Reprinted
with permission from ref 371. Copyright 2014 Wiley-VCH Verlag
GmbH & Co. KGaA.
the PPA ligand was used to replace the oleic acid ligand for
both the improvement of the hydrophilicity of the Yb3+, Er3+,
Tm3+ codoped NaYF4 UCNPs and the trapping of the HClO
responsive RBH1. This rhodamine derivative was nonuorescent itself, but the HClO-induced cyclization reaction of
RBH1 led to the formation of a uorescent compound, which
can absorb the green UCL of Er3+ at 541 nm. Therefore, the
decrease of the intensity of this emission was used together
with the NIR emission of Tm3+ at 800 nm, which remained
unchanged during the reaction of RBH1 and HClO, as the
detection signals for the ratiometric sensing of HClO. This
UCNPs-RBH1 conjugate has also been used for the ratiometric
UCL imaging of the HClO released in living NIH3T3 cells.371
4.5.3.1.3. Glucose Sensing. Glucose is a vital energy supplier
for the central nervous system and metabolism of human
beings. After a UCNPs-GO nanocomposites for glucose sensing
in human serum was developed by Liu and co-workers,372 a
new approach for the monitoring of glucose levels in whole
blood samples mediated by UCNPs and enzyme was described
recently by Galban et al. This optical sensor consists of UCNPs
of hexagonal NaYF4:Yb,Tm@NaYF4 and enzyme glucose
oxidase modied with uorescein (GOx-FS), both of which
were immobilized in a polymer lm. The enzymatic reaction of
GOx-FS with glucose led to a change in its green uorescent
density upon absorption of the blue UCL. As the uorescence
background was minimized by NIR excitation, this nanoprobe
Figure 28. Schematic illustration of the UCNPs-mediated dual sensing

of SMN1 DNA and uidA DNA. Reprinted with permission from ref
383. Copyright 2014 American Chemical Society.
target DNA absorbing the green UCL and Cy5 labeled uidA
target DNA absorbing the red UCL of the UCNPs to give
separate uorescence. The LOD for the targets of SMN1 DNA
and uidA DNA was found as low as 22.1 and 1260 fmol,
respectively.383 In the other demonstration, LiYF4:Ln UCNPs
were used as the luminescent label on the probe DNA
fragment. Upon the selective and rapid conjugation of this
probe DNA with the target DNA, a genetic marker, and the
following hybridization with the capture DNA immobilized on
the paper, the UCL of the immobilized UCNPs was used as the
detection signals.384
Recently, a biosensor consisting of BaGdF5:Yb/Er UCNPsAuNPs nanocomposite for the detection of avian inuenza
virus H7 subtype was reported. The AuNPs could conjugate
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quench the green UCL at 546 nm upon 980 nm NIR

irradiation. The stronger interaction between CEA protein and
CEA aptamer caused the unstacking of the CNPs and thus the
return of the green UCL.388
4.5.3.2.3. Enzymes (Activity) Detection. Enzymes are highly
selective macromolecular biological catalysts that take part in
numerous metabolic chemical reactions. The real time
information on the concentration of a target enzyme and its
activity is essential for investigating the biological process where
the enzyme is involved.
Two UCNP-based aptasensors for thrombin detection have
been reported in 2014, developed by dierent research groups
using QDs/AuNRs as the UCL energy acceptor. In the studies
by Krulls group, the sandwich assay of thrombin was realized
by combining UCNPs of NaYF4:Yb,Tm@NaYF4 and QDs of
CdSxSe1x@ZnS, both functionalized with thrombin-specic
aptamers. The presence of thrombin led to the assembling of
UCNPs with QDs, causing the ecient UC-LRET process
where both the UV and the blue UCL were absorbed by the
QDs to give its emission at 614 nm. Because the UCNPs
oered no luminescence near 614 nm, the uorescence of QDs
was collected as the detection signal with negligible noise. Apart
from the low LOD of 230 fmol (in buer solution) this
nanoprobe aorded, it is also the rst example of covalent
immobilization of UCNPs for the applications of biosensing.389
A similar thrombin aptamer assisted specic biosensing carried
out by Wangs group used AuNRs to quench the NIR UCL at
804 nm of NaYF4:Yb,Tm UCNPs. This system was used in
human serum and gave a LOD of 0.129 nM.390
In another work by Chu and co-workers, the ratiometric
sensing and imaging of phospholipase D (PLD) based on
phospholipid-functionalized UCNPs was reported for the rst
time. With the aim of early stage diagnosis and targeted drug
delivery for cancers where the abnormal PLD expressions are
involved, NaYF4:Yb,Er UCNPs were modied with rhodamine
B-labeled phospholipid, where the green UCL at 540 nm was
absorbed by the rhodamine B upon 980 nm NIR excitation.
The PLD-mediated hydrolysis of the phosphodiester bond
connecting rhodamine dye and the phospholipid ligand led to
the departure of the dyes from the surface of the UCNPs and
thus inhibited the UC-LRET process. The restored green UCL
and the unchanged red UCL were used as the detection signals
for ratiometric sensing and imaging in living MCF-10A cells
and MDA-MB-231 cells for comparative studies.391
The bioactivity of pentaerythritol tetranitrate reductase
(PETNR), a avoenzyme, was monitored in terms of its
redox behavior on the basis of the UC-LRET process from
Gd4O2S:Yb,Tm UCNPs to PETNR, whose avin core has
variable absorption proles depending on its oxidation states.
As shown in Figure 30, the oxidized form of the enzyme
absorbed the blue UCL of Tm3+ upon 980 nm NIR excitation,
while this UC-LRET process cannot be supported by the
reduced version of PETNR. Therefore, the quenching and
restoration of the blue UCL at 475 nm could be used together
with the NIR UCL at 800 nm as the internal reference to
monitor the redox behavior of PETNR and thus obtain
information on the biocatalytic reactions.392
The monitoring of enzymatic redox reactions utilizing UCL
has also been investigated by Hirsch et al. With hexagonal
NaYF4:Yb,Tm@NaYF4 UCNPs as the resource of UV/blue
UCL, the reaction of the coenzyme of Flavin adenine
dinucleotide (FAD) and the cosubstrate of nicotinamide
adenine dinucleotide (NADH) can be monitored by the
with the H7 hemagglutinin gene sequence-modied oligonucleotide, and the PEI coated UCNPs were linked with the
capture oligonucleotide probes that contain the complementary
strands of H7 hemagglutinin gene. The hybridization between
these two NP ligands led to the quenching of the green UCL at
540 nm upon 980 nm NIR excitation as a result of the UCLRET process from the UCNPs to the AuNPs. This quenching
eciency-based detection system oers a remarkably low LOD
of 7 pM for H7 hemagglutinin gene.385
4.5.3.2.2. Antigens/Disease Biomarkers Detection. The
ecient detection of antigens/disease biomarkers is essential
for in time diagnosis and therapy. In 2014, LiLuF4:Yb,Er@
LiLuF4 UCNPs were used for the rst time as a biosensor for
the detection of the subunit of human chorionic
gonadotropin (hexagonalhCG antigen), which is an important
disease marker. Avidin was incorporated onto the surface of
ligand-free UCNPs via electrostatic attraction, and these
conjugates could capture the biotinylated hexagonalhCG
antibody through avidinbiotin interaction. The specic
recognition and the subsequent binding of hexagonalhCG
antibody to hexagonalhCG antigen result in the recovery of the
quenched UCL of Er3+. The LOD of this biosensor was
estimated to be 3.8 ng/mL.386
In another study by Wang and co-workers, the selective trace
detection of the cancer marker -fetoprotein (AFP) with a low
LOD of 0.16 ng/mL was realized using the nanoplatform
combining gold nanorods (AuNRs) and NaYF4:Yb,Tm@
NaGdF4 UCNPs. When exposed to 980 nm NIR light, the
UCL at 800 nm could be quenched by the AuNRs, which were
electrostatically attracted to the anti-AFP functionalized
UCNPs. However, the binding of AFP and anti-AFP led to
the departure of AuNRs and thus the restoration of the NIR
UCL of Tm3+. This system has been applied to monitor the
AFP level in human serum samples.387
An aptasensor consisting of UCNPs and carbon nanoparticles for the determination of carcinoembryonic (CEA)
antigen and based on the UCL quenching-based turn-on
detection mechanism, which is similar to that in the previous
example, was designed by Liu et al. As shown in Figure 29, the
carbon nanoparticles (CNPs) stacked via interaction on
the CEA aptamer ligands of NaYF4:Yb,Er UCNPs were used to
Figure 29. Schematic illustration of the sensing process of CEA

biosensor based on the energy transfer from UCNPs to CNPs.
Reprinted with permission from ref 388. Copyright 2015 Elsevier B.V.
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signicant promise by overcoming the above drawbacks of

quantum dots and organic dyes.
For example, Li and co-workers presented a straightforward
comparison between UCNPs and organic dyes in their
photostability.401 UCNPs and organic dyes of DAPI and DiI
were excited simultaneously with 980, 405, and 543 nm lasers,
respectively (Figure 31a). As depicted in Figure 31b, the
emission intensity from UCNPs still remained at 96% of its
initial value after continuous irradiation for 400 s, while the
uorescence intensity of DAPI and DiI decreased signicantly
to 1% and 2.5% of their initial values, respectively. Cohen and
co-workers studied the photostability characteristics of
upconversion emissions from a single UCNP.22 As a result,
no photobleaching or photodamage was observed after 1 h of
continuous laser illumination, suggesting the excellent photostability of UCNPs. Kobayashi and co-workers assessed the
eect of autouorescence from biosamples when using UCNPs
and quantum dots.402 The autouorescence emission spectra of
the mouse abdomen were monitored with 468 and 980 nm
excitation, respectively. As shown, a broad and high amplitude
autouorescence spectrum resulted from 468 nm excitation,
while no detectable background was produced by 980 nm
excitation (Figure 31c). The elimination of autouorescence
from biosamples gives rise to a high signal-to-noise ratio for
imaging with UCNPs. Moreover, as compared to the
broadband emissions from quantum dots and organic dyes,
the full width at half-maximum (fwhm) of upconversion
emissions is narrower than 12 nm, which is quite promising for
multicolor imaging and multiplexed analyte detections. In
addition, due to the specic NIR excitation and visible to NIR
emissions, the scattering eect by biological tissues is less
signicant, leading to remarkable penetration depth for
UCNPs. As for the biosafety of UCNPs, no signicant
histological and hematological toxicity was detected at the
imaging dose, indicating the good biocompatibility of
UCNPs.403,404 On the basis of the above considerations,
Figure 30. Schematic illustration of the monitoring of the redox state

of PETNR on the basis of UC-LRET. Reprinted with permission from
ref 392. Licensed under CC BY 3.0.
quenching/restoring of the UCL at 360 and 475 nm when

excited by 980 nm NIR light. The absorbance of both FAD and
NADH matches well with the blue UCL, while a signicant
blue shift in the absorption prole of their FADH2/NAD
counterparts was observed, resulting in the return of the blue
UCL but quenching of the UV UCL.393
4.6. Upconversion Nanoparticles for Bioimaging
Luminescent imaging is a noninvasive diagnostic manner for

visualizing various biological processes, which might be crucial
for the pathogenesis and progression of many diseases.
Moreover, beneting from the high-sensitivity and capacity of
real-time monitoring, luminescence imaging has been adopted
as an excellent approach to detect the morphological,
anatomical, and physiological details in tissues as well as the
full range of biosamples from cells to animals.394398 As
potential biomarkers, quantum dots399 and organic dyes400
have been widely studied due to their tunable emissions and
high emission eciency. However, poor photostability, low
signal-to-noise ratio, cross-talked emissions, limited penetration
depth, and prominent biotoxicity hinder their generalization in
bioimaging studies. By contrast, Ln3+ doped UCNPs exhibit
Figure 31. Photostability and background uorescence studies with UCNPs. (a) Comparison of photostability among UCNPs, DAPI, and DiI. The
luminescence signals of UCNPAs, DAPI, and DiI are shown in green, blue, and red, respectively. (b) Quantitative analysis of the changes in
uorescence intensities of UCNPs, DAPI, and DiI. (c) Comparison of autouorescence emission spectra from the mouse abdomen excited with 468
and 980 nm. (a,b) Reprinted with permission from ref 401. Copyright 2009 American Chemical Society. (c) Reprinted with permission from ref 402.
Copyright 2009 Royal Society of Chemistry.
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proliferation and dierentiation.407 The eect of incubation

time and nanoparticle concentration on cellular labeling was
assessed. According to the upconversion emission intensity
from cells, the level of PEI-UCNPs uptake in individual cells
was proportional to the exposure time and nanoparticle
concentration. The localization of PEI-UCNPs was determined
within the cytoplasm of stem cells by costaining for cytoskeletal
actin and nuclei. Moreover, PEI-UCNPs labeled stem cells not
only exhibited normal early proliferation, but were also able to
undergo osteogenic and adipogenic dierentiation upon in vitro
induction. Lee and co-workers monitored the spatiotemporal
distribution of UCNPs in single living HeLa cells, which
presented an excellent understanding of the interaction
between the UCNPs and biological systems at the cellular
level.408 It was found that the UCNPs were internalized
through endocytosis, transported by microtubule-dependent
motor proteins (dyneins), accumulated at the perinuclear
region, transported by another type of motor proteins
(kinesins), and nally released out of the cells through
exocytosis.
4.6.1.2. Eect of Surface Characters on Cellular Imaging.
The surface characters are crucial for the eciency of
intracellular uptake and thus aect the cellular imaging greatly.
Generally, positively charged UCNPs exhibited enhanced
cellular uptake. Wong and co-workers studied the chargedependent cellular imaging with dierent polymer coated cubic
NaYF4:Yb,Er nanoparticles.409 A ligand exchange procedure
was performed on polyvinylpyrrolidone coated UCNPs (PVPUCNPs), with the assistance of PEI and poly(acrylic acid)
(PAA) molecules, to generate PEI-UCNPs and PAA-UCNPs.
On the basis of the same experiment condition, it was found
that the positively charged PEI-UCNPs evinced greatly
enhanced cellular uptake in comparison with the PVPUCNPs and PAA-UCNPs counterparts. Moreover, the cationic
PEI-UCNPs can be eectively internalized mainly through the
clathrin endocytic mechanism. Very recently, Hao and coworkers also noticed the surface charge-dependent cellular
uptake property.410 Three types of PEG-UCNPs, PEI-UCNPs,
and 6-aminocapronic acid capped UCNPs (6-AA-UCNPs)
were prepared and incubated with HeLa cells with the same
nanoparticle concentration. The cellular imaging results
indicated that intracellular uptake occurred most eectively
with PEI-UCNPs.
4.6.1.3. Cellular Target Imaging. Featured by facile surface
modication, various molecules, including peptides and antibodies, can be decorated on UCNPs to undergo specic
functional expression or cell targeting. For example, Wong and
co-workers modied NaGdF4:Yb,Er UCNPs with cyclin Dspecic peptides, which were able to target the CDK4/cyclin D
complex.411 The cyclin D-specic peptides-modied UCNPs
were able to cause cell cycle disruption, which correlated with a
striking inhibiting eect and prominent toxicity toward cancer
cells. Capobianco and co-workers functionalized NaGdF4:Yb,Er
UCNPs with heparin and basic broblast growth factor
(bFGF).412 These nanoparticles exhibited specic binding to
the cell membrane of HeLa cells with high contrast
upconversion emissions. Li and co-workers introduced folic
acid on NaYF4:Yb,Er UCNPs for purposefully targeting cells
with folate receptors, like KB cells.413 Meanwhile, MCF-7 cells
without folate receptors were used as control groups. After
incubation with nanoparticles, KB cells exhibited intense
upconversion emissions. By contrast, no obvious upconversion
emissions can be detected from MCF-7 cells, indicating the
UCNPs could be recognized as promising biomarkers for UCL

imaging studies.
4.6.1. Cellular Imaging. Cellular imaging oers an
intuitionistic visualization for the physiological processes at
the cellular or subcellular level. The interactions among cells,
proteins, and molecules can be obtained with cellular imaging.
However, because the anti-Stokes emission modality of
upconversion emissions is quite dierent from that of singlephoton and two-photon emissions, the out-of-focus upconversion emission becomes a signicant hindrance for cellular
imaging with UCNPs. To address the problem, Li and coworkers developed a setup of laser scanning UCL microscopy
system (Figure 32), where a reverse excitation dichroic mirror
Figure 32. Schematic illustration of the laser scanning UCL

microscopy setup for cellular imaging with UCNPs. Reprinted with
and the confocal pinhole technique were introduced.401 With

similar techniques, numerous works have been carried out to
study the capacity and eciency of UCNPs for cellular imaging.
In general, the incubation concentration of UCNPs with cells is
usually 10200 g/mL.
Zhang and co-workers studied the cellular imaging capacity
of silica coated NaYF4:Yb,Er nanoparticles.405 The UCNPs
were incubated with rat bone marrow-derived mesenchymal
stem cells and skeletal myoblasts. When the UCNPs labeled
cells were exposed to 980 nm NIR light, intense upconversion
emissions with a high signal-to-noise ratio can be obtained
(Figure 33ad). Moreover, the UCNPs were mainly located at
the cytoplasmic and the perinuclear regions, indicating the
intracellular uptake of silica coated UCNPs. Meanwhile, with
the imaging dose of UCNPs, the cell viability still remained
above 80%, suggesting the good biocompatibility of silica
coated UCNPs. Li and co-workers prepared polyethylene glycol
(PEG)-modied LaF3:Yb,Ho UCNPs and assessed their
cellular imaging feasibility.406 After incubation with PEGLaF3:Yb,Ho UCNPs, the KB cells exhibited strong intracellular
upconversion emissions. Moreover, spectrum scan experiments
showed that the maximum emission wavelengths were around
545 and 645 nm, which were in good agreement with the
upconversion emissions of Ho3+, conrming that the intracellular emission should be attributed to UCNPs. Control
experiments measured at low temperature exhibited quite weak
upconversion emissions, suggesting the intracellular uptake of
UCNPs rather than merely staining the membrane surface.
4.6.1.1. Physiological Activity Tracking. In addition to cell
labeling, UCNPs can also be used to track the physiological
activity of cells. Recently, Han and co-workers labeled rat
mesenchymal stem cells with polyethylenimine (PEI) conjugated NaYbF4:Tm@CaF2 UCNPs and tracked the cell
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Figure 33. UCNPs for cellular imaging. (ad) Bright eld and UCL images showing the uptake of NaYF4:Yb,Er UCNPs by rat bone marrowderived mesenchymal stem cells (a,b) and skeletal myoblasts (c,d). The cells were maintained in their respective culture mediums and incubated with
50 g/mL UCNPs for 24 h. Schematic design for immunolabeling of HeLa cells using UCNPs (e) and UCL images of HeLa cells after incubation
with rabbit anti-CEA8 Ab-UCNPs (f), amino-UCNPs (g), and rabbit antigoat Ab-UCNPs (h). Left rows are images in bright eld; the middle rows
are UCL images; and the right rows are overlays of the left and middle rows. (ad) Reprinted with permission from ref 405. Copyright 2008 Elsevier
B.V. (e,f) Reprinted with permission from ref 414. Copyright 2009 American Chemical Society.
hamster ovary CHO-K1 cells, which were used as the control

group. This indicated that specic cell targeting can be realized
when UCNPs are modied with certain type of antibodies.
4.6.2. In Vivo Imaging. Because of the remarkable
penetration depth, high signal-to-noise ratio, and low toxicity,
Ln3+ doped UCNPs are quite promising biomarkers for in vivo
imaging.395 The morphological, anatomical, and physiological
details can be obtained with in vivo imaging. To date, various
biological models have been employed for in vivo imaging
studies using UCNPs, including bacteria, Caenorhabditis elegans
(C. elegans), mice, rabbits, and even plants. For bacteria and C.
elegans, the setup for cellular imaging is applicable to perform
the in vivo imaging studies. However, for small animals, the
imaging system should be reconsidered. A commonly used in
vivo imaging setup for small animals is depicted in Figure 34.416
As shown, small animals are immobilized on a sample table in
the light-tight house. The injected UCNPs are excited with NIR
lights from a laser source, and the emissions could be collected
by an electron multiplying charge coupled device (EMCCD).
In this part, we will present a systematic discussion on the in
vivo imaging studies of UCNPs.
feasibility of cell targeting with folic acid. Xu and co-workers

covalently linked rabbit anticarcinoembryonic antigen8 (CEA8)
antibodies to hexagonal NaYF4:Yb,Er UCNPs to form the
antibody-UCNPs (Figure 33e).414 The antibody-UCNPs were
used as biomarkers for the detection of CEA, a cancer
biomarker expressed on the surface of HeLa cells. As a result,
successful conjugation of antibody to the UCNPs was found to
lead to the specic attachment of UCNPs onto the surface of
HeLa cells from the cellular imaging results. In comparison, no
apparent upconversion emission can be observed from HeLa
cells incubated with amino-UCNPs and rabbit antigoat AbUCNPs, indicating that UCNPs can be used as biomarkers for
cell immunolabeling (Figure 33fh). Recently, Zvyagin and coworkers employed hexagonal NaYF4:Yb,Er UCNPs to image
the breast cancer lesion.415 The scFv4D5 mini-antibodies were
grafted onto UCNPs via a high-anity molecular linker
barstar:barnase (Bs:Bn) to allow the specic bonding to the
human epidermal growth factor receptor HER2/neu, which was
overexpressed in human breast adenocarcinoma cells SK-B-3.
Cellular imaging results exhibited that sc-FV4D5-Bs:BnUCNPs were immobilized on the SK-BR-3 cells with a 10
times higher signal intensity as compared to the Chinese
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Recently, Zhang and co-workers performed bacterial imaging

with UCNPs.418 In this study, green uorescent protein (GFP)
expressing Escherichia coli (E. coli) bacteria were employed as a
biological model, while anti-E. coli antibody-modied hexagonal
NaYF4:Yb,Er nanoparticles were used to provide upconversion
emissions. They compared the labeling photostability of
UCNPs and bacterial GFP, and studied the infection process.
The results indicate that the antibody-UCNPs coincubated E.
coli displayed intense upconversion emissions upon NIR light
excitation. Moreover, the upconversion emission delineated
uniform rod shape morphology of bacteria, which colocalized
with the bacterial GFP signal (Figure 35af), indicating
successful binding on the E. coli. However, the GFP signals
rapidly faded within 5 min of irradiation by blue light and were
no longer detectable after 10 min. By contrast, the
upconversion emissions were clearly visible throughout the
irradiation by NIR light for 20 min. Furthermore, upon
infection of dendritic cells, the upconversion emissions from
the labeled E. coli colocalized and persisted with the bacteria for
a 6 h observation period, strongly suggesting the possibility of
using the labeled bacteria for long-time tracking studies. This
work pioneered the use of UCNPs for promising bacterial
labeling and tracking.
Figure 34. Schematic illustration of the setup for small animal in vivo
imaging with UCNPs. Reprinted with permission from ref 416.
4.6.2.1. Bacteria and C. elegans Imaging. For bacteria,

which may be employed as vaccine candidates or carriers, it is
important to investigate their biodistribution, persistence, and
clearance in the host for establishing their safety and ecacy
proles. Therefore, bacteria labeling is quite desirable.417
Figure 35. UCNPs for in vivo imaging with bacteria (af) and C. elegans (gl). (ac) Bacterial imaging with anti-E. coli antibody-modied
NaYF4:Yb,Er UCNPs. (df) Zoomed-in view of individual bacteria (highlighted in white boxes). (a,d) GFP uorescent images, (b,e) UCL images,
(c,f) overlay images of GFP and UCL images. (gi) UCL images of NaYF4:Yb,Tm labeled C. elegans. (jl) The overlay images of UCL images and
the bright eld images. Note that images in (h) and (i) are zoomed-in images in (g), respectively. (af) Reprinted with permission from ref 418.
Copyright 2014 Elsevier B.V. (gl) Reprinted with permission from ref 423. Copyright 2011 Elsevier B.V.
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Figure 36. Imaging the biodistribution of UCNPs in vivo. Real-time in vivo UCL images of nude mice with intravenous injection of PAANaYF4:Yb,Tm UCNPs (15 mg/kg) at dierent time points. Reprinted with permission from ref 425. Copyright 2010 American Chemical Society.
retained in the worms when they were deprived of food.

Throughout monitoring for 24 h, no photoblinking or
photobleaching was observed in the UCNPs, indicating the
excellent photostability. When food was available to the C.
elegans, the UCNPs were secreted within 2 h, and no obvious
eect appeared for further feeding with UCNPs, suggesting the
biocompatibility of UCNPs. Later, sub-10 nm Yb2O3:Yb,Er
nanoparticles were used for in vivo imaging.420 No signicant
toxicity of the small sized UCNPs was found, conrming the
well biocompatibility of UCNPs. Xu and co-workers studied the
eect of incubation time, concentration, particle size, and
As one of the simplest multicellular eukaryotic organisms

with a nervous system, C. elegans has been used as a model
organism due to the benets of an optically transparent body,
relatively short lifecycle, invariable number of cells, and so
forth. Lim and co-workers reported the rst case of using
UCNPs for C. elegans imaging.419 They examined the imaging
capacity, photostability, and biocompatibility of Y2O3:Yb,Er
nanoparticles (150 nm). After inoculating C. elegans with
UCNPs, the UCNPs were found in the intestines, with most
nanoparticles found beyond the pharynx, extending to the
rectum. Moreover, imaging results show that UCNPs are
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Figure 37. In vivo target imaging with folic acid (ad) and pepide (eh)-modied UCNPs. (ad) In vivo UCL imaging of subcutaneous HeLa
tumor-bearing nude mice (right hind leg, pointed by white arrows) after intravenous injection of folic acid conjugated (a,b) and unconjugated (c,d)
UCNPs. (eh) Time-dependent in vivo UCL imaging of subcutaneous U87MG tumor (left hind leg, indicated with short arrows) and MCF-7
tumor (right hind leg, indicated by long arrows) borne by nude mice after intravenous injection of RGD-UCNPs for 1 h (e,f) and 24 h (g,h). (ad)
Reprinted with permission from ref 426. Copyright 2009 Elsevier B.V. (eh) Reprinted with permission from ref 416. Copyright 2009 American
Chemical Society.
capping ligands of UCNPs on the in vivo imaging of C.

elegans.421 It was noticed that increasing the incubation time
and concentration of nanoparticles can enhance the upconversion emissions in C. elegans, which was favorable for the in vivo
imaging studies. In addition, the C. elegans tended to ingest
UCNPs with smaller size, uniform shape, and good
dispersibility. No apparent selectivity for capping ligands was
observed. It is worth noting that a small number of UCNPs in
the gut cavity were internalized into the intestinal cells via
endocytosis without a signicant eect on C. elegans behaviors.
The incubation concentration of UCNPs-dependent in vivo
imaging eciency in C. elegans was also noticed by Zhang and
co-workers.422 Recently, Yan and co-workers presented
comprehensive investigation of in vivo imaging and toxicity
assessments of NaYF4:Yb,Tm UCNPs with C. elegans.423 When
the worms were fed with OP50 E. coli media (B-growth media)
and UCNPs together, NIR upconversion emissions of Tm3+
can be observed in the gut of C. elegans upon NIR excitation
(Figure 35gl). Further, these UCNPs can be excreted out as
the worms were fed with only E. coli again, which was in
agreement with the experimental results of Lim and Xu. No
signicant dierence in the ingesting of UCNPs was observed
between the hermaphrodite and male C. elegans. Moreover,
toxicity assessments on the GFP expression, life span, egg
production, egg viability, and growth rate exhibited no apparent
dierence between worms fed with a mixture of B-growth
media and UCNPs and intact ones. All of the in vivo imaging
studies using C. elegans indicate that UCNPs can work as
eective biomarkers to track the physiological processes of C.
elegans with no obvious toxicity.
4.6.2.2. In Vivo Imaging with Mice. Most in vivo imaging
studies are performed with mice. Zhang and co-workers
reported in vivo imaging with mice using UCNPs and quantum
dots.424 NaYF4:Yb,Er UCNPs were injected intradermally and
intramuscularly into some tissues either near the body surface
or deep in the body of Wistar mice, and exhibited intense green
upconversion emissions upon NIR excitation. By contrast, no
obvious emissions can be observed from the quantum dots,

which required UV excitation. This study highlighted the
promise of UCNPs for in vivo imaging. Since then, various
models including biodistribution tracking, specic targeting,
and high-resolution and high-sensitivity imaging have been
carried out with UCNPs.
4.6.2.2.1. In Vivo Biodistribution Tracking. Li and coworkers studied the long-term biodistribution by in vivo
imaging with UCNPs.425 In this study, PAA-modied
NaYF4:Yb,Tm nanoparticles were employed and injected
intravenously into nude mice. As shown in Figure 36, PAAUCNPs uptake and retention took place primarily in the liver
and the spleen. Moreover, no signicant uptake was observed in
other organs. At 0.5 h postinjection, no PAA-UCNPs can be
detected, indicating the rapid clearance from the systemic
circulation. An interesting phenomenon was found that uptake
by the spleen increased while uptake by the liver decreased
within 24 h, which should be partially due to the spleen being
the largest organ of the immune system. The upconversion
emission was signicantly reduced in the liver and spleen at 7
days postinjection, and almost no upconversion emissions can
be detected in the liver and spleen parts at 14 days. However,
the presence of UCL signals in the intestinal tract indicated a
clearance of PAA-UCNPs via hepatobiliary transport. At 21
days postinjection, upconversion emissions can be only
detected in the intestinal tract and remained up to 90 days.
At 115 days postinjection, almost no UCL signals were
observed, showing the UCNPs were excreted from the body of
mice. Meanwhile, no signicant toxicity eects (observational,
histological, hematological, and biochemical) were observed in
the 115 days survival of nude mice.
4.6.2.2.2. In Vivo Target Imaging. Target imaging is very
important for understanding the drug function mechanism. Li
and co-workers prepared folic acid conjugated NaYF4:Yb,Er
UCNPs and studied the in vivo tumor targeting ability.426 It
was found that signicant UCL signals can be detected in the
tumor after intravenous injection of folic acid conjugated
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Figure 38. High spatial resolution in vivo imaging with UCNPs. (ad) Optical imaging of blood vessels in the mouse ear following intravenous
injection of Y2O3:Yb,Er UCNPs: bright eld image (a), UCL image (b), NIR uorescence image (c), and the overlay image of UCL and NIR
uorescence image. (ej) In vivo lymphatic drainage UCL imaging with LaF3:Yb,Tm UCNPs was clearly detected at four draining lymph basins (1,
2, 3, and 4) along the right antebrachium of the nude mouse. Detection of UCL signals in dierent positions: prostrate (eg) and lateral (hj)
position. Note that ALNs represent for axillary lymph nodes. (ad) Reprinted with permission from ref 428. Copyright 2009 Royal Society of
Chemistry. (ej) Reprinted with permission from ref 429. Copyright 2011 Elsevier B.V.
the tumor site of the nude mouse, which was intravenously

injected neurotoxin conjugated UCNPs. By contrast, no
upconversion emissions can be detected from the control
group, which was injected unconjugated UCNPs.
4.6.2.2.3. High-Resolution in Vivo Imaging. On the basis of
the above progress, it is desirable to achieve the in vivo imaging
of local tissues or organs with high spatial resolution.
Hilderbrand and co-workers studied the in vivo vascular
imaging with Y2O3:Yb,Er nanoparticles.428 Following the
intravenous injection of UCNPs, blood vessels in the mouse
were clearly imaged (Figure 38a,b). Moreover, long circulation
of the UCNPs can be imaged in the blood over 2 h
postinjection. In addition, an NIR uorophore was also coated
on the UCNPs to track the colocalization. The result shows
excellent colocalization of the NIR uorophore emissions and
UCL signals can be observed, indicating the uorophore
coating of UCNPs remained intact in vivo (Figure 38c,d).
Kobayashi and co-workers reported multicolor lymphatic
imaging with UCNPs.402 NIR-emitting and green-emitting
UCNPs were independent, and clearly depicted the draining
lymph nodes in vivo. Because of the high signal-to-noise ratio,
single shot UCL images can be obtained. Moreover, the two
UCNPs were injected serially and revealed enhancement of the
same draining lymph nodes at the NIR and green wavelengths.
However, the NIR upconversion emission signal moved further
due to the earlier injection. Li and co-workers presented
UCNPs for 24 h (Figure 37a,b). Meanwhile, no obvious UCL

signals can be observed in the tumor of mice injected with
unconjugated UCNPs (Figure 37c,d). In addition, the authors
also modied NaYF4:Yb,Er,Tm UCNPs with arginine-glycineaspartic peptides, which exhibited high anity to the v3
integrin receptors of U87MG cells, to generate RGDUCNPs.416 The RGD-UCNPs were injected intravenously
into a nude mouse bearing a U87MG tumor on the left hind
leg. Meanwhile, an MCF-7 tumor without v3 integrin
receptors was planted on the left hind leg as control. As a
result, UCL signals were observed in the U87MG tumor, while
more intense UCL signals were seen in the liver and spleen
parts (Figure 37e,f). The maximum U87MG tumor binding for
RGD-UCNPs appeared at about 4 h postinjection and was
retained after 24 h, while the intensity of UCL signals weakened
in the liver and spleen parts after 24 h of injection, indicating
the successful binding and accumulation of RGD-UCNPs at the
tumor part (Figure 37g,h). From the ex vivo imaging of the
dissected organs, apparent UCL signals can be observed in
tumor, liver and spleen, conrming the in vivo imaging results.
Cao and co-workers prepared neurotoxin conjugated UCNPs
for visualization of tumor targeting.427 In this study,
recombinant chlorotoxin molecules, which exhibit specic
binding to many types of cancer cells, were decorated on
NaYF4:Yb,Er,Ce nanoparticles. From the in vivo imaging
results, intense upconversion emissions can be observed from
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quantitative data of signal-to-noise ratio in lymphatic imaging in

vivo with LaF3:Yb,Tm UCNPs.429 As depicted in Figure 38ej,
signicant UCL signals can be detected at three dierent
lymphatic basins (regions 1, 2, 3, 4) from the upper extremity
to axillary lymph nodes. Moreover, the lymphatic drainage
UCL signals can be detected from the nude mice with dierent
positions. Quantitative analysis of UCL signals revealed a high
signal-to-noise ratio between the UCNPs and background.
4.6.2.2.4. High-Sensitivity in Vivo Imaging. Enhancing the
detection sensitivity for in vivo imaging implies minimized
imaging dose, which is crucial for biosafety. In general, red
upconversion emission from Er3+ and NIR upconversion
emission from Tm3+ are more suitable for in vivo imaging
studies due to less scattering eect induced by tissue. Liu and
co-workers realized whole-body imaging at near single cell level
using ultrasensitive stem cell labeling with oligo-argininemodied UCNPs.430 It was found that conjugation of the
oligo-arginine was able to dramatically enhance the cellular
uptake of UCNPs by stem cells, and thus oered highly
ecient stem cell labeling. As a result, as few as 10 cells labeled
with UCNPs were successfully detected. Li and co-workers
developed hexagonal NaLuF4:Yb,Tm nanoparticles and studied
the detection sensitivity with these UCNPs.431 In vivo imaging
results showed that as few as 50 KB cells labeled with UCNPs
can be detected at the subcutaneous injection site. In addition,
apparent UCL signals can be detected with 1000 KB cells
labeled with UCNPs after intravenous injection at the liver and
spleen parts of nude mouse. Prasad and co-workers developed a
novel category of NIR-emitting UCNPs, cubic NaYbF4:Tm@
CaF2, for high-contrast deep tissue bioimaging.432 Whole-body
imaging of a BALB/c nude mouse intravenously injected with
the UCNPs showed a high signal-to-noise ratio of 310, about
10 times higher than that previously reported for in vivo
imaging by UCNPs. Moreover, upconversion emissions can be
imaged through 3.2 cm pork tissue, with a high contrast against
the background. Recently, Huang and co-workers reported
sensitive and high-resolution subcutaneous in vivo imaging with
UCNPs and their microarrays.433 In this work, a high
subcutaneous detection sensitivity of 0.93 104 wt % could
be achieved with 10 L UCNPs in tissue phantoms.
Moreover, a 50 m microarray of UCNPs can be detected by
subcutaneous imaging.
4.6.2.3. In Vivo Imaging with Other Models. Recently,
rabbit and seedling have been employed as biological models
for in vivo imaging studies. Li and co-workers prepared sub-20
nm cubic NaLuF4:Yb,Tm nanoparticles and studied the in vivo
imaging capacity in rabbits, which was considered an example
of large animals.434 One hour after injection of UCNPs into an
ear vein, signicant UCL signals can be observed from the
rabbit (Figure 39a). Ex vivo imaging revealed that the
NaLuF4:Yb,Tm UCNPs congregated in the liver of the rabbit.
Haase and co-workers performed the in vivo analysis of sizeand time-dependent uptake of NaYF4:Yb,Er@NaGF4 UCNPs
by pumpkin seedlings.435 It was found that the UCNP
accumulation took place eventually in the leaf margin (Figure
39b,c). The uptake of smaller UCNPs was faster than that of
larger UCNPs, leading to higher concentrations of smaller
UCNPs at early times of incubation. Moreover, both the small
and the large UCNPs were taken up and translocated to all of
the plant organs via the vascular system within 3 h.
Figure 39. UCNPs for in vivo imaging with rabbit and pumpkin
seedling. (a) In vivo UCL imaging of rabbit through ear vein injection
of NaLuF4:Yb,Tm UCNPs. Inset is the ex vivo imaging of the liver of
rabbit. (b,c) Pumpkin seedling hydroponically grown for 8 days in a
0.1 wt % solution of NaYF4:Yb,Er@NaGdF4 UCNPs. Seedling under
daylight (b) and under NIR excitation (c). (a) Reprinted with
permission from ref 434. Copyright 2012 Elsevier B.V. (b,c) Reprinted
with permission from ref 435. Licensed under CC BY 3.0.
4.7. Upconversion Nanoparticles for Imaging Guided

Therapy
In recent years, Ln3+-based UCNPs have been positively

involved in theranostic studies, where the upconversion
emissions can be used as luminescence signals to determine
the accurate site and time that required therapy, so-called
imaging guided therapy. With the remarkable penetration
depth and excellent biocompatibility of UCNPs, UCL guided
therapy should be more promising as compared to those
utilizing UV and visible lights. Among various therapeutic
technologies, PDT and PTT are considered as alternative
approaches to conventional chemotherapy and radiotherapy
due to their noninvasive nature and excellent biological
friendliness. On the basis of their intrinsic therapeutic
mechanism, UCNPs can be integrated to provide UCL imaging
guided PDT and PTT.
4.7.1. Photodynamic Therapy. Because of the noninvasive nature, PDT has been widely recognized for cancer
treatment.436439 Because of the remarkable penetration depth
of NIR irradiation, UCNP-based PDT technologies have gained
considerable attention in recent years. Light, photosensitizer
(PS), and oxygen are three key components in a typical PDT
process. Initially, UCNPs generate upconversion emissions
upon NIR irradiation, and then donate the energy to
surrounding PS molecules, resulting in excited PS molecules.
Excited PS molecules can further transfer the energy to
neighboring triplet oxygen (3O2), generating singlet oxygen
(1O2), which is a typical reactive oxygen species (ROS) and is
responsible for oxidative damage to cancer cells.
Zhang and co-workers reported the rst case of UCNP-based
PDT in 2007.440 NaYF4:Yb,Er UCNPs were employed as
energy transducers to generate visible emissions. Merocyanine
540 (MC 540) was used as PS and doped into the thin silica
layer during the coating process. After NIR light irradiation and
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Figure 40. UCL imaging guided PDT in vivo. (a) Representative gross photos of a mouse showing tumors (highlighted by dashed white circles) at
14 d after treatment with the conditions described for groups 14. Scale bars are 10 mm. Corresponding tumor volumes in the four treatment
groups at 6, 8, 10, 12, and 14 d after treatment are shown in (b). (c) Representative gross photos of a mouse intravenously injected with folic acid
(FA) and PEG-modied UCNPs, unmodied UCNPs, and PBS showing the change in tumor size (highlighted by dashed white circles) before and 7
d after PDT treatment. Scale bars are 10 mm. Corresponding tumor volumes in the three treatment groups at 1, 4, 6, 8, and 11 d after treatment are
shown in (d). Reprinted with permission from ref 455. Copyright 2012, Nature Publishing Group.
successive energy transfers, 1O2 molecules were generated from

the nanocomposites, leading to prominent cell death. R. Austin
and co-workers demonstrated a functional prototype that
colocalized insoluble porphyrin with UCNPs that eciently
generated 1O2 molecules under NIR illumination.441 Zhang and
co-workers loaded zinc(II) phthalocyanine (ZnPc) molecules
into the mesoporous silica shell of NaYF4:Yb,Er UCNPs to
produce 1O2 molecules upon NIR excitation.442 It was found
that the nanocomposites with the concentration of 100 g/mL
can induce 70% cell death upon NIR irradiation. Zhang and coworkers presented a highly ecient nanocomposite for UCL
imaging guided PDT. Rose Bengal (RB) molecules were
employed as PS to extract the energy from NaYF4:Yb,Er
UCNPs.443 It was found that 80% green emissions can be
transferred to PS molecules to yield 1O2 molecules. When the
nanoparticle concentration was 100 g/mL, 50% cell death was
induced. Zhao and co-workers rst developed a novel category
of nanocomposites combining blue-emitting NaGdF4:Yb,Tm@
NaGdF4 UCNPs with blue-light excited PS (hypocrellin A,
HA) as NIR photosensitizing nanocomposites for PDT of
cancer cells.444 In vitro analysis on A549 and HeLa cells proved
the high eciency of PDT eect. Apart from these systems,
MC540-NaYF4:Yb,Er,445 5,10,15,20-tetra(m-hydroxyphenyl)chlorin-LiYF4 :Yb,Tm, 446 and Chlorin e6 (Ce6)-NaGdF4:Yb,Er447 have been studied for cellular PDT treatment
with satisfying ecacy. Very recently, Zhang and co-workers
prepared RB-modied NaYF 4:Yb,Ho@NaYF 4:Nd@NaYF 4

UCNPs for 808 nm triggered cellular PDT.448 With 200 g/
mL of these nanoparticles, the cell viability was lower than 50%
upon 808 nm irradiation. Moreover, the heating eect induced
by 980 nm irradiation was reduced.
In addition to the PDT at cellular level, in vivo PDT have
also been demonstrated. Liu and co-workers presented the rst
demonstration of NIR light-induced in vivo PDT of cancer with
UCNPs.449 Ce6 molecules were loaded onto NaYF4:Yb,Er NCs
to selectively absorb red emission of Er3+. Both in vitro and in
vivo tests proved that UCNP-Ce6 nanocomposites were able to
enter cancer cells and induce cell death upon irradiation of NIR
light. The tumor volume of mice treated with Ce6-UCNPs and
NIR light irradiation was about 60% of that of mice treated with
saline and visible light irradiation. Moreover, a much deeper
tissue penetration depth could be obtained by NIR irradiation
than that of visible illumination. Later, they successfully
developed charge-reversible UCNPs for pH-sensitive in vivo
PDT.450 Ce6 loaded NaYF4:Mn,Yb,Er UCNPs were coated
with a pH-sensitive polymer. Considerably improved cancercell killing ecacy was realized in slightly acidic environment
with the Ce6-NaYF4:Mn,Yb,Er UCNPs upon NIR irradiation.
Moreover, the tumor volume was signicantly conned to 25%
of the control group treated with saline. Gu and co-workers
realized in vivo targeted deep-tissue PDT based on UCNPs.451
In this study, folic acid-modied chitosan was coated over
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Figure 41. UCNPs for PTT in vivo. Bright eld (a) and UCL imaging (b) of a 4T1 tumor-bearing mouse 2 h after intravenous injection of
NaYF4:Yb,Er@Fe3O4@Au nanocomposites under the tumor-targeted magnetic eld. (b,c) In vivo T2-weighted MRI images of a 4T1 tumor-bearing
mouse 2 h after intravenous injection of NaYF4:Yb,Er@Fe3O4@Au nanocomposites with magnetic targeting. The tumor region is highlighted by a
dashed white circle. (ei) Representative photos of mice after various treatments indicated. Note that MFNP and MF refer to NaYF4:Yb,Er@
Fe3O4@Au multifunctional nanoparticles and magnetic eld, respectively. (j) The growth of 4T1 tumors in dierent groups of mice after treatment.
The tumors were normalized to their initial sizes. (k) Survival curves of mice bearing 4T1 tumor after various treatments indicated. Reprinted with
permission from ref 462. Copyright 2012 Elsevier B.V.
NaYF4:Yb,Er UCNPs to anchor PS molecules of ZnPc. With

the folate-modied ligands, the nanocomposites were demonstrated to possess tumor-selectivity to cancer cells that
overexpressed folate receptor, which was conrmed by the
UCL imaging images. Moreover, 1O2 molecules were detected
under a 1 cm tissue upon NIR excitation, and the tumor
inhabitation ratio reached 50%. Modied with folic acid, ZnPc
coated NaYF4:Yb,Er UCNPs were also found to possess tumor
targeting property.452 The growth of tumor cells in mice treated
with nanocomposites was signicantly inhibited upon NIR
irradiation, with a tumor inhibition of approximately 80.1%. By
comparison, the tumor volume of untreated mouse increased
apparently. In addition, the feasibility of in vivo tumor PDT for
ZnPc-LiYF4:Yb,Er453 and 5-aminolevulinic acid-NaYF4:Yb,Er@
CaF2454 has also been veried.
The above-mentioned PDT nanocomposite comprises one
type of PS molecules. In 2012, Zhang and co-workers
discovered greater PDT ecacy with a dual-photosensitizer
approach.455 MC 540 and ZnPc were encapsulated into the
mesopores of the silica layer coated on NaYF4:Yb,Er UCNPs to
extract green and red emissions from Er3+, respectively. As
compared to singly loaded UCNPs, the dual PSs loaded
UCNPs were more eective in generating 1O2 molecules. Form
the in vivo PDT treatment (Figure 40a,b), it can be found that
the volume of tumor treated with UCNPs and NIR irradiation
was much smaller than that of other groups, indicating the high
PDT ecacy. Furthermore, folic acid molecules were modied
on the UCNPs for tumor targeting PDT. As depicted in Figure
40c,d, the volume of tumor treated with folate-UCNPs and
NIR irradiation was smaller than that of the other two groups,
suggesting that the folate-UCNPs were an ideal platform for

PDT treatment.
Aside from organic PS molecules, monomalonic fullerene
(C60MA) has been demonstrated as an excellent energy
acceptor and PS molecule.456 Zhang and co-workers prepared
novel nanoparticles comprising C60MA and NaYF4:Yb,Er@
NaYF4:Yb,Tm for PDT. Upon NIR irradiation, all emissions of
Er3+ and Tm3+ can be absorbed by C60MA due to its
broadband absorption property. As compared to the nanocomposites comprising UCNPs and RB molecules, C60MAUCNPs exhibited more signicant PDT eciency. Recently,
Zhang and co-workers developed a novel series of NaYF4:Yb,Tm@TiO2 nanocomposites for in vivo tumor PDT.457 In
NaYF4:Yb,Tm@TiO2 nanocomposites, electrons in the valence
band of TiO2 shell can be excited to the conduction band,
leading to the formation of an electronhole pair eliciting
further redox reactions for the generation of ROS. The in vivo
tumor PDT treatment ecacy exhibited that the tumor growth
can be signicantly delayed after intratumoral injection of
NaYF4:Yb,Tm@TiO2 nanocomposites.
Recently, MRI has also been introduced to UCL imaging
guided PDT to provide dual-mode imaging guided PDT. Yan
and co-workers constructed two types of nanocomposites with
potential applications for dual-mode imaging (UCL/MRI)
guided PDT. 458 NaGdF 4 :Yb,Er@CaF 2 UCNPs and PS
(hematoporphyrin and silicon phthalocyanine dihydroxide)grafted mesoporous silica were employed as core and shell,
respectively. The composite nanomaterials exhibited excellent
PDT eciency in HeLa cells through an energy transfer
process between the core and PS containing shell layer under
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oxide, which were used to convert light into heat.464 To

further enhance the therapeutic ecacy, ZnPc molecules were
also introduced on the surface of graphene oxide to provide a
synergistic eect of PTT and PDT. It was found that when two
lasers (808 nm for PTT, 630 nm for PDT) irradiated the
nanocomposites labeled cancer cells simultaneously, more
cancer cell death was induced, suggesting the synergistic eect
of PTT and PDT. Recently, Shi and co-workers realized
trimode imaging guided synergistic PTT and radiation therapy
(RT).465 In this study, CuS nanoparticles were selected as PTT
agents and loaded on the silica shell of NaGdF4:Yb,Er UCNPs.
The feasibility of RT was attributed to the high X-ray
absorption coecients of lanthanide elements. With the
NaGdF4:Yb,Er@SiO2@CuS nanocomposites, trimode UCL/
MR/CT imaging can be obtained to assist extended synergistic
PTT and RT. Remarkably, a serious burn and a considerable
tumor growth inhibition of 79% was observed for tumor treated
with PTT, suggesting the great potential for PTT in vivo. When
RT was introduced, the tumor was thoroughly eradicated in 4
days without later recurrence during a long course of 120 days.
NIR laser irradiation. The viability of HeLa cells treated with

100 M of nanocomposites decreased to 15% after 10 min of
irradiation (2.5 W/cm2). Heyon and co-workers prepared Ce6modied NaYF4:Yb,Er@NaGdF4 UCNPs for in vivo UCL/
MRI guided tumor PDT.459 Because of the lyphophilic
property of Ce6, Ce6-UCNPs would tend to accumulate in
tumors. After intravenous injection of the Ce6-UCNPs, intense
UCL signals can be found in the tumor site. Meanwhile,
signicant contrast enhancement in the tumor site was found
from the MRI images. The in vivo tumor PDT experiments
exhibited that tumor growth was inhibited with Ce-6 UCNPs
upon NIR irradiation, while nontreated tumors grew
signicantly.
4.7.2. Photothermal Therapy. In a typical PTT treatment,
lights are converted into heat by proper agents, resulting in
local hyperthermia to kill cancer cells.460 A prerequisite for
PTT agents is a strong optical absorption characteristic.
Therefore, gold nanoparticles, organic dyes, graphene oxides,
and quantum dots are eective agents for PTT. For UCNPsbased PTT studies, UCNPs are combined with these
mentioned materials into nanocomposites to oer imaging
guided PTT.
Liu and co-workers developed PEG-modied NaYF4:Yb,Er@
Fe3O4@Au nanocomposites for dual-mode imaging guided
PTT.461 In this nanocomposite, NaYF4:Yb,Er core is ecient
for generating upconversion emissions, Fe3O4 intershell is
responsible for the T2-weighted MRI, while Au shell is
employed to convert NIR light into heat. Signicant
upcoversion emission signals can be observed from the liver
and tumor sites after intravenous injection of the nanocomposites. Meanwhile, an obvious darkening eect can be
detected in the liver and tumor sites, which agreed with the
UCL imaging result. After being exposed to NIR laser for 5 min
(1 W/cm2), the temperature of the nanocomposite solution
increased by 30 C, while a minor change occurred in the
control groups. The above results indicated the capacity of
dual-mode imaging guided PTT. Because of the existence of
Fe3O4, magnetic targeting can be realized. Later, the authors
achieved magnetically targeted in vivo tumor PTT with the
same nanocomposites.462 When the nanocomposites were
injected intravenously, the surface temperatures of tumors
increased to 50 C, in marked contrast to 38 C for
irradiated tumors without nanocomposites. As shown in Figure
41, tumors on mice that were injected with the nanocomposites
under tumor-targeted magnetic eld disappeared after NIR
light irradiation. Moreover, no tumor regrowth was noticed
over a course of 40 days. By contrast, tumors in other
controlled groups continued their rapid growth, and the mice
had an average life span of 1418 days. This suggests that the
NaYF4:Yb,Er@Fe3O4@Au nanocomposite is quite promising
for imaging guided PTT of cancer.
Hilderbrand and co-workers discovered promising PTT
agents by incorporating UCNPs and organic dyes into
nanocomposites.463 Carbocyanine dyes were loaded into the
silica shell of NaYF4:Yb,Er UCNP. Upon 980 nm excitation,
excellent cellular imaging results can be obtained. With 750 nm
laser irradiation for 2 min (2.5 W/cm2), the temperature of the
suspension of NaYF4:Yb,Er@SiO2/dye nanocomposites increased by 21 C. Moreover, 42% of RAW cells were killed
when using the nanocomposites upon irradiation by 750 nm
laser for 3 min, indicating the great ecacy of PTT treatment.
Zhang and co-workers covalently conjugated poly(allylamine)modied NaYF4:Yb,Er,Tm@NaYF4 UCNPs with graphene
4.8. Upconversion Nanoparticles for Drug Delivery and

Chemotherapy
Chemotherapy is recognized as a main method for the eective

cure for diseases like cancer, suggesting the signicance of drug
delivery in biomedical applications. One of the major problems
in chemotherapy nowadays involves the diculties in the
control of local eective therapeutic concentration, as a low
dosage of drug can be ineective and a high dosage causes the
side eect of cytotoxicity.
Ideal nanoparticle-based drug delivery systems should feature
both imaging and curing functions, where locating of disease
sites can be achieved by imaging nanoprobes and targeted
therapeutic delivery by nanocarriers. Such multimodal nanoplatforms can minimize side eects on noninfected areas and
provide real-time monitoring of the treatment, enabling
photocontrolled targeting.
As compared to imaging approaches such as MRI and radiolabeling, optical imaging can aord rapid in situ diagnosis and
enable intraoperative feedback without suering from radiative
risks. With the developments in nanotechnology in the past
decades, NIR upconversion-based controlled delivery systems
have been found of enormous interest. Ln3+ doped UCNPs,
combining the physical properties of nanoparticles, including
high surface to volume ratio, and the unique ability to
upconvert low energy NIR light to visible or UV luminescence,
oer a promising platform for drug delivery. As it has been
mentioned previously that the synthetic strategies toward
monodispersed UCNPs with controlled sizes and shapes have
been well established, the physical properties can be easily
manipulated according to the requirements in the designing of
the drug delivery systems. The surface tailoring of UCNPs has
also been well studied, which allows the introduction to their
surface a wide range of ligand functionalities, oering diverse
platforms out of UCNPs for controlled drug delivery.440
In general, UCNPs-assisted chemotherapeutic processes fall
into two categories: (a) UCL guided monitoring of the degree
of drug release; and (b) NIR triggered drug release based on
UCNPs. Both strategies will be discussed here, with the focus
on the latter.
4.8.1. UCL Imaging for Drug Delivery. In these
applications, Ln3+ doped UCNPs were simply combined with
drug delivery and act only as imaging probes due to the ideal
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carrier. Under 980 nm NIR light irradiation, the surface

plasmon resonance (SPR) eect of the Au nanoparticles led to
a wavelength-dependent enhancement in UCL intensities and a
photothermal eect that induced the rapid release of Dox.486
Aside from Dox releasing systems, upconverting nanocarriers
have also been designed for biomedical imaging monitored
cisplatin(IV) prodrug delivery. For example, Lin and coworkers have successfully prepared a novel multifunctional
UCNPs/polymer composite loaded with Pt(IV) prodrugs
(Figure 42).487 The endocytosis of these nanoparticles by
penetration depth of NIR light, but do not interfere with the

therapeutic process. For this reason, such investigations are
only shortly summarized here.
As suggested by a series of in vitro (and in vivo) studies, the
most well-established drug delivery systems with simultaneous
UCL imaging involve the release of the antitumor drug
doxorubicin (Dox) from upconverting nanocarriers. In these
cases, the Dox molecules were accommodated in the hollow
sphere or mesopores of the UCNPs to be protected from
premature releasing. The drug release is induced by the
decrease of pH in the ambient environment (e.g., the acidic
microenvironment inside cancer cells), when the protonation of
the hydrophobic Dox molecules converts the drug into a
hydrophilic one.466474 Typically for Yb3+, Tm3+ codoped
UCNPs, the spectral overlap between the upconverted
emissions of Tm3+ at 450 nm (1D2 3F4) and 475 nm (1G4
3H6) and the broad absorbance of Dox centered at around
480 nm enables energy transfer from UCNPs to Dox
molecules. The quenching and recovery of UCL resulting
from this energy transfer process was utilized as an optical
probe to conrm the UCNP-Dox conjunction and monitor the
release of Dox.475
Apart from these systems, eorts have been made to improve
the targeting and therapeutic eectiveness of upconverting
nanocarriers for specic drug delivery. For instance, Lin and coworkers synthesized PEI ligands-modied uniform NaYF4:Yb,Er nanospheres with mesoporous shell and hollow
interior structure. These nanoparticles were then conjugated
with folic acid/folate (FA) and loaded with Dox. FA is a lowmolecular-weight vitamin that binds with high anity to folate
receptor (FR), a membrane-anchored protein. As it has been
found that FR is overexpressed on cancer cells, and that the
bound FA-NP conjugates enter cells via endocytosis,476478 the
use of FA as a tumor cell targeting ligand has been intensively
explored for cancer therapeutic interests.479481 The FAmodied nanoparticles were observed to exhibit greater
cytotoxicity to HeLa cell than Dox-loaded cubic NaYF4
nanoparticles due to the enhanced cell uptake specicity by
FA ligands. In addition, these UCNP-FA conjugates oered
bright green emission without background noise under 980 nm
NIR excitation, and were thus considered ideal for simultaneous targeted anticancer drug delivery and cell imaging.482
Similar enhancement on the cancer cell-targeting of UCNPs
via ligand modication was also reported by Shi et al. By the
surface conjugation of TAT peptide on NaYF4:Yb,Er@NaGdF4,
which features both MRI and UCL imaging performances, the
yielding UCNPs were further endowed with nuclear targeting
properties. These multifunctional UCNPs were used to achieve
direct Dox delivery to the nucleus of HeLa tumor cells under
synchronous monitoring guided by either UCL imaging or
MRI, providing opportunities for advanced nuclear -targeted
therapy based on UCNPs.483
In some other cases, UCNPs were combined with other
types of nanoparticles to form multifunctional materials. For
example, Fe3O4UCNPs nanocomposites featuring both
upconversion luminescence and magnetic properties can be
directed by an external magnetic eld. Such nanoparticles can
be used for magnetically targeted Dox release484 or synergistically combined chemotherapy of Dox delivery and sonodynamic therapy.485 In another demonstration, Yang and coworkers integrated gold nanocrystals onto the surface of a Yb3+,
Er3+ doped gadolinium-assembled mesoporous silica nanocomposite, and then introduced Dox into the hybrid nano-
Figure 42. UCNPs for drug delivery. Schematic illustration of the

preparation of UCNPs/cisplatin(IV)/RhB nanocomposites and
possible cellular pathways for cisplatin and the nanocomposites. The
nanocomposites are endocytosed by cancer cells and cisplatin was
released via intracellular reduction of cisplatin(IV) prodrug, while
cisplatin is internalized by passive diusion or uptaken actively via
CTR1. Most of the internalized cisplatin will be deactivated by
glutathione (GSH) and metal-lothionein (MT) wth a tiny percentage
to bind to DNA. Reprinted with permission from ref 487. Copyright
HeLa cells and tumor tissue was successfully observed via the
Er3+ doped UCNP-based in vitro and in vivo imaging, and the
releasing and anticancer activities of the Pt(IV) prodrug system
have been conrmed by the observed toxicity in the cellular
environments or tumor-bearing animal models.
4.8.2. Photoactivation/Photorelease for Therapeutics.
To protect the drug from deactivation or decomposition before
delivery to the targeted area, or to prevent undesirable damage
to an untargeted area, it is necessary to load the therapeutic
agents within the nanocarriers and release solely upon
stimulation. Such loadings can be realized by encapsulation
into polymer frameworks or shells, electrostatic absorption by
charged ligands on the surface of nanoparticles, or covalent
grafting of prodrugs by various linkers on the nanoparticles. For
this reason, intelligent stimuli-responsive materials are utilized
as an eective tool for spatial or temporal control over the
delivery process. Light is a noninvasive stimuli that can be
readily tuned and focused for both temporal and spatial control,
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allowing on-command delivery of bioactive molecules such as

drugs. It is worth mentioning here that photocaging is a process
where a molecule is rendered biologically inert through
functionalization with a photolabile protecting group,488490
which is also known as a phototrigger. Conventional phototriggers are generally UV light-activated, but the use of a UV
lamp in biomedical application is considered undesirable due to
the serious phototoxicity and low tissue penetration power of
UV irradiation.
NIR stimulated nanoplatforms based on UCNPs, on the
other hand, have been found as ideal stimuli-responsive systems
for drug delivery. While NIR light oers deep penetration into
biological tissues and negligible photodamage, UCNPs convert
NIR excitation energy into visible or UV luminescence that can
be absorbed by a variety of photosensitizers, which can be
utilized for photocaging/photorelease of drugs. Also, it has
been mentioned previously that UCNPs are biocompatible as
they do not contain toxic elements,403 and have a large surface
area for conjugation with therapeutic agents.439
As compared to molecular photorelease, delivery vehicles
based on UCNPs have additional benets in biological
applications: the surface modication of UCNPs with hydrophilic ligands can be easily done to render them soluble in
aqueous environments; and the luminescence emitted by
UCNPs can be used to monitor the delivery, featuring
upconverting nanocarriers with release and report functions.491,492
Strategies for the photoactivation of caged prodrugs that are
covalently grafted to the photolabile protecting group
(uncaging) and the photorelease of drugs loaded in the carriers
through noncovalent interactions can be categorized according
to the type of the process that the photoresponsive functional
group undergoes to initiate the release or activation of
therapeutics upon NIR stimulation: (a) chemical bond
cleavage, leading to the decomposition of the matrix carrying
the drug, or (b) photoisomerization to generate in situ
photomechanical stirring force.
4.8.2.1. NIR Triggered Chemical Bond Cleavage. The rst
example of NIR triggered photorelease based on chemical bond
cleavage mediated by UCNPs was described by Branda et al.
using an organicNP hybrid system. In this work, 3,5di(carboxymethoxy)benzoin, which belongs to one of the most
commonly used classes of photocages,493 was employed. This
type of compound has been found to undergo photolysis under
UV irradiation, releasing carboxylic acid (see Figure 43). 3,5Di(carboxymethoxy)benzoin acetate attached to the hexagonal
NaYF4:Yb,Tm@NaYF4 nanocrystals was demonstrated as a
remote control release system.
Upon the irradiation of 980 nm CW laser, a noticeable

change in the absorption prole of the photocage was observed.
This spectral change was found almost the same as that
observed when the nanocomposite was exposed to UV light
(290 nm), indicating the high eciency of the hydrolysis by
indirect irradiation with NIR. Control experiment was also
carried out to expose the CH3CN solution of the free benzoin
acetate to 980 nm NIR. No changes in its UV/vis absorption
spectrum were noticed after 1 h of exposure, suggesting that the
photosensitive molecule is not responsive to direct NIR
irradiation in the absence of the UCNPs.494
This work pointed out that NIR light responsive organicUCNP nanocomposites can be used as an alternative to UV
lamp for UV-triggered organic reactions, some of which can be
adopted for photorelease of therapeutic species. In such a way,
both the undesirable photodamage and the inadequate
penetration depth of using a UV lamp can be overcome.
4.8.2.1.1. ortho-Nitrobenzyl Group as Phototriggers. Of all
of the photocleavable organic functional groups, 2-nitrobenzyl
and its derivatives have become the most widely used
photocage in NIR upconversion-based nanoplatfroms for the
remote control of biocompatible photoactivation of therapeutic
agents.495514 This is mainly because the absorption prole of
the ortho-nitrobenzyl containing compounds matches well with
the emission bands of Yb3+, Tm3+ codoped NaYF4 UCNPs at
the UV regime, typically at 290 nm (1I6 3H6) and 345 nm
(1I6 3F4). Thereby, such applications of UCNPs involving 2nitrobenzyl groups as the photolabile cage for the controlled
release of bioactive species were briey summarized here.
4.8.2.1.1.1. Polymers as Capsules of Payloads. Two
demonstrations of NIR-triggered release of trapped/encapsulated payloads, where 2-nitrobenzyl derivatives were used as the
photolabile group that underwent photocleavage under
upconverted UV irradiation, were presented by Brandas
group in collaboration with Zhao et al. In the rst
demonstration, a model hydrophobic cargo Nile Red495497
and NIR-to-UV UCNPs of hexagonal NaYF4:Yb,Tm@NaYF4
were encapsulated inside the hydrophobic core of the diblock
copolymer micelles of poly(ethylene oxide)-block-poly(4,5dimethoxy-2-nitrobenzyl methacrylate). The block copolymer
is composed of a hydrophilic block of poly(ethylene oxide)
(PEO) and a hydrophobic block of polymethacrylate bearing 2nitrobenzyl group (PNBMA) on each monomer, and
consequently in the aqueous environment the hydrophobic
block formed the core of the micelle. Upon the excitation of
980 nm NIR light, the UV emission of the UCNPs was
absorbed by the 2-nitrobenzyl moieties. The subsequent
photocleavage converted PNBMA into hydrophilic poly(methacrylic acid), causing the dissociation of the micelles as
well as the release of the UCNPs and the coloaded Nile Red
(scheme shown in Figure 44).498 The on demand release was
monitored by analyses of the absorption or emission of Nile
Red in the mixed system. This is a novel strategy for the remote
control of the disruption of block copolymer micelles or
vesicles, where UCNPs can be used as an internal UV and
visible light source upon excitation of NIR light.
In the second demonstration, the circumvention of the use of
UV lamp for UV light-triggered chemical bond cleavage
reaction of 2-nitrobenzyl derivatives was again realized by a
NIR upconversion-based system. In this design for the on
demand release of trapped bioactive molecules (protein or
enzyme), a UV light responsive polymer hydrogel was loaded
with Yb3+, Tm3+ codoped UCNPs and the biomacromolecules
Figure 43. Scheme of the remote control photorelease system

consisting of Ln3+-doped UCNPs attached with benzoin photocage.
Reprinted with permission from ref 494. Copyright 2010 Wiley-VCH
Verlag GmbH & Co. KGaA.
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F4:Yb,Tm UCNPs and uorophores. These polymers contain

2-nitrobenzyl units in each of their cresol monomers, and
highly ecient depolymerization caused by UV upconverted
luminescence as well as the subsequent release of uorophores
was observed upon NIR irradiation. This degradation of
polymer capsules is also the rst demonstration of the
harnessing of UCNP luminescent energy for degradation of
polymer particles and cargo release.505
4.8.2.1.1.2. Mesoporous Silica Coated Upconverting
Nanocarriers. Apart from using polymers as the carriers of
payload, mesoporous silica nanoshell has been found a suitable
capsule for drug delivery due to its biocompatibility and its
porous or hollow nanostructures, and was therefore used in a
series of in vitro studies on NIR upconversion-based
therapeutic releasing systems.506,507
Zhang et al. have reported the coating of NaYF4:Yb,Tm
UCNPs with thin layers of silica mesopore.442 Aimed for
photocontrolled gene expression, plasmid DNA/small interfering RNA (siRNA) was caged with DMNPE (4,5-dimethoxy-2nitroacetophenone) and loaded into the mesoporous silica shell
of the UCNP core. The uncaging of DNA/siRNA occurs when
the UCNPs were irradiated by NIR light and gave UV emission,
and the biofunctionalities of these nucleic acids can thus be
activated.508
Another piece of work on the photocontrolled delivery of
nucleic acid was later reported by the groups of Xing and Liu.
Instead of caging siRNA with phototriggers, these anionic
nucleic acids were electrostatically absorbed on the positively
charged photocleavable ligands, which were linked to the
surface of the silica coated UCNPs through covalent binding.
While the naked highly negatively charged siRNA cannot
freely cross cellular membranes, which seriously hampers their
utility for gene therapy, these UCNP@mSiO2-based upconverting nanocarriers can deliver the siRNA in host living cells via
cellular internalization. The photorelease of RNA occurred
when the upconverted UV luminescence was absorbed by the
2-nitrobenzyl contained linkers upon NIR irradiation, enabling
the target therapeutic delivery of siRNA.509
The same research groups in collaboration designed in the
same year the photocontrolled selective intracellular delivery of
Dox utilizing caged mesoporous silica coated UCNPs. In the
rst stage of the work, the Dox drug was encapsulated inside
the silica nanoshell that was caged with a cross-linker made
from 2-nitrobenzyl derivatives (Figure 46). The release of Dox
molecules was observed in the presence of NIR laser irradiation
by uorescence analysis of Dox, suggesting the high eciency
of the photocleavage reaction mediated by NIR-to-UV UCNPs.
These upconverting nanocarriers were then further functionalized with FA, and the hexagonal NaYF4:Yb,Tm@NaYF4@
SiO2FA conjugates were successfully used in NIR-triggered
targeted intracellular drug delivery to the cell lines with a high
level expression of FR.510
A similar nanocarrier system was developed by Yeh et al.
combining Dox and 2-nitrobenzyl protecting group caged FA
molecules with UCNPs@mSiO2. The eectiveness of this
nanoplatform for selective targeting of cancer cells has been
veried by both in vitro and in vivo studies.511 Later, an
example of NIR-controlled cell adhesion assisted with UCNPs
was presented by Qu and co-workers. Using a 2-nitrobenzyl
contained photoresponsive linker between the cell and the silica
coated upconverting nanorod, the on demand release of cells
can be realized by simply applying NIR in-deep tissue
irradiation.512 This novel demonstration of NIR upconver-
Figure 44. (a) Schematic illustration of NIR-triggered disruption of

block copolymer micelles. The UCNPs are depicted as red spheres, the
coloaded hydrophobic cargo as dark spheres, the hydrophilic PEO
block of the polymer as red lines, the PNBMA core-forming block as a
blue sphere. (b) Reaction scheme of the NIR upconversion-mediated
decomposition of the diblock polymer. Reprinted with permission
rendered inactive after the trapping. As shown in Figure 45, the

hydrogel contains the photocleavable ortho-nitrobenzyl groups
Figure 45. (a) Schematic illustration of the structural degradation of a

photosensitive polymer hydrogel triggered by indirect NIR irradiation.
The polymer framework is depicted as black curves with the 2nitrobenzyl group-based photocleavable cross-linkers as red triangles,
the entrapped UCNPs as green spheres, and the coloaded proteins/
enzymes as yellow rods. (b) Reaction scheme of the NIR
upconversion-mediated decomposition of polymer. Reprinted with
as the cross-linkers of the trapping framework. Therefore, when

this loaded hydrogel was exposed to a 980 nm CW NIR light,
the UV light generated by the entrapped UCNPs triggered the
degradation of the entire hydrogel, releasing the load
components and restoring the bioactivity of the protein/
enzyme.499 This is the rst example of the remote activation of
the structural breakdown of photosensitive hybrid hydrogel by
CW NIR laser. Because polymer hydrogels have been used in
many biomedical applications as stimuli-responsive materials
for the controlled release of biomacromolecules,500504 this
reported work of NIR-induced structural disruption of hydrogel
is a novel development of the application of UCNPs for
therapeutic interest.
Another good example of the therapeutic applications of NIR
triggered chemical bond cleavage of 2-nitrobenzyl moieties was
demonstrated by Almutairi et al. using UV light-degradable
polymetric nanoparticles encapsulating core/shell NaYAR
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co-workers reported the controlled release of Dox by the

upconverted blue luminescence of Yb3+, Tm3+ codoped NaYF4
UCNPs. As demonstrated in Figure 47, the antitumor drug
Figure 46. Schematic illustration of the phototriggered release of Dox

molecules from NaYF4:Yb,Tm@NaYF4@SiO2 cross-linked by 2nitrobenzyl derivatives. Reprinted with permission from ref 510.
Copyright 2013 Wiley-VCH Verlag GmbH & Co. KGaA.
Figure 47. Schematic illustration of upconverted blue emission
triggered release of Dox from UCNP@mSiO2, where the UCNP
core is depicted as the orange sphere, the mSiO2 shell in blue, the Dox
molecules as green spheres, and the ruthenium complexes in red.
Reprinted with permission from ref 519. Licensed under CC BY 3.0.
sion-mediated cell manipulation further extends the growing

therapeutic applications of UCNPs to tissue engineering and
cell-based therapy.
Among all of the applications of the NIR upconversionmediated photolysis of ortho-nitrobenzyl for biomedical
interest, an in vivo study was carried out by Xing et al.513
The designed conjugates of D-luciferin/hexagonal NaYF4:Yb,Tm@NaYF4@SiO2 release the caged D-luciferin, which
can recognize rey luciferase reporter genes and give
bioluminescence at 560 nm when excited by 980 nm NIR light.
4.8.2.1.2. Other Phototrigger-Controlled Drug Release
Devices. Rather than using ortho-nitrobenzyl derivatives as
the phototrigger, other types of photolabile groups have also
been used for NIR upconversion-based controlled drug
delivery. The rst example of such drug release systems in
living tumor tissue was reported by Li and co-workers. In this
work, the anticancer drug chlorambucil was caged with a
coumarin514516 derivative and encapsulated in the mesoporous
silica shell of the yolkshell upconverting nanocarrier of
NaYF4:Yb,Tm@NaLuF4@SiO2. By the triggering of CW 980
nm NIR light, the release of the drug molecules occurred upon
the absorption of the upconverted UV emission by the
photocages, and this response to NIR stimuli was found
eective in a living mice model.517
Later, a novel upconverting nanocarrier enabled remote
control of the activation and release of an antitumor
platinum(IV) prodrug, and simultaneous imaging was designed
and synthesized by Xing et al. through the incorporation of the
photoactivatable Pt(IV) prodrug and an apoptosis-sensing
caspase imaging peptide onto the surface of NaYF4:Yb,Tm@
SiO2. The photoactivation of the Pt(IV) prodrug and the
subsequent release of Pt(II) therapeutic agent were triggered by
the UV luminescence of UCNPs upon NIR light illumination.
Furthermore, induced by cytotoxicity, the caspase enzymes
cleaved the peptide imaging probe, thus oering real-time
monitoring of apoptosis. In this design, the side eects of Pt(II)
drugs (e.g., severe toxicity and drug resistance eects) caused
by poor tumor specicity can also be avoided.518
Apart from the utilization of photolysis caused by UV light,
phototriggers based on visible absorption can also be used as a
powerful tool for drug delivery. In a very recent paper, Wu and
molecules were loaded in the mesoporous silica shell of the

UCNP core. The shell was also grafted with ruthenium
complexes, which act as photoresponsive molecular valves to
block Dox from escaping the upconverting nanocarrier. Upon
NIR excitation, the blue emission from UCNPs was absorbed
by the ruthenium complexes, causing ligand-exchange reactions
on the Ru center. This dissociation of the ligand grafted on the
silica shell led to the opening of the valve and subsequent
release of the drugs. It is also worth mentioning here that only a
low NIR light intensity of 0.35 W/cm2 was found required to
trigger the drug release, which is favored by biomedical
applications as a minimized overheating eect can be
achieved.519
The NIR triggered delivery of caged nitric monoxide (NO)
mediated by Yb3+, Er3+ doped UCNPs is another example of
the therapeutic application of phototrigger activated by
upconverted visible light. As a mammalian bioreglulatory
molecule that plays essential roles in vasodilation, immune
response, both tumor growth and suppression,520 and as a radiation sensitizer that can enhance the killing of the hypoxic
cells,521,522 NO has therefore received considerable interest for
its controlled delivery.523527
The rst report of NIR light controlled release of NO was
given by Zhao et al., where the sodium salt of the iron/sulfur/
nitrosyl cluster anion Fe4S3(NO)7 (RBS, Roussins black salt)
was used as the NO source, and the nanocarrier of
NaYF4:Yb,Er@NaYF4@mSiO2 was modied with ligands
containing the cation terminal of NH3+ to attract the RBS
anions through electrostatic absorption. Upon excitation of 980
nm NIR, the green emission of the UCNPs triggered the
photolysis of RBS and the consequent release of NO.528 This
new approach for the release of NO from RBS salt based on
NIR upconversion was later improved in design by loading the
ammonium RBS salt and UCNPs in a biocompatible polymer
disk. In such a way, the components were made more
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5. NEAR-INFRARED EMITTING LANTHANIDE

NANOPARTICLES FOR BIOIMAGING AND THERAPY
Nanoparticles with NIR excitation have been found essential
for preclinical in vivo imaging due to the remarkable
penetration depth in biological tissues they oer. To achieve
ideal preclinical imaging, apart from the excitation wavelength,
the emission wavelength of the imaging probes is another
important factor. In terms of the penetrability of light, two
tissue transparent windows have been proposed, the rst tissue
transparent window (7001000 nm)532,533 and the second
tissue transparent window (10002300 nm).28,534 In the rst
tissue transparent window, the absorption from water,
hemoglobin, melanin, and lipids is alleviated, resulting in better
penetrability. For instance, Tm3+ doped UCNPs with 800 nm
UCL are ecient for UCL imaging as this emission falls in the
rst tissue transparent window. In the second tissue transparent
window, nonetheless, the scattering eects of the size,
composition, and morphology of biological tissues are
minimized. Ln3+ have been found to be promising candidates
for down-shifting NIR emission thanks to their abundant native
energy states. Recently, Nd3+, Nd3+Yb3+, and Yb3+Ln3+ (Ln
= Er, Ho, Tm, or Pr) doped nanoparticles have been developed
for highly sensitive bioimaging studies. In this part of this
Review, a discussion on the basic mechanism and emerging
bioimaging applications with down-shifting NIR emitting
nanoparticles is presented.
concentrated and isolated from external medium, resulting in

reduced toxicity and improved eciency of the NO releasing
system.529
4.8.2.2. NIR-Induced Photoisomerization. Instead of
resorting to photolysis reactions to prevent premature drug
release, some photocontrolled releasing systems are designed
via applying physical means.
Shi et al. rst reported a strategy for NIR light-triggered
release of Dox utilizing both the upconverted UV and the
visible luminescence of the UCNPs of NaYF4:Yb,Tm@
NaYF4@SiO2. Azobenzene molecules (azo) were coloaded
with Dox molecules in the mesopores of silica as stirrers, as
the transformation of azo from trans- to cis-isomer occurs upon
its absorption of UV light, and from cis- to trans- under visible
light (Figure 48). Before applying NIR illumination, only little
5.1. Basic Mechanisms of Lanthanide Near-Infrared

Emissions
In general, NIR emissions are generated via down-shifting

processes. In terms of the dierent Ln3+ activators, three main
mechanisms for NIR emissions are involved: (a) Nd3+ doped
NPs (Figure 49a). Nd3+ can be excited with 808 nm light,
Figure 48. Schematic illustration of the photoisomerizaiton of azo
groups and the NIR triggered release of Dox molecules from silica
mesopores mediated by upconverted luminescence. Reprinted with
permission from ref 530. Copyright 2013 Wiley-VCH Verlag GmbH &
Co. KGaA.
Dox release in aqueous environments can be observed as a

result of the strong interactions of Dox and silica via hydrogen
bonds and charge interactions. However, upon 980 nm
irradiation, the reversible photoisomerization of azo molecules
was triggered by the simultaneous UV and visible emission of
UCNPs, producing photomechanical forces that cause the
release of Dox molecules.530
In a very recent publication, a new multifunctional dualcompartment Janus mesoporous silica nanocomposite (NaGdF4:Yb,Tm@NaGdF4@mSiO2&PMO, with PMO representing
periodic mesoporous organosilica) was synthesized by Zhao
and co-workers. The hybrid silica shell of the nanoparticles
enables the dual encapsulation of both hydrophilic and
hydrophobic cargos. These nanoparticles were further modied
with light-sensitive azo molecules and heat-sensitive 1tetradecanol molecules, allowing dual heat and NIR light
triggered controllable dual drug release. This work oers a new
concept for the design of upconverting nanocarriers for
multiple drug delivery and combined therapy.531
Figure 49. Principle energy transfer diagrams for down-shifting NIR

emissions from (a) Nd3+, (b) Nd3+Yb3+ pairs, (c) Yb3+Er3+ pairs,
(d) Yb3+Ho3+ pairs, (e) Yb3+Pr3+ pairs, and (f) Yb3+Tm3+ pairs.
resulting in upward transition of 4I9/2 4F5/2. Electrons then

can be relaxed to the 4F3/2 states. Finally, emissions can be
released from 4F3/2 4I9/2 (900 nm), 4F3/2 4I11/2 (1050
nm), and 4F3/2 4I13/2 (1330 nm) transitions. With multiple
excitation bands, Nd3+ can also be excited with 730 nm light.
(b) Nd3+Yb3+ codoped NPs (Figure 49b). Nd3+ is employed
as the energy donor, while Yb3+ is used as the energy acceptor.
The excitation process is similar to that in the Nd3+ activated
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Figure 50. Down-shifting NIR emitting nanoparticles for in vivo imaging. Real-time biodistribution studies of NaYF4:Yb,Er nanoparticles in nude
mice from both ventral (a) and left lateral (b) aspects. (c) Nude mice bearing melanoma xenografts were intravenously injected NaYF4:Yb,Er
nanoparticles and imaged under surrounding tumor regions before dissection from the ventral aspect. (d) Multicolor down-shifting NIR imaging
performed from the dorsal aspect in a nude mouse xenografts after NaYF4:Yb,Er and NaYF4:Yb,Ho nanoparticles were separately injected into the
tumor sites. Reprinted with permission from ref 537. Copyright 2013 Nature Publishing Group.
system. After populating the 4F3/2 state of Nd3+, a nonresonant

energy transfer, 4F3/2 (Nd3+) + 2F7/2 (Yb3+) 4I9/2 (Nd3+) +
2
F5/2 (Yb3+), occurred from Nd3+ to Yb3+, leading to 980 nm
emission of Yb3+ (2F7/2 2F5/2). Meanwhile, emissions from
Nd3+ can also be obtained. (c) Yb3+Ln3+ (Ln = Er, Ho, Tm,
and Pr) pairs activated NPs. Yb3+ is generally used as the
photosensitizer to endow the nanoparticles with NIR excitation
(980 nm) due to the large absorption cross-section and donate
as-absorbed energy to Ln3+ including Er3+, Ho3+, Tm3+, and
Pr3+. For energy transfer processes where the Yb3+Er3+ pair is
involved, the energy transfer from Yb3+ to Er3+, 2F5/2 (Yb3+) +

I15/2 (Er3+) 2F7/2 (Yb3+) + 4I11/2 (Er3+) triggers the
population on the 4I11/2 state of Er3+ (Figure 49c) and the
subsequent nonradiative relaxation to the 4I11/2 state, yielding
down-shifting NIR emission at 1532 nm of Er3+ via 4I15/2
4
I13/2. Similarly, with the down-shifting energy transfer from
Yb3+, down-shifting NIR emissions can be generated from Ho3+
(Figure 49d, 1185 nm, 5I6 5I8) and Pr3+ (Figure 49e, 1310
nm, 1G4 3H5), except that the down-shifting NIR emission of
Yb3+Tm3+ pairs is based on the two-photon upconversion
4
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Figure 51. Down-shifting NIR emitting nanoparticles for PTT and simultaneous intratumoral thermal reading. (a) Optical image of a nude mouse
with two tumors. The left tumor was treated with LaF3:Nd nanoparticles and laser irradiation, while the right tumor was treated with PBS and laser
irradiation. (b,c) Luminescent and thermal images of the same mouse upon 808 nm laser irradiation, respectively. (d) Diagram of temperature versus
irradiation time. (e) Tumor volume analyses of the two groups at various days after treatment. Reprinted with permission from ref 539. Copyright
process (Figure 49f). When the 3H4 state of Tm3+ is populated,

radiative 3H4 3F4 can occur to produce 1475 nm downshifting NIR emission. It should be noticed that the downshifting NIR emission eciency of Yb3+Ln3+ pairs diers
greatly with the activator ion (Er3+, Ho3+, Tm3+ an Pr3+). Yb3+
Er3+ oers the most ecient down-shifting NIR emissions,
while Yb3+Tm3+ and Yb3+Pr3+ are less ecient due to the
requirement for the upconversion process, and densely
arranged energy states of Pr3+, respectively.
With this advanced imaging probe, a high contrast imaging of

HeLa cells and nude mice was demonstrated.536
Moghe and co-workers realized real-time and multicolor
down-shifting NIR in vivo imaging with NaYF4:Yb,Er and
NaYF4:Yb,Ho nanoparticles.537 As depicted in Figure 50a,b, the
down-shifting NIR emissions of Er3+ were rst observed in the
tail vein immediately following the injection of NaYF4:Yb,Er
NPs (5 s), then in heart and lungs (10 s). Even the heart
beating of the mouse was visualized. Over the course of 60 s
after the injection, the down-shifting NIR signal gradually
enhanced in organs such as the liver and spleen, which was
consistent with the metabolism process monitored by UCL
imaging. In addition, the disease tracking potential of downshifting NIR emitting nanoparticles was evaluated by intravenous injection of the NPs into melanoma-bearing nude mice,
and irregular branching patterns near tumors were observed
shortly after the injection (Figure 50c). NaYF4:Yb,Er and
NaYF4:Yb,Ho nanoparticles with dierent down-shifting NIR
emissions were then injected directly into the tumor sites for
multicolor down-shifting NIR in vivo imaging, and emissions at
1525 nm (Ho3+) and 1175 nm (Er3+) were detected (Figure
50d). Recently, Yan et al. also realized down-shifting NIR in
vivo imaging of nude mouse using NaGdF 4 :Yb,Er@
NaGdF4:Nd,Yb nanoparticles, where the overheating eect
induced by 980 nm irradiation was minimized by the excitation
of an 808 nm CW laser.310 The Nd3+ sensitized NaGdF4@
NaGdF4:Yb,Er@NaYF4:Yb@NaNdF4:Yb nanoparticles developed by Zhang et al. for sensitive in vivo imaging exhibited
great potential for in vivo imaging with deep penetration depth
(18 mm) and low detection thresholds (5 nM for the stomach
of nude mice and 100 nM for the stomach of SD rats).538
Very recently, based on their previous work on LaF3:Nd
down-shifting NIR emission nanoparticles, Jaque and co-
5.2. Near-Infrared Bioimaging and Therapeutic

Applications
LaF3:Nd down-shifting NIR emitting NPs prepared by Jaque

and co-workers aording down-shifting NIR luminescent
images with a high signal-to-noise ratio can be obtained for a
penetration depth close to 1 cm.535 This is considered dicult
for most UCNPs, although it is worth mentioning that
dierences in the experimental settings including the imaging
dose, excitation power density, and the sensitivity of the CCD
camera inevitably lead to dierences in the detected penetration
depth, and therefore it is inappropriate to compare the
penetration depth obtained from dierent works. Female
CD1 mice were further selected as a model to test the imaging
capacity of LaF3:Nd nanoparticles. After subcutaneous, intramuscular and intravenous injection of LaF3:Nd nanoparticles,
respectively, high contrast down-shifting NIR luminescent
images can be obtained with a complete absence of any
background uorescence. To further enhance the down-shifting
NIR emission eciency of Nd3+, Prasad and co-workers
developed the core/shell structured nanoparticles of
NaGdF4:3%Nd@NaGdF4. With the shell about 2.5 nm in
thickness, the quantum yield of the down-shifting NIR
emissions increased from 22% to 40%. Moreover, the downshifting NIR emission lifetime prolonged from 190 to 240 s.
AV
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1/E3) but proportional to the cube of the atomic number (Z)

of an object ( Z3).
Under X-ray irradiation, the hard body parts (such as bones
and hardened tissues), soft tissues (such as blood vessels, brain,
muscles, and tumors), and air cavities in the body can be easily
discerned from each other due to their dierences in
attenuation coecients. In human body, the CT numbers
range from 1000 HU (Hounseld unit) for lungs to 1000 HU
for bones. However, such a dierence in attenuation
coecients between dierent soft tissues is quite subtle, as
the CT numbers of most soft tissues range from 40 to 80 HU.
For this reason, exogenous substances, also know as CT CAs,
are often utilized to produce a reliable contrast. 55% of the CT
scans performed in 2010 involved CAs.543,546 Dierent from
MRI CAs, which indirectly enhance the contrast through
accelerating the relaxation of protons, the X-ray CAs can
directly generate the contrast.
Two types of X-ray CAs have been approved for human:
barium sulfate suspensions (only for gastrointestinal tract
imaging) and water-soluble aromatic iodinated CAs. In fact, the
iodinated CAs used in clinic still have several problems, despite
the great eorts that have been made for their developments in
past few decades.546 Iodine has relatively small atomic number
(Z = 53) and low K-edge value (33.2 keV), resulting in less
ecient attenuation of X-ray in CT scanning. Therefore, to
obtain images with high quality, large doses of iodinated CAs
are required, which may induce adverse eects in patients.547,548
Moreover, these iodinated CAs are excreted through the kidney
rapidly, allowing only short imaging times. Besides, the
nonspecical distribution of these CAs is also undesirable.
6.1.2. Lanthanide Nanoparticles for CT Imaging. To
date, many heavy metal elements (such as Au, Pt, Bi, and Ta)
have been investigated as candidates for CT CAs.549555
Lanthanide nanoparticles have been reported as promising
candidates, because lanthanides have large atomic numbers and
thus big X-ray attenuation coecient values (Table 2), and
workers achieved intratumoral thermal reading during the PTT

process.539 The local temperature was determined by the NIR
emission ratio at 865 and 885 nm. Apart from oering downshifting NIR emissions, Nd3+ is also able to generate heat
through the appropriate choice of Nd3+ doping concentration.540 A nude mouse model with two tumors is employed
with the left tumor injected with 808 nm excited LaF3:Nd NPs
and the right tumor with PBS along with a control group under
808 nm light irradiation (Figure 51a). It was observed that
down-shifting NIR emission signal can be detected for the left
tumor, while the intratumoral temperature can also be
calculated from the emissions ratio of Nd3+ (Figure 51b,c).
Remarkably, the obtained intratumoral temperature was 20%
higher than that measured at the surface (Figure 51d). After the
PTT treatment for 5 days, the tumor volume was signicantly
decreased (Figure 51e).
6. LANTHANIDE NANOPARTICLES FOR DUAL- AND

MULTIMODE IMAGING
When two or more imaging modalities are integrated into one
nanoparticle, the advantages of these imaging modalities are
thus combined. Ln3+ doped nanoparticles are considered as
promising candidates for multimode bioimaging. Most dualand multimode imaging CAs are based on the combination of
UCL imaging with other imaging modalities: on the one hand,
the unique highly ecient anti-Stokes emissions of Ln3+ oer
great opportunities for both in vitro and in vivo UCL imaging;
on the other hand, other imaging modalities including MRI,
CT, SPECT, X-ray imaging, and PET can be realized through
delicate design of UCNPs. It is noteworthy that due to the
intrinsic paramagnetic and X-ray attenuation properties of
lanthanides (e.g., gadolinium), some UCNPs could sever as
dual- and multimode imaging agents without further
modication. Integrated information provided by dierent
imaging modalities can be fused into a single cross-sectional
image via simultaneous (or consecutive) data acquisition and
appropriate image registration. In the following section of this
Review, the application of lanthanides nanoparticles in CT,
SPECT, and PET, as well as the recent progress of dual- and
multimode bioimaging studies, will be introduced.
Table 2. K-Edge Energies and X-ray Mass Attenuation

Coecients for Heavy Elements
6.1. Lanthanide Nanoparticles for X-ray and CT Imaging
6.1.1. Basic Principles of X-ray and CT Imaging. X-ray

imaging (XI) and CT imaging are two widely used diagnostic
techniques in clinic, due to their advantages including wide
availability, noninvasive detection, low cost, high eciency,
deep penetration in biological tissue, and facile imaging
processes.110,541 X-ray imaging provides 2D images, which
can be reconstructed into 3D CT images.542 Although X-ray is
well-known for its superior penetrating power, some X-ray
photons can interact with the object by absorption or
scattering, leading to the attenuation of X-ray. The contrast
in CT images originates from the dierent attenuation
coecients () of various tissues. The coecients of X-ray
attenuation can be dened by I = Ix
0 , where I and I0 are the
intensity of the transmitted and incident X-ray, respectively,
and x is the thickness of the object. Photoelectric eect, which
involves the interaction between X-ray photons and the innershell electrons of objects, is the most dominant factor for X-ray
attenuation.543545 In general, the X-ray attenuation manifests
itself only when the photon energy (E) is higher than the
binding energy of electrons, and the coecient value is
inversely proportional to the cube of the photon energy (
AW
element
atomic
number (Z)
K-edge
energy (keV)
X-ray mass attenuation coecient at

100 keV (cm2 g1)
I
Ba
La
Ce
Pr
Nd
Pm
Sm
Eu
Gd
Tb
Dy
Ho
Er
Tm
Yb
Lu
Ta
Pt
Au
Bi
53
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
73
78
79
83
33.2
37.4
38.9
40.4
42.0
43.6
45.2
46.8
48.5
50.2
52.0
53.8
55.6
57.5
59.4
61.3
63.3
67.4
78.4
80.7
90.5
1.94
2.20
2.32
2.44
2.59
2.69
2.84
2.90
3.04
3.11
3.25
3.36
3.49
3.63
3.78
3.88
4.03
4.30
4.99
5.16
5.74
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their unique uorescent and magnetic properties are excellect

for multifunctional purposes. Among all of the lanthanide
elements, gadolinium has been most intensively studied
because it can be used for both T1-weighted MRI CAs and
host matrix of UCNPs. The X-ray attenuation properties of
dierent Gd-based nanoparticles, with Gd as either the matrixes
(Gd2O3,125 GdF3,173 NaGdF4,556,557 GdVO4,189 and Gd(IO3)3
H2O,193 etc.) or the dopants,116,117 have been well studied.
Yb has the second largest atomic number among lanthanides,
and is well-known for its uorescent properties. Yb-based
nanoparticulate CT CAs were rst reported by Lu and coworkers (Figure 52), where the synthesized Er doped NaYbF4
nanoparticles were modied with PEG.558 The great advantage
of Yb is its proper K-edge energy (61 keV), which locates just
within the higher-energy region of the X-ray spectrum used in
clinical CT (120 kVp). Qu and co-workers synthesized
PEGylated Yb2O3:Gd nanoparticles as nanoprobes for CT
and MRI imaging.559 Other Ln3+ (such as La3+, Dy3+, and
Lu3+)-based nanoparticles, with La and Lu as the host matrixes
for photoluminescence and Dy for the T2 relaxation enhancement in addition to their X-ray attenuation properties, have also
been studied.252,560563
The operating voltage in clinical CT examination ranges
from 80 to 140 kVp according to the patient, and dierent
metal elements show distinctive changes in their X-ray
attenuation coecients with varying voltage. CT CAs
containing a single contrast element cannot be tailored to
meet the clinical requirement of changing voltage. Binary CT
CAs, which contain two elements that show X-ray attenuation
properties,544,564 aord great advantages over single CT CAs.
For insance, Yb and Ba have dierent K-edge values (61 and 37
keV for Yb and Ba, respectively),565,566 allowing BaYbF5
nanoparticles to maintain high X-ray attenuation at dierent
operation voltages (Figure 53).
6.2. Lanthanide Nanoparticles for PET and SPECT
6.2.1. Basic Principles of PET and SPECT. PET and

SPECT are two radionuclide-based imaging techniques, where
the images are acquired by the collection of photons
produced from radioactive isotopes, and the subsequent
distribution mapping.542,567 In a typical PET process, after
the positron-emitting radionuclide (such as 18F, 11C, 15O, 13N,
124
I, and 68Ga) is injected into the body, the radioisotope emits
a positron. This positron interacts with an electron, and the
following annihilation makes a pair of photons. SPECT, on
the other hand, uses radionuclides (99mTc, 131I, 123I, and 111In)
that directly emit photons. The major advantage of PET and
SPECT is their high sensitivity, that is, a measurable signal that
can be obtained with only picomolar concentration of
radiotracers, while MRI and CT are several orders of magnitude
less sensitive. Although both PET and SPECT can provide
information about molecular processes exquisitely, the missing
anatomic information and low spatial resolution are the main
drawbacks.110 Hence, to provide anatomical and physiological
information at the same time, PET and SPECT are usually
integrated with MRI and CT (e.g., PET/CT, SPECT/MRI, and
PET/MR).568570
6.2.2. Lanthanide Radionuclides for SPECT. For
SPECT, the radionuclides should meet several criteria such as
relatively long physical half-life, suitable gamma energy range,
and stable daughter radionuclides.571 99mTc, a commonly used
radionuclide, has a physical half-time of 6 h and photon
energy of 140 keV. In addition to 99mTc, 111In (major photon
Figure 52. (a) Schematic illustration of the synthesis and surface

modication of OA-stabilized NaYbF4:Er NPs. (b) CT value (HU) of
PEG-NaYbF4:Er NPs (red square) and iobitridol (black circles) as a
function of the concentration of Yb (red trace) and I (black trace),
respectively. (c) CT images of solutions of PEG-NaYbF4:Er NPs and
iobitridol with dierent concentrations of Yb and I, respectively. (d) In
vivo CT coronal view images of a rat after intravenous injection of 1
mL of PEG-NaYbF4:Er NPs (70 mg Yb mL1) solution at timed
intervals (a, heart and liver; b, spleen and kidney; c and d, the
corresponding 3D renderings of in vivo CT images). Reprinted with
Co. KGaA.
lines at 171 and 245 keV) is another isotope especially suitable

for long-term tracking, due to its suciently long half-life (68
h). A large class of radionuclides, the lanthanide radioisotopes,
have disparate nuclear properties and could be used as SPECT
AX
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emitting lanthanides can also be useful for radioisotope

therapy.573
In recent years, Ln3+-based nanomaterials have been used as
imaging agents due to their unique optical, electronic, and
magnetic properties. However, one major concern in their in
vivo applications is their circulation and distribution in body.574
The radionuclide can be used to track these nanomaterials. For
example, Li and co-workers investigated the long-term in vivo
distribution of 153Sm-labeled Gd(OH)3 nanorods using SPECT
imaging (Figure 54).575 Through time-resolved SPECT
Figure 54. (ad) In vivo SPECT/CT images of the mouse acquired 1

h after intravenous injection of 153Sm doped Gd(OH)3 nanorods. (a)
Whole-body 3D projection, (b) coronal, (c) sagittal, and (d) transveral
images are shown, respectively. The arrows inset point to the lung
(Lu), liver (Li), and spleen (S). (e) SPECT/CT images of the mouse
at dierent time points postinjection of 153Sm-doped Gd(OH)3
nanorods. Reprinted with permission from ref 575. Copyright 2013
Elsevier B.V.
Figure 53. (a) In vitro CT images of BaYbF5@SiO2@PEG, NaYbF4@

PEG, and iobitridol with dierent concentrations. (b) CT values (HU)
of BaYbF5@SiO2@PEG, NaYbF5@PEG, and iobitridol as a function of
the agent concentration at 120 kVp, respectively. (c) CT values of the
BaYbF5@SiO2@PEG and iobitridol with dierent concentrations
determined at various voltages. (df) in vivo CT imaging. (d and e)
Coronal view images of a rat after intravenous injection of BaYbF5@
SiO2@PEG (800 L, 0.2 M of BaYbF5) solution at timed intervals (d,
heart and liver; e, spleen and kidney). (f) The corresponding 3Drenderings of in vivo CT images. (gj) In vivo blood pool CT
imaging. (g and i) Coronal view images of a rabbit collected at 10 min
after intravenous injection of BaYbF5@SiO2@PEG solution. (h and j)
The corresponding 3D-rendering of in vivo CT images. The arrows
indicate several great vessels: (1) auricular vein, (2) jugular vein, (3)
carotid artery, (4) subclavian vein, (5) axillary vein, (6) aortic arch, (7)
inferior vena cava, and (8) aorta. Besides, the atrium and ventricle are
also clearly distinguished from each other. Reprinted with permission
from ref 566. Copyright 2012 Wiley-VCH Verlag GmbH & Co. KGaA.
imaging, they found the uptake and retention of the Gd(OH)3

nanorods took place primarily in the liver, spleen, and lung.
Because of their similar atomic radii and chemical properties,
153
Sm can be readily doped into other Ln3+-based matrixes to
form the 153Sm-labeled nanoparticles.576579 Another labeling
method, cation-exchange-based post labeling method, has also
been developed by Li and co-workers.580,581
6.3. Lanthanide Nanoparticles for UCL-Based Dual-Mode
Imaging
6.3.1. UCL/MRI Dual-Mode Imaging. For nanoparticles

with UCL/MRI dual imaging modalities, the high detection
sensitivity and planar resolution at cellular and subcellular level
of UCL imaging, and the excellent spatial resolution and
penetration depth of MRI were combined. Gao and co-workers
imaging agents, such as 153Pm, 153Sm, 166Dy, 166Ho, 175Yb, and

177
Lu.568,572 Except for applications in bioimaging, photonAY
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Figure 55. UCNPs for UCL/MRI dual-mode imaging. (ac) UCL and uorescence imaging of glioblastoma-bearing brain in 1 h postinjection with
ANG/PEG-UCNPs (a), PEG-UCNPs (b), and 5-ALA (c). (df) In vivo MRI in glioblastoma-bearing mice pre- and postinjection of ANG/PEGUCNPs (d), PEG-UCNPs (e), and Gd-DTPA (f) at various time points. Reprinted with permission from ref 583. Copyright 2014 American
Chemical Society.
the nanoparticles were mainly accumulated in the liver and

spleen parts. Meanwhile, T2-weighted MRI images indicated
that the MRI signal was negatively enhanced after intravenous
injection, which agreed with the UCL imaging results.
6.3.2. UCL/CT Dual-Mode Imaging. For nanoparticles
with UCL/CT dual imaging modalities, the UCL signals and
the outstanding anatomical information from CT can be
obtained. As mentioned, due to the high atomic number of
lanthanide elements, Ln3+-based UCNPs are considered as
excellent CAs for CT imaging. Lu and co-workers found high
performance of NaYbF4:Gd,Er nanoparticles for UCL and CT
imaging in vivo.585 The upconversion emission proles
exhibited promising UCL imaging capacity, while CT imaging
results can convey the anatomical information. A clear signal
enhancement in the heart and vessels of the mouse can be
observed within 20 min. After 1 h, the enhancement decreased
rapidly. By contrast, the signals for liver and spleen enhanced
and continued for over 2 h.
Cui and co-workers prepared FA-modied LaF3:Yb,Tm@
SiO2 nanoparticles to realize dual-mode lymphatic UCL and
CT imaging, as well as tumor targeting at the same time.586
When the UCNPs were intradermally injected into the right
paw of a mouse, a clearly distinguished upconversion emission
signal can be observed at the corresponding lymphatic node.
Meanwhile, the lymphatic site displayed an enhanced positive
contrast as compared to other soft tissues, which was attributed
to the strong X-ray attenuation induced by UCNPs. Moreover,
signicant upconversion signals can be detected at the tumor,
which was implanted and grown from gastric cancer MGC-803
cells (folic acid positive), indicating the successful targeting of
the UCNPs.
Li and co-workers employed NaLuF4:Yb,Tm nanoparticles
for in vivo lymphatic imaging utilizing their UCL and CT dual
imaging modality.587 The NaLuF4:Yb,Tm nanoparticles were
injected intradermally into the right hind limb of a mouse.
Thirty minutes later, intense UCL signals can be observed from
prepared NaGdF4:Yb,Er nanoparticles for UCL/MRI dualmode imaging of tiny tumor in vivo,582 where the Yb3+Er3+
pairs are responsible for generating UCL signals and the Gdbased host matrixes can work as excellent T1-weighted MRI
CAs. The subcutaneously and intraperitoneally transplanted
tumors can be successfully detected by UCL imaging and MRI.
Quite outstandingly, subcutaneous tumors as small as 1.7 1.9
mm were clearly identied by UCL imaging. Bloodbrain
barrier (BBB), which is one of the most exclusive biological
barriers, limits the intracephalic uptake of nanoparticles.
Recently, Shi and co-workers realized dual UCL/MRI
targeting of intracranial glioblastoma across the BBB (Figure
55).583 In this study, NaYF4:Yb,Er,Gd@NaGdF4 nanoparticles
were used to oer UCL imaging and T1-weighted MRI capacity.
Angiopep-2 (ANG) molecules, which can specically bind to
the low density lipoprotein receptor related protein (LRP)
overexpressed on both BBB and glioblastoma cells, were
employed as dual-targeting ligand. From the UCL imaging and
MRI results, it can be found that the ANG-modied UCNPs
(ANG/PEG-UCNPs) exhibited great potential in preoperative
diagnosing and intraoperative positioning the brain tumors by
UCL imaging and MRI, exhibiting more excellent imaging
performances as compared to clinically used Gd-DTPA and 5ALA (5-aminolevulinic acid). Except for T1-weighted MRI, T2weighted MRI modality has also been introduced into UCNPs.
In another recent study, Tan et al. developed a series of dualmode imaging NaDyF4:Yb@NaGdF4:Yb,Er nanoparticles,
where the Yb3+ and Er3+ together aord upconversion
emissions, while Dy3+ and Gd3+ in the host matrixes work as
T2 and T1 CAs.254 The nanoparticles were observed to give
excellent negative T2 enhancement in the MRI images of mice,
and tunable positive or negative T1 enhancement. Another
method to achieve MRI modality is incorporating transition
metal ions. For example, Shen and co-workers doped Co2+ into
NaYF4:Yb,Tm UCNPs to provide both T2-weighted MRI and
UCL imaging capacities.584 In vivo UCL imaging showed that
AZ
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Figure 56. UCNPs for UCL/CT dual-mode imaging. (a) In vivo UCL imaging of the lymphatic vessel with NaLuF4:Yb,Tm UCNPs. (b) 3D
rendering CT, (c) raw CT, and (d) high-resolution CT imaging of the lymphatic vessel. Reprinted with permission from ref 587. Licensed under CC
BY-NC-ND 3.0.
the lymph vessel (Figure 56a). Meanwhile, CT lymphography

can oer accurate localization. To further study the in vivo CT
imaging capacity, the mouse that had undergone UCL imaging
was then subjected to CT imaging. From the CT imaging
results shown in Figure 56b,c, comprehensive perception of the
anatomy of the lymphatic pathway can be observed.
Furthermore, the high-resolution CT imaging revealed more
information by observation from dierent sides (Figure 56df).
6.3.3. UCL/SPECT Dual-Mode Imaging. For nanoparticles with UCL/SPECT dual imaging modalities, true 3D
images with high sensitivity can be provided by SPECT imaging
modality, which works synergistically with UCL imaging in
vivo. With the dual imaging modalities of UCL and SPECT, the
biodistribution and metabolism processes can be well visualized
in vivo. Typically, 153Sm is the most frequently used
radioisotope for SPECT studies.
For example, Li and co-workers introduced 153Sm into the
lattice of NaLuF4:Yb,Tm UCNPs to endow the 153Sm-UCNPs
with dual imaging modality of UCL and SPECT, and studied
the biodistribution and metabolism processes of these UCNPs
in vivo.580 1 h after intravenous injection of 153Sm-UCNPs
(20 nm), UCL signals can be signicantly found to be located
in the liver and spleen parts (Figure 57ac). Meanwhile, 153Sm
signals were detected from the in vivo SPECT images (Figure
57dg), which veried the UCL signals and excluded the
signals were from isolated 153Sm ions. Furthermore, long-term
biodistribution was monitored. It was found that the 153Sm
signal from liver reached a maximum at about 4 h postinjection,
and maintained the maximum value for 8.5 h. For the spleen, its
153
Sm signal enhanced quickly beyond 4 h and reached a
maximum at 8.5 h, more intense than that from liver, which
may contribute to the spleen being the largest organ of the
immune system. With time further increased, the signals from
both the liver and the spleen parts decreased. Therefore, the
153
Sm-UCNPs were prone to be excreted from the body,
although the excretion was slow. Moreover, the radioactive
signal was very low in urine and bladder, indicating the
excretion pathway was not amenable to renal excretion. By
contrast, a signicant 153Sm signal was found in intestine,
indicating that the main excretion pathway was biliary secretion
of 153Sm-UCNPs to the intestine and nally excretion with the
feces. Later, the authors noticed particle size-dependent
biodistribution and metabolism processes using dual-mode
UCL and SPECT imaging. When the particle size was sub-10
nm, the excretion pathway was quite distinctive.579 After
intravenous injection of sub-10 nm 153Sm-UCNPs, radioactive
Figure 57. UCNPs for UCL/SPECT dual-mode imaging. (ac) In

vivo UCL imaging 1 h postinjection of 153Sm-UCNPs. (dg) In vivo
SPECT imaging after intravenous injection of 153Sm-UCNPs at
dierent time point. Reprinted with permission from ref 580.
Copyright 2013 Elsevier B.V.
signal of 153Sm can be measured in the bladder during the

period from 0.5 to 6 h. Moreover, 153Sm-UCNPs were found in
the kidney and urine, with a lower level in the small intestine
and large intestine, indicating the prominent renal excretion.
Beyond that, the authors also realized blood pool imaging using
153
Sm-UCNPs.578 A clear upconversion emission signal can be
observed in blood 5 min postinjection of 153Sm-UCNPs. With
respect to the organs, strong UCL signals can be detected from
liver and spleen, which was consistent with the just mentioned
results. Moreover, intense radioactive signals can be detected in
the blood during the rst 30 min postinjection with SPECT
imaging. The carotid artery, vertebral arteries, and superior
epigastric artery of the mouse can be clearly visualized,
indicating the high resolution of SPECT imaging.
6.3.4. UCL/X-ray Dual-Mode Imaging. For nanoparticles
with UCL/X-ray dual imaging modalities, the synergistic
advantages can also be combined with high detection sensitivity
BA
Chemical Reviews
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Figure 58. UCNPs for UCL/PET dual-mode imaging. (ac) In vivo UCL imaging of mouse at 5 min after intravenous injection of NaYF4:Yb,Tm
UCNPs. (dg) In vivo micro-PET imaging of mouse from the whole-body (d), transverse (e), coronal (f), and sagittal (g) view at 5 min after
intravenous injection of 18F-NaYF4:Yb,Tm UCNPs. Reprinted with permission from ref 589. Copyright 2011 Elsevier B.V.
Table 3. Typical Dual-Mode in Vivo Imaging Studies with UCNPs
imaging modalities
composition of UCNPs
surface modication
biological model
ref
UCL/MRI
UCL/MRI
UCL/MRI
UCL/MRI
UCL/MRI
UCL/MRI
UCL/MRI
UCL/CT
UCL/CT
UCL/CT
UCL/CT
UCL/SPECT
UCL/XI
NaGdF4:Yb,Er@NaGdF4:Yb
NaYF4:Yb,Tm@NaGdF4
CaF2:Gd,Yb,Tm
NaYF4:Yb,Er,Tm
NaYF4:Yb,Er,La
Fe3O4@NaGdF4:Yb,Er
Fe3O4@LaF3:Yb,Er
Yb2O3:Er
BaYbF5:Er
BaGdF5:Yb,Er
NaGdF4:Yb,Er
NaLuF4:153Sm,Yb,Er
BaLaF5:Mn,Yb,Er
SiO2, PEG
SiO2
citrate
Gd-DOTA,a RGD
Gd-DTPA, PEG
PEG
PAA
PEG
RGD
PEG
EDTA
6-AA
SDSb
tumor imaging
zebra sh imaging, tumor imaging
biodistribution
tumor imaging
biodistribution
cell, tissue imaging
biodistribution, tumor imaging
biodistribution
tumor imaging
biodistribution
tumor imaging
biodistribution
biodistribution
591
592
115
593
594
255
595
596
565
597
598
576
599
Gd-DOTA refers to gadoterate meglumine. bSDS refers to sodium dodecylsulfate.
imaging.589 From the UCL imaging results (Figure 58ac), an

intense upconversion emission signal can be collected from the
liver and spleen parts as they were the main organs for
eliminating foreign particles. Meanwhile, signicant radioactive
signals were detected exclusively in the liver and spleen, which
conrmed the UCL imaging results. Moreover, the ex vivo
biodistribution studies also showed the accumulation of
UCNPs in liver and spleen (Figure 58dg). The above results
indicated that 18F-UCNPs can be used as radiotracers for realtime tracking with high sensitivity in vivo for bioimaging. With
18
F-UCNPs, the authors also achieved in vivo lymphatic
imaging.590
Aside from the aforementioned dual-mode imaging systems,
many other investigations on the UCL/MRI, UCL/CT, UCL/
SPECT, and UCL/XI featured nanoplatforms have also been
reported. In Table 3, we summarized recent published works
that highlighted the synergistic imaging with UCL and other
imaging modalities. Form these studies, it can be found that the
high sensitivity, high resolution, and true 3D anatomical
information can be integrated into the UCNPs simultaneously,
which are quite important for understanding the biodistribution
and metabolism processes of nanoparticles in vivo and
extended biotherapy studies.
and high resolution. Ln3+ ions, with high K-edge values, exhibit
high X-ray mass absorption coecients. Therefore, Ln3+-based
UCNPs can work as eective agents for XI studies. It is worth
noting that heavy lanthanide elements, such as Yb and Lu, are
more suitable for XI due to higher X-ray mass absorption
coecients. Zeng and co-workers prepared PEG-modied
NaLuF4:Yb,Er UCNPs for synergistic UCL/XI study.588 A
Kunming mouse was injected subcutaneously with UCNPs and
underwent simultaneous UCL and XI. As compared to the
untreated mouse, high-contrast X-ray absorption signals were
observed in regions that were injected UCNPs. Meanwhile,
intense UCL signals can be detected in the same sites upon
NIR excitation. Beyond subcutaneous imaging, long-term
biodistribution and metabolism processes were examined.
Through UCL measurements, it was found that the UCNPs
were rst accumulated in the lung and gradually transferred to
the liver and spleen, which was further veried with ex vivo
imaging. Recently, the same research group prepared
BaLuF5:Gd,Yb,Er UCNPs for dual-modal in vivo UCL imaging
and XI.564 In these UCNPs, Ba2+ ions also contributed to X-ray
mass absorption besides Ln 3+ ions. As expected, the
BaLuF5:Gd,Yb,Er UCNPs exhibited excellent UCL imaging
and XI results.
6.3.5. UCL/PET Dual-Mode Imaging. For nanoparticles
with UCL/PET dual imaging modalities, the detection
sensitivity can be signicantly enhanced to picomolar due to
the incorporation of PET imaging. 18F is an excellent
radioisotope that can be easily labeled on uoride-based
UCNPs. Li and co-workers prepared 18 F-UCNPs and
investigated their biodistribution in vivo with UCL and PET
6.4. Lanthanide Nanoparticles for Multimode Imaging
Motivated by the excellent synergistic eects from various

imaging modalities, in recent years, UCNPs that are capable of
oering multiple imaging modalities have been developed.
UCNPs with UCL/MRI/CT triple modalities dominated the
multimode in vivo imaging studies. In addition, many other
BB
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Figure 59. UCNPs for trimode imaging. (a,b) In vivo and ex vivo UCL imaging dissected mouse and organs after intravenous injection with
NaYbF4:Ho UCNPs at 2 h. (c) In vivo T2-weighted MRI images of coronal view of the liver of mouse before and at various time points after
intravenous injection of UCNPs. (d) In vivo CT coronal images and 3D rendering CT image of mice after intravenous injection of UCNPs at
dierent time points. (e) In vivo T2-weighted MRI of glioblastoma-bearing mice before and at various time points after intravenous injection of
UCNPs. Reprinted with permission from ref 603. Copyright 2014 Wiley-VCH Verlag GmbH & Co. KGaA.
Fe3O4@NaLuF4:Yb,Er nanocomposites,600 and greatly enhanced upconversion emission, T2-weighted MR, and 3D
rendering CT signal in the tumor site were demonstrated.
Aside from in situ injection, intravenous injection has also
been performed to study the biodistribution, tumor, and
lymphatic imaging with UCL/MRI/CT trimode imaging CAs.
Lin and co-workers observed intense UCL signals and
signicant contrast enhancement in the liver and spleen parts
of a Kunming mouse with gelatin-modied BaGdF5:Yb,Er@
BaGdF5:Yb UCNPs after intravenous injection.601 Meanwhile,
in vitro CT measurements exhibited promising CT imaging
capacity. With proper design, Shi and co-workers developed a
novel category trimode imaging agent of NaYF4:Yb,Er,Tm@
NaGdF4@TaOx (x 1), where TaOx was uorescence
transparent and thus can be used as excellent CT CAs.602 As
a result, trimode in vivo imaging was successfully achieved. In
vivo UCL imaging indicated that the nanoparticles were
accumulated in the liver and spleen parts, which was in
excellent agreement with the MRI and CT imaging results.
Moreover, in this study, the nanoparticles were found to
possess both T1- and T2-weighted imaging capacity.
Very recently, a series of trimode imaging CAs of lipidic lm
capped NaYbF4:Ho, where Ho3+ can provide ecient T2
weighted MRI, were developed.603 Through the biodistribution
analysis, it was found that the UCNPs were mainly accumulated
combinations have been reported, such as UCL/MRI/PET,

UCL/CT/XI, and UCL/MRI/XI-based trimode imaging, and
UCL/MRI/CT/XI and UCL/MRI/CT/SPECT-based fourmode imaging.
When UCL/MRI/CT triple imaging modalities are
integrated into one type of nanoparticles, they are endowed
with plenty of merits including high detection sensitivity, no
limitation for penetration depth, and outstanding anatomical
resolution. For example, Lin and co-workers prepared PEImodied NaGdF4:Yb,Er nanoparticles, in which Yb3+Er3+
pairs are ecient for yielding upconversion emissions, Gd3+based host matrixes can be sued MRI imaging, and the overall
Ln3+ ions are responsible for CT imaging.562 A tumor bearing
nude mouse was employed as a model to test the trimode
imaging capacity. Intense green emission, positive contrast
enhancement, and enhanced CT signal were imaged, suggesting
the feasibility of multifunction imaging applications. Shi and coworkers reported PEG-modied NaYF4:Gd,Yb,Er,Tm@SiO2
Au nanoparticles.557 In these nanocomposites, both RE and Au
elements can attenuate X-ray due to their high X-ray absorption
coecients. As the nanocomposites were subcutaneously
injected into the tumor, prominent upconversion emissions,
enhanced T1-weighted MRI signals, and CT signals can be
observed at the tumor site. Except Gd3+-based MRI imaging,
Fe3O4 was also adopted for trimode tumor imaging with
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Figure 60. (a) Unit cell of the CeO2 structure, and (100) [or (200)], (110), and (111) planes of the CeO2 structure. (b) Schematic of the standard
picture of charge redistribution following the formation of an oxygen vacancy in CeO2. (a) Reprinted with permission from ref 609 Copyright 2003
American Chemical Society. (b) Reprinted with permission from ref 610. Copyright 2012 IOP Publishing.
in the liver from the UCL signals, T2-weighted MRI images,

and 3D rendering CT images (Figure 59ad). Moreover,
glioblastoma bearing mice were selected to test the tumor
imaging feasibility. As depicted in Figure 59e, the T2-weighted
MR signal intensity remarkably reduced 15 min postinjection
and was maintained for 2 h. Li and co-workers fabricated GdDTPA coated NaLuF4:Yb,Tm@SiO2 nanoparticles for their
biodistribution assessments.561 Similar to the results from the
previous investigations, liver and spleen uptake occurred.
Aiming at realizing in vivo lymphatic imaging, sodium
glutamate and DTPA comodied NaLuF4:Gd,Yb,Tm UCNPs
were obtained.563 When the UCNPs were injected intradermally into the right paw of the mouse, an intense
upconversion emission signal can be detected from the sentinel
lymph node. Meanwhile, signicant contrast enhancement in
the lymph node was also observed from T1-weighted MR and
CT imaging results.
For nanoparticles with UCL/MRI/PET trimode imaging
modalities, ultrahigh detection sensitivity and high spatial
resolution can be integrated. Li and co-workers developed 6AA-modied 18FGdNaYF4:b,Er UCNPs, where Gd3+ ions
were introduced by cation exchange.604 With these UCNPs, the
authors studied the biodistribution process. Ten minutes
postinjection of UCNPs, intense upconversion emissions can
be detected from the liver and spleen. As compared to the MRI
image preinjection, signicant contrast enhancement in the
liver and spleen can be found. Moreover, intense radioactive
signals were observed exclusively in the spleen and tumor from
the in vivo PET imaging. In addition, citrate-modied 18FNaYF4:Gd,Yb,Er UCNPs were also prepared to monitor the
biodistribution and metabolism process.605 Similarly, accumulation of UCNPs in the liver and spleen parts was also noticed.
Beyond the trimode imaging mentioned above, ligand-free
NaErF4:Yb227 and PEI coated BaYF5:Yb,Er606 UCNPs were
developed for trimode UCL/MRI/XI and UCL/CT/XI,
respectively. PAA coated NaYF4:Gd,Yb,Er607 and citratemodied 153Sm-NaLuF4:Yb,Tm@NaGdF4 UCNPs608 were
prepared for four-mode UCL/MRI/CT/XI and UCL/MRI/
CT/SPECT imaging, respectively. These nanoparticles with

multimode imaging capacity are quite ecient and convenient
for monitoring the biodistribution and tumor diagnosis.
7. NANOCERIA FOR NANOMEDICINE

Ceria has the uorite crystal structure with space group Fm3m
(Figure 60a), each Ce4+ cation in the middle of a cube with
eight nearest-neighbor O2 anions as the corners, while each
O2 anion is surrounded by a tetrahedron with Ce4+ cations as
the corners. The (100), (110), and (111) planes are also shown
in Figure 60a, with the (111) planes as the most stable surface
for having the highest density of surface atoms and the lowest
surface energy.609
The oxygen vacancies result from the intrinsic defects in the
lattice of CeO2, where the loss of an oxygen atom provides two
electrons that can fully localize on two of the four equivalent
Ce4+ ions. These two Ce4+ ions are thus reduced to Ce3+ ions,
and this process can be written in the following KrogerVink
notation:
Oo + 2CeCe = 1/2O2 + V o + 2CeCe
(4)
4+
where CeCe is a Ce cation on a Ce lattice site, OO is an O2

anion on an O lattice site, CeCe is a Ce3+ occupying the site
normally occupied by a Ce4+, and V o represents the O2
vacancy produced by the release of O 2 . The charge
redistribution following the formation of an oxygen vacancy
in CeO2 can be illustrated in Figure 60b.610
Beneting from the coexistence and facile reversible
conversion of Ce4+/Ce3+ couples, CeO2 nanoparticles have
been extensively used as catalysts, and more recently as mimic
natural enzymes for promising biomedicine and bioanalysis
applications. In the following section of this Review, a
comprehensive introduction to potential antioxidant mechanisms, key factors in the activities of nanoceria, and applications
are presented.
7.1. Roles of Reactive Oxygen/Nitrogen Species in Diseases
Reactive oxygen species (ROS) is a collective term that includes

both oxygen-derived free radicals611 such as superoxide (O2),
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Figure 61. (a) A model of the reaction mechanism for the oxidation of hydrogen peroxide by nanoceria and the regeneration via reduction by
superoxide. (b) A model of the reaction mechanism for the complete dismutation of hydrogen peroxide. Reprinted with permission from ref 622.
Copyright 2011 Royal Society of Chemistry.
hydroxyl radical (OH), and nonradical oxygen derivatives of

high reactivity such as singlet oxygen (1O2), hydrogen peroxide
(H2O2), and ozone (O3). ROS and reactive nitrogen species
(RNS) are necessary to living systems at low/moderate
concentrations. However, excessive free radicals may induce
high oxidative stress that can damage cell structures, nucleic
acids lipids, and protein.612 Many acute and chronic diseases,
such as cancer,613 neurological disorders,614 diabetes,615
ischemia/reperfusion, 616 chronic inammation, 617 and
aging,618 are related to molecular and cellular damage induced
by oxidative stress. However, the principles of the traditional
enzymatic and nonenzymatic antioxidants-based therapies in
clinics are rather ambiguous. Therefore, more eective and
controllable new antioxidant agents are required to evaluate
their biological activities in oxidative stress diseases.619,620
Ce3 + + H 2O2 + H+ Ce 4 + + OH + H 2O
(7)
OH + H 2O2 HO2 + H 2O
(8)
Ce3 + + HO2 O2 + Ce3 + + H+
(9)
38
Lee et al. conrmed that antioxidant properties of ceria

nanocrystals proceed through a Fenton type process, as 2 mol
of H2O2 reacted with each mole of Ce3+. Celardo et al.622
proposed a possible route for the regeneration of nanoceria and
combined it with the mechanism of the reactions of CeO2 with
superoxide/H2O2 in an attempt to explain the ideal antioxidant
behavior of nanoceria (Figure 61).
Recently, Xue et al. provided strong evidence for the
hydroxyl radical (OH) scavenging activity of CeO2 nanoparticles.623 The size and Ce3+ at the surface of the particles
were found to play an important role in determining their
hydroxyl radical scavenging activity. Smaller size and larger
Ce3+ concentration at the surface result in better scavenging
capabilities. The OH scavenging ability of CeO2 of dierent
morphologies was also studied, and it was observed that all of
the samples could protect DNA from the damage caused by
hydroxide radicals in a pH 7.4 or 4.7 solution.624
The eect of Ce3+/Ce4+ ratio on the nitric oxide radical
(NO) scavenging ability of nanoceria was investigated by
Dowding et al.625 It was found that CeO2 nanoparticles with a
lower Ce3+/Ce4+ ratio are better NO scavengers. However, it
was also discovered that CeO2 nanoparticles signicantly
accelerated the decay of ONOO regardless of the Ce3+/
Ce4+ ratio on the surface.626
7.2. Potential Antioxidant Mechanisms of Nanoceria
The redox potential of nanoceria favors the cycling of cerium to

scavenge a variety of ROS and RNS. It has been reported that
nanoceria exhibit superoxide dismutase (SOD) mimetic
activity, catalase mimetic activity, hydroxyl radical, and nitric
oxide radical (NO) scavenging activity.
In 2007, Korsvik et al.35 rst reported that CeO2 nanoparticles can eciently scavenge superoxide radicals. SOD
activity assay indicted that a single ceria nanoparticle was more
ecient than an authentic enzyme molecule. The dismutation
of superoxide by ceria nanoparticles could be described with the
following equations:
O2 + Ce 4 + O2 + Ce3 +
(5)
O2 + Ce3 + + 2H+ H 2O2 + Ce 4 +
(6)
7.3. Key Factors Inuencing the Antioxidant Properties of

Nanoceria
They further suggested that the surface oxidation state of

nanoceria plays an integral role in the SOD mimetic activity of
nanoceria. A decrease in the Ce3+/Ce4+ ratio at the surface of
nanoceria can directly lead to a loss of SOD mimetic activity.36
Pirmohamed et al. have found that CeO2 nanoparticles
exhibit catalase mimetic activity.37 However, nanoceria with a
higher ratio of Ce3+ are usually inecient catalase mimetics.
Heckert et al.621 hypothesized that cerium ions might react with
H2O2 through an analogue of the Fenton/HarborWeiss
reaction:
Several factors can aect the antioxidant applications of

nanoceria, such as the physiochemical properties of the
nanoceria themselves, surface modication with various coating,
and the composition of the biological environment (buer
species, pH conditions, etc.). In this section, the most
important factors inuencing the antioxidant properties of
CeO2 nanocrystals are discussed in detail.
7.3.1. Eects of Particle Size. The concentration of
oxygen vacancies or Ce3+ on ceria surfaces, which is dependent
on the size of ceria nanoparticles, can have a signicant
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Figure 62. (a) Polymer-coated nanocerias cell internalization, localization, and proposed toxicity mechanism. (b) Autocatalytic activity of dextrancoated nanoceria at physiological and acidic pH. (a) Reprinted with permission from ref 631. Copyright 2010 American Chemical Society. (b)
Reprinted with permission from ref 87. Copyright 2010 Wiley-VCH Verlag GmbH & Co. KGaA.
results suggest that both antioxidant activities and cytotoxic

eects should be considered when fabricating dierent CeO2
nanostructures with dierent morphologies for biological
applications.
7.3.3. Eects of Surface Charge. Surface charge also plays
a key role in antioxidant applications of nanoceria, as it aects
the adsorption of ions and biomolecules and may subsequently
change the biodistribution of nanoceria. For instance, Asati et
al.630 engineered a series of CeO2 nanoparticles coated with
either poly(acrylic acid), aminated poly(acrylic acid), or
dextran. They found that their cell internalization and
subcellular distribution depends on the surface charge of the
nanoparticles. Positively or negatively charged nanoceria
exhibited signicant toxicity when they localized in the
lysosomes of cancer cells, while nanoceria with a neutral
surface did not induce cellular damage (Figure 62a).
Tuning the surface charge of nanoparticles is very signicant
for dening its protein adsorption and the following cellular
uptake. For instance, Vincent et al.631 found that the higher is
the surface charge of CeO2 nanoparticles, the stronger is the
transferrin adsorption. Furthermore, transferrin-conjugated
nanoceria can be preferentially internalized by normal and
cancer cells via ligandreceptor-mediated endocytosis.
7.3.4. Eects of Surface Coatings. Polyethylene glycol
(PEG) has been used extensively for coating nanoparticles due
to their good biocompatibility. Karakoti et al.88 developed an
eective wet chemical route to synthesize CeO2 nanospheres
directly in PEG solution. PEGylation can tune the regeneration
of Ce3+. Perez et al.87 reported that dextran coating can not
only improve the water solubility and reduce the toxicity of
CeO2, but also enable a unique pH-dependent antioxidant
activity (Figure 62b). The dextran-coated nanoceria showed
irreversible autocatalytic behavior in the acidic tumor microenvironment, but protected normal cells from oxidative
damage. Water-soluble chitosan-coated nanoceria was obtained
using a similar wet chemical method. Chitosan coating can
stabilize particles in high pH environments, extending the
application range of nanoceria in the bioantioxidant eld.632
Liu et al.633 obtained apoferritin-encapsulated CeO2 nanoparticles via a dissociationreconstruction route. The apoferritin-CeO2 nanotrue showed more ecient ROS scavenging
inuence on the antioxidative eects of nanoceria. Lee et al.

synthesized near-spherical CeO2 nanocrystals with diameters
ranging from 3 to 10 nm from the thermal decomposition of
cerium precursors. With a decrease in particle size, the
nanocrystals had more Ce3+ content. The smaller CeO2
nanoparticles also exhibited substantially higher reactivity as
compared to larger nanoparticles when reacted with H2O2 in
aqueous solutions.64 This group further studied the eect of
nanocrystal diameter and surface coating on the reactivity of
CeO2 nanoparticles with H2O2. The results revealed that the
smallest nanoparticles (3.8 nm in diameter) with the thinnest
surface coating (oleic acid) had the highest reactivity.38
The size of nanoceria also inuences its biopersistence and
biodistribution within the major tissue components. Dan et
al.627 characterized the distribution in, and clearance from,
blood of dierent-sized CeO2 nanoparticles (as compared to
the cerium ion) following intravenous infusion. The results
showed that 5 nm CeO2 nanoparticles were cleared much more
slowly from blood than larger CeO2 nanoparticles because
reticuloendothelial organs may not readily recognize 5 nm
nanoceria. Subsequently, the biodistribution, translocation, and
persistence of 5, 15, 30, or 55 nm nanoceria in the brain and
selected peripheral organs were determined to be 1, 20, or 720
h after treatment. The liver and spleen contained a large
percentage of the dose, while very little nanoceria entered the
brain parenchyma. The results suggest the application of
nanoceria in the central nervous system will be a challenge.628
7.3.2. Eects of Particle Shape. The shape and aspect
ratio of nanoceria have a great impact not only on its catalytic
performance but also on its interaction with cells and
consequently its biological compatibility. Three kinds of
CeO2 nanoparticles with dierent morphologies were synthesized by a hydrothermal method by changing the base
concentration, hydrothermal temperature, and reaction time.
CeO2 nanowires enclosed by (100) and (110) planes were
more active in hydroxyl radical scavenging than nanoparticles
and nanobars due to the easy Ce4+/Ce3+ recycling on the
surface.624 Recently, Ji et al.629 showed that CeO2 nanorods
with a high aspect ratio can induce progressive proinammatory eects and cytotoxicity. However, no inammatory response was observed with short CeO2 nanorods. These
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Figure 63. (a) CeO2 nanoparticles treatment inhibited ovarian tumor growth in vivo. (b) CeO2 nanoparticles protect normal human colon tissue
from radiation-induced cell death. (a) Reprinted from ref 647. Licensed under CC BY 3.0. (b) Reprinted with permission from ref 650. Copyright
2010 Elsevier B.V.
activity than uncoated CeO2 by changing the Ce3+/Ce4+ ratio at

the surface of the nanoparticles. Besides, more apoferritincoated nanoceria could be internalized by cells due to the
change of the cellular internalization process. Ting et al.634
reported the heparin functionalized nanoceria was a more
potent ROS scavenger than nanoceria alone. Heparin
modication also increased the uptake of nanoceria in human
monocyte cell line U937.
7.3.5. Eects of Doping and Loading. Impurity-doping
or supporting eects can adjust the chemical reactivity of
nanomaterials through modication of the electronic structure.
Tsai et al.635 synthesized a series of CexZr1xO2 nanoparticles at
room temperature using the reverse micelle method. The ROSscavenging activity of Ce0.7Zr0.3O2 nanoparticles could be
enhanced 4-fold as compared to CeO2 nanoparticles. On the
contrary, Celardo et al.636 found that Sm doping dosedependently blunts the antioxidant and antiapoptotic abilities
of nanoceria, which demonstrated that Ce3+/Ce4+ redox
reactions were responsible for the outstanding biological
properties of nanoceria.
Gold or platinum nanoparticles have been reported to exhibit
antioxidant activities that reduce the concentration of reactive
oxygen and nitrogen species.637,638 Menchon et al. 639
synthesized ceria-supported gold nanoparticles that exhibit
peroxidase activity and act as radical traps. The intrinsic
antioxidant activity of CeO2 nanoparticles is dramatically
enhanced by the supported gold nanoparticles while maintaining remarkable biocompatibility.
7.3.6. Eects of External Factors. Sigh et al.640 found that
the presence of phosphate altered the surface chemistry and
catalytic activity of CeO2 nanoparticles due to the binding of
phosphate anions to cerium. XPS analysis showed that these
phosphate treated particles have predominantly Ce3+ on the
surface due to the formation of cerium phosphate, which blocks
the redox cycling between Ce3+/Ce4+. Interestingly, the catalase
mimetic activity of nanoceria was increased and the SOD
mimetic activity was decreased after phosphate buer treatment.

Similarly, Xue et al.641 studied the eects of dierent buer
anions (Tris-HCl, sulfate, and phosphate) on the antioxidant
activity of CeO2 nanoparticles by studying their DNA
protective eect. The results show that the nanoceria can
protect DNA from damage in Tris-HCl and sulfate systems in
both acidic and neutral conditions. However, nanoceria lacks
DNA protection capability in phosphate buer solution (PBS)
systems. The selectively protective eects can be ascribed to the
formation of cerium phosphate on the surface of nanoparticles.
The SOD and catalase mimetic activity of CeO2 nanoparticles are greatly aected by the external pH environment.
For example, autocatalytic activity of dextran-coated nanoceria
was blocked due to the high concentration of protons at acidic
pH.87 Moreover, nanoceria favors the scavenging of superoxide
radical over hydroxyl peroxide in acidic environments, while the
preference is not observed in neutral pH.642
7.4. Nanoceria as Therapeutic Agents
7.4.1. Cancer Therapy. Nanoceria have shown direct

innate cytotoxicity and indirect anti-invasive eect on tumor
cells. It has been found that the CeO2 nanoparticles can induce
oxidative stress and cell membrane leakage.643 In another study
by Babu et al.,644 the proliferation of cancerous lung cells
(CRL-5803) was decreased by 33.7% by their synthesized
Yb3+,Er3+ codoped CeO2 UCNPs, while no toxicity toward
healthy human lung broblasts cell line was observed.
The size, shape, agglomeration state, surface charge, and
surface modication of CeO2 nanoparticles together determine
their bioresponse toward cancer cells. For example, dextrancoated nanoceria exhibited pH-dependent antioxidant properties for targeted cancer therapeutics. However, the acidic tumor
microenvironment can also inhibit the H2O2 scavenging activity
of nanoceria.87 Dextran-coated CeO2 nanoparticles have also
been used to prevent myobroblast formation and tumor
invasion in tumorstroma interaction,630 providing a valuable
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Figure 64. (a) CeO2 nanoparticles increase the lifespan of neuron cells isolated from adult rat spinal cord. (b) Ceria nanoparticles considerably
reduce infarct volumes, to as little as 50% of those of the control grouph. (c) Intravitreal injection of nanoceria particles protects rat retina
photoreceptor cells from light-induced degeneration. (a) Reprinted with permission from ref 654. Copyright 2007 Elsevier B.V. (b) Reprinted with
permission from ref 657. Copyright 2012 Wiley-VCH Verlag GmbH & Co. KGaA. (c) Reprinted with permission from ref 659. Copyright 2006
Nature Publishing Group.
tool for the chemoprevention of tumor invasion. The surface

charge of CeO2 nanoparticles plays a key role in their cell
internalization, subcellular distribution, and therapeutic behav-
ior. PAA coated CeO2 has been successfully used to treat A549
lung cancer cells as they could enter the cells via internalization,
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neurodegenerative diseases arising from free radical accumulation in biological systems.

Recently, CeO2 was reported to reduce ischemic cell death in
a mouse hippocampal brain slice model of cerebral ischemia.
The neuroprotective eects of CeO2 nanoparticles result from
the reductions in ischemia-induced ROS and the damaging
downstream eects of peroxynitrite.656 Kim et al. rst
demonstrated the neuroprotective eects of CeO2 nanoparticles against ischemic stroke in living animals.657 With the
optimal dose of CeO2 nanoparticles (0.50.7 mg/kg), up to
50% infarct volume was reduced as compared to the control
(Figure 64b). Furthermore, they found ceria nanoparticles did
not suciently permeate normal brain tissue but were able to
permeate ischemic brain tissue. Taken together, nanoceria
treatment may be a promising strategy for patients with
ischemic stroke.
Nanoceria can also oer protection against a free radicalmediated autoimmune degenerative disease in the brain.658
Citrate/EDTA-stabilized CeO2 nanoparticles of 2.9 nm in
diameter were obtained and exhibited a long circulation time
due to less protein adsorption on the surface of the nanoceria.
More importantly, the CeO2 nanoparticles were also found to
be able to cross the blood brain barrier (BBB), reduce ROS
levels, and alleviate clinical symptoms/motor decits in murine
models of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE).
7.4.3. Retinal Damage Treatments. Chen et al. reported
that CeO2 nanoparticles were able to prevent retinal
degeneration by decreasing the intracellular concentrations of
reactive oxygen intermediates (ROIs).659 In the light-damage
model in vivo, the signicant dose-dependent protection of
retinal morphology and function was observed (Figure 64c). In
their next work, nanoceria was shown to decrease intracellular
ROS, the expression of vascular endothelial growth factor
(VEGF) in the photoreceptor layer, and the formation of
intraretinal and subretinal neovascular lesions in the Vldlr
knockout mouse, and cause down-regulation of VEGF and
regression of existing pathologic neovessels.660
Kong et al. demonstrated that nanoceria increased photoreceptor cell lifespan in tubby mice by scavenging ROS, upregulating the expression of neuroprotection-associated genes,
down-regulating apoptosis signaling pathways, and/or upregulating cell survival signaling pathways to slow photoreceptor degeneration.661 Surprisingly, nanoceria exhibited
sustained protection of retinal structure and function in tubby
mice for more than a month after a single intravitreal injection.
These ndings conrm the great potential of nanoceria for
treatment of neurodegenerative diseases such as diabetic
retinopathy, age related macular degeneration, and retinopathy
of prematurity.662
On the other hand, the toxicological eects of CeO2
nanoparticles on ocular tissues need to be systematically
studied. Pierscionek et al. suggested that low concentrations of
nanoceria (up to 10 g/mL) caused no measurable damage to
DNA663 or any signicant eects on chromatographic or
electrophoretic proles of eye lens proteins.664 They also found
that human lens epithelial cells exposed to higher concentrations of nanoceria for prolonged time may cause potential
genotoxicity.665 Wong et al. explored the biodistribution and
pharmacokinetics of nanoceria in ocular tissues after a single
intravitreal injection. Nanoceria preferentially retained in the rat
retina even after 120 days and have not shown any acute or
and the low pH in the organelle activated the mimetic oxidase

activity of CeO2.631
The anticancer performance of nanoceria could be improved
by modications with cancer cell targeting agents. Vincent et al.
found that the transferrin adsorption on naked CeO 2
nanoparticles enhanced their cellular uptake in human lung
cancer cells (A549), which was not observed for normal
embryo lung cells.645 Investigations on heparin functionalized
nanoceria as an antiangiogenic agent showed that the
intracellular localization and ROS scavenging ability of CeO2
nanoparticles depended on the level of heparin coating.646 Giri
et al. investigated the eectiveness of CeO2 nanoparticles in
ovarian cancer and demonstrated the inhibition of ovarian
tumor growth utilizing the antiangiogenic behavior of nanoceria
in a mouse model (Figure 63a).647
The unique regenerative antioxidant activity of CeO2
nanoparticles has also led to the exploration of the reduction
of radiative side eects in radiation therapy. Tarnuzzer et al. for
the rst time showed that nanoceria exhibited radioprotection
of normal human breast epithelial cells but not to MCF-7
cancer cells.648 Colon et al. investigated the radioprotective
ecacy of CeO2 nanoparticles in vitro and in vivo under highdose radiation. When exposed to a single dose of 20 Gy
radiation, the activity of caspase 3/7 in normal broblast cells
was signicantly decreased. In vivo study showed that CeO2
nanoparticles could protect athymic nude mice from radiation
induced pneumonitis.649 This group also examined the
protection of gastrointestinal epithelium by CeO2 nanoparticles
(Figure 63b), where the nanoceria scavenged free radicals and
increased the production of SOD2.650 This selective radioprotection by CeO2 nanoparticles can also be used to treat
xerostomia and radiation-induced dermatitis in mice.651 Briggs
et al. revealed that the radioprotective ecacy of CeO2
nanoparticles varied with the energy of X-ray radiation.652
While radioprotection of the rat brain gliosarcoma cell line was
observed when using a 10 MV photon beam, a contrary eect
was observed with a 150 kVp X-ray beam. This energydependent ecacy must therefore be considered when using
CeO2 nanoparticles for radiation protection.
Wason et al. reported that ceria oxide nanoparticles were able
to sensitize pancreatic cancer cells to radiation therapy.
Nanoceria was found to increase the radiation-induced ROS
levels preferentially in acidic cancer cells due to the increasing
SOD activity in acidic pH and H2O2 scavenging activity in
neutral pH. Both in vitro and in vivo experiments showed that
CeO2 nanoparticles not only enhanced radiation-induced
pancreatic cancer cell apoptosis but also desensitized normal
cells to the toxic side-eect of radiation therapy.642 These
results identify nanoceria as a potential radiation sensitizer and
normal tissue protectant for the treatment of human pancreatic
cancer.
7.4.2. Neurological Disorder Treatments. Studies have
shown that CeO2 nanoparticles were able to protect neurons
from oxidative damage. Schubert et al. reported cerium and
yttrium oxide nanoparticles could promote the hippocampal
nerve cell line (HT22) survival under glutamate-induced
oxidative stress.653 Das et al. synthesized nonagglomerated
CeO2 nanoparticles by a microemulsion process, and used them
to enhance the survival of the spinal cord neurons of adult rats
(Figure 64a).654 Cimini et al. conjugated antiamyloid
antibodies to PEG-coated CeO2 nanoparticles for the specic
targeting of A aggregates to protect neurons against Amediated cytotoxicity.655 This design can be applied in
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Figure 65. (a) Nanoceria accelerates the healing of skin wounds in mice. (b) Wound sizes at the indicated time points in control and nanoceriatreated mice. Reprinted with permission from ref 671. Copyright 2013 Elsevier B.V.
and stabilizing hypoxia. A subsequent study has shown that

water-soluble CeO2 nanoparticles accelerate skin wound
healing processes in a mice model (Figure 65).671 Moreover,
nanoceria reduced the nitrotryosine level in the wounded
region and protected the regenerative tissue from oxidative
stress. Similarly, CeO2 nanoparticles synthesized by Davan et al.
enhanced wound healing activity by increasing the amount of
hydroxylproline content and wound tensile strength, and
shortening wound closure time.672 These studies suggest
CeO2 nanoparticles can function as a broad spectrum
therapeutic agent for treatment of cutaneous wounds such as
diabetic foot ulcers.
7.4.5. Reduction of Chronic Inammation. Oxidative
stress caused by excessive production of ROS or RNS is
considered one of the pathological processes in inammatory
diseases. Hirst et al. reported that nanoceria can decrease ROS
production and inhibit inammatory mediator production in
J774A.1 murine macrophages.673 Nitric oxide synthase protein
and mRNA expression level were inhibited in a concentrationdependent manner in cells. Next, in vivo studies showed
nanoceria deposition in mouse tissue following intravenous
injections, without overt pathology. Taken together, these
results suggest CeO2 nanoparticles could act as antioxidant
agents for inammatory-related diseases.
Lord et al. obtained rhombohedral-shaped nanoceria by
ame spray pyrolysis with tunable particle diameters between 3
and 94 nm by changing the liquid precursor ow rate. The
cellular uptake and ROS scavenging ability of the synthesized
nanoceria have been explored with human tumor monocytes
(U937) as a suitable model of inammatory cells. All particles
with diameters in the range of 794 nm were not toxic to U937
cells and equally eective in scavenging ROS. The smaller
particles had more oxygen vacancy sites to scavenge ROS, while
chronic negative side eects on retinal function or cytoarchitecture.666

7.4.4. Potential for Treating Diabetic Complications.
Oxidative stress has been proposed to be one of the major
causes in the development and progression of diabetes and its
complications. Pourkhalili et al. found that CeO2 nanoparticles
and sodium selenium possessed a potential antioxidant eect in
a murine model of diabetes.667 A signicant increase in
antioxidant enzymes and high-density lipoproteins, and a
decrease in oxidative stress, energy compensation (ADP/
ATP), cholesterol, triglyceride, and low-density lipoproteins,
were observed. The results show the combination of CeO2
nanoparticles and sodium selenite is more eective than either
alone in alleviating diabetes-induced oxidative stress. Moreover,
CeO2 nanoparticles and sodium selenite were also found to
improve rat pancreatic islet transplantation outcome and graft
function by reducing oxidative stress damage. The combination
of CeO2 nanoparticles and sodium selenite signicantly
increased islet viability, insulin secretion, and ATP/ADP ratio,
and reduced ROS production.668
High glucose-induced oxidative stress also plays a major role
in the onset of diabetic complications including damage to the
eyes, kidneys, and skin.669 As previously mentioned, nanoceria
has therapeutic potential for treatment of diabetic retinopathy,
a kind of diabetes-specic microvascular disease.660 Recently,
the antioxidant capacity of CeO2 nanoparticles has been
explored to enhance wound healing for use in chronic skin
ulcers caused by diabetes mellitus. Das et al.670 showed
nanoceria can induce endothelial cell proliferation and tube
formation in the in vitro cell culture and vascular sprouting in
vivo. The molecular mechanism of nanoceria as a novel
angiogenic agent was further investigated. Nanoceria activated
factor 1 by modulating the intracellular oxygen environment
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Figure 66. Nanoceria delivered in vivo appear to be eective in decreasing oxidative stress and angiogenesis in mice with endometriosis. Reprinted
with permission from ref 678. Copyright 2013 Elsevier B.V.
more cells responded to the larger particles.674 Other reports

indicated that it was the Ce3+ concentration, rather than oxygen
vacancies, that played the key role in the antioxidant and
antiapoptotic behavior of CeO2 nanoparticles.636
Both inammation and oxidative stress are related to
cardiovascular tissue injury.675 Niu et al.676 demonstrated that
the administration of CeO2 nanoparticles protected the heart
from oxidative and inammatory injury in a transgenic murine
model of cardiomyopathy. CeO2 nanoparticles inhibited the
myocardial oxidative stress and inammatory processes through
its potential autoregenerative antioxidant properties. The eects
of CeO2 nanoparticles on cigarette smoke extract-induced
oxidative stress and inammation in cultured rat H9c2
cardiomyocytes were also investigated.677 Nanoceria showed
the ability to inhibit ROS generation, NF-B activation,
inammatory gene expression, and antioxidant depletion. In
summary, CeO2 nanoparticles have the potential to be antiinammatory agents for cardiovascular diseases related to
cigarette smoke.
It has been demonstrated that oxidative stress and intrinsic
inammatory status may be associated with the development
and progression of endometriosis. Chaudhury et al. observed
that nanoceria can mitigate endometrial lesions induced in mice
model by decreasing oxidative stress and inhibiting angiogenesis. In addition, nanoceria also protected against
endometriosis-related adverse eects on the oocytes (Figure
66).678
7.4.6. Treatments of Other Oxidative Stress-Related
Diseases. Karakoti et al. showed that the nanoceria
synthesized in water in porous 3D bioactive glass foam
scaolds enhanced the osteoblastic dierentiation and collagen
formation ability of human mesenchymal stem cells (hMSCs).
It is worth noting that the initial oxidation state and oxygen
vacancies in nanoceria might regulate the dierentiation of
hMSCs.679
In another work, the adhesion and proliferation of murine
derived cardiac and mesenchymal stem cells were enhanced by
nanostructured CeO2 powders embedded into poly(lacticcoglycolic acid) (PLGA) scaolds (Figure 67).680 The results
may be related to the antioxidant eects of ceria nanoparticles
through scavenging excessive free radical during cellular growth.
This study show that CeO2 nanoparticles in PLGA scaolds
hold great potential for tissue engineering applications.
Pagliari et al.681 reported that CeO2 nanoparticles could be
used as a potent tool to control the oxidative stress and growth
Figure 67. Immunouorescence-culture monitoring of the adult

cardiac stem cell seeded composite supports: (a) 5, (b) 10, and (c)
20 wt % CeO2/PLGA, together with (d) unlled PLGA as a control.
Cell nuclei, cytoskeleton, and vinculin can be distinguished in blue,
red, and green, respectively (all scale bars 20 mm). Reprinted with
Co. KGaA.
of adult cardiac progenitor cells (CPCs). Nanoceria did not

aect cell growth and dierentiation function in CPCs up to 7
days while promoting a time-dependent decrease in ROS
produced by the addition of H2O2. These results indicate that
nanoceria can function as catalytic antioxidants to protect CPCs
from oxidative stress.
7.5. Nanoceria for Bioanalytical Applications
Recently, some enzyme-like nanomaterials have been extensively studied for a variety of biomedical assays due to their
better stability, lower cost, higher sensitivity, better robustness,
and recyclability than natural enzymes.682 CeO2 nanoparticles
have been reported to have peroxidase, oxidase, and
phosphatase mimetic activity that depends on Ce4+/Ce3+
recycling on the surface, which makes nanoceria an ideal
agent for detection purposes.
7.5.1. CeO2 as a Peroxidase Mimetic. Peroxidases are a
large family of enzymes that catalyze the reduction of peroxide
and oxidize various substrates as shown below:
ROOR + AH 2 ROH + ROH + A
(10)
This enzyme activity plays an important role in many biological

processes including antioxidation, fatty acid oxidation, defense,
and various other metabolism activities.
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Figure 68. (a) Comparison of traditional ELISA and nanoceria-based ELISA. (b) The ability of nanoceria to oxidize ampliu to a stable uorescent
product in the pH range 68 will facilitate its use in ELISA. (a) Reprinted with permission from ref 40. Copyright 2009 Wiley-VCH Verlag GmbH
& Co. KGaA. (b) Reprinted with permission from ref 685. Copyright 2011 American Chemical Society.
Recently, Jiao et al.39 reported that well-redispersed CeO2

nanoparticles exhibited excellent peroxidase-like catalytic
activity. This property was successfully developed into a
colorimetric method for the determination of glucose level in
human serum samples, which is simpler, cheaper, more
sensitive, and selective as compared to traditional methods.
This new approach may also be applied to the detection of
various compounds in environmental chemistry, biotechnology,
and medicine.
Deng et al.683 synthesized GO@SiO2@CeO2 hybrid nanosheets (GSCs) via a wet-chemical strategy. GSCs exhibited
higher intrinsic peroxidase-like activity due to the introduction
of GO. A bioactive lateral-ow paper for multianalyte detection
was then fabricated, which was able to detect glucose, lactate,
uric acid, and cholesterol at the same time.
7.5.2. CeO2 as an Oxidase Mimetic. Oxidases catalyze
oxidationreduction reactions with oxygen as the electron
acceptor. In reactions involving the donation of a hydrogen
atom, oxygen is reduced to either water or hydrogen peroxide,
sometimes even superoxide radical:684
AH 2 + O2 A + H 2O2
(11)
2AH 2 + O2 2A + H 2O
(12)
to develop cellular ELISA to detect folate-receptor-expressed

cancer cells (Figure 68b).
The oxidase activity of CeO2 nanoparticles can also be
utilized to indirectly detect nucleic acids. The results showed
that DNA can electrostatically adsorb on the surface of
nanoceria and inhibit TMB oxidation by nanoceria. Thus, a
signicantly reduced colorimetric signal was used to detect
target nucleic acids within a few minutes and without the need
for postpurication of PCR products.686
7.5.3. CeO2 as a Phosphatase Mimetic. The phosphate
ester bond widely exists in biological molecules, such as DNA,
RNA, phosphorylated proteins, and ATP. Phosphatase can
hydrolyze phosphoric acid monoesters into a phosphate ion
and a molecule with a free hydroxyl group.
Some studies have shown CeO2 nanoparticles exhibit
phosphatase mimetic activity.687689 Kuchma et al.689 found
that nanoceria could hydrolyze the phosphate ester bonds of pnitrophenylphosphate, ATP, and o-phospho-L-tyrosine. However, no fragments were detected when nanoceria interacted
with DNA, indicating that DNA cannot be hydrolyzed by
nanoceria. Dowding et al.690 reported that exposure to CeO2
nanoparticles prepared by a hexamethylenetetramine-based
method (HMT-CNPs) reduced the viability of human
umbilical vein endothelial cells. Mechanistic studies revealed
that HMT-CNPs exhibited ATPase activity and resulted in a
signicant reduction in ATP levels in cell lysates. These results
suggest that the ATPase activity of nanoceria should be
considered when synthesizing CeO2 nanoparticles for use in
biomedical applications.
Xu et al.691 reported that the hydrolysis reaction of
nucleoside triphosphates (NTPs) can enhance the oxidaselike activity of nanoceria. The improvement was ascribed to the
coupling of the oxidative reaction with the hydrolysis reactions
of NTPs, because nanoceria has both oxidase-like and
phosphatase-like activities. Moreover, serial colorimetric assays
for single-nucleotide polymorphism have been developed on
the basis of NTPsnanoceria systems.
7.5.4. Other Utilizations of the Surface Properties of
Nanoceria. Ornatska et al.692 designed a novel paper-based
bioassay based on CeO2 nanoparticles as chromogenic
indicators. When CeO2 nanoparticles reacted with H2O2, the
visible color changed from white-yellowish to dark orange due
It has been found that CeO2 nanoparticles possess unique

oxidase-like activity at acidic pH values, as they can quickly
oxidize several colorimetric substrates (ABTS, DOPA, and
TMB) without H2O2.40 Poly(acrylic acid)-coated nanoceria
conjugated with folic acid can specically recognize certain
tumor cells with elevated expression of folate receptors (Figure
68a). As compared to traditional enzyme-linked immunosorbent assay (ELISA), nanoceria-based assays eliminated the use of
unstable H2O2, horseradish peroxidase, and antibodies, which
make the assay rather stable. Moreover, other advantages
include lower cost, simpler operation, and easier storage.
Asati et al.685 also showed that the oxidase-like activity of
nanoceria can be tuned by modulating pH. The mild oxidase
mimetic activity of nanoceria at neutral pH can oxidize ampliu
to the uorescent product resorun, whereas the strong oxidase
activity of nanoceria in acidic conditions would further oxidize
the substrate to the nonuorescent product resazurin. The
selective nanoceria-mediated oxidation of ampliu can be used
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Figure 69. (a) Ceria-based paper assay for the detection of H2O2. (b) Sensing H2O2 by displacing adsorbed uorescent DNA from nanoceria. (a)
Reprinted with permission from ref 692. Copyright 2011 American Chemical Society. (b) Reprinted with permission from ref 695. Copyright 2015
Figure 70. (a) Cell viability of Raw264.7, S18, and PC12 cells after incubation with dierent concentrations of Gd2O3:Eu nanoparticles (Gd3+
concentrations, 10, 1, and 0.1 M) for 48 h. (b) Proliferation of hMSCs after labeling with Gd2O3:Eu nanoparticles. Media without nanoparticles
served as controls. (c) Osteogenic, adipogenic, and chondrogenic dierentiation of unlabeled and Gd2O3:Eu labeled hMSCs stained by (1, 2) alizarin
red S, (3, 4) oil red O, and (5, 6) alcian blue, respectively (scale bar: 200 mm for parts 16 and 50 mm for insets in 3 and 4). (d) Concentrationdependent hemolysis of BaYbF5:Tm nanoparticles. Inset: Photographic images for direct observation of hemolysis. (a) Reprinted with permission
from ref 152. Copyright 2014 American Chemical Society. (b,c) Reprinted with permission from ref 696. Copyright 2010 Wiley-VCH Verlag GmbH
& Co. KGaA. (d) Reprinted with permission from ref 699. Copyright 2013 Elsevier B.V.
to the change of the oxidation state and formation of surface

complexes on the ceria nanoparticle surface.38 Therefore, CeO2
nanoparticles and glucose oxidase were coimmobilized onto a
lter paper to construct a glucose-sensing paper (Figure 69a),
providing a sensitive, robust, and inexpensive platform for
H2O2-related molecular analysis. Similarly, using color changing

and thermally regenerable capability of nanoceria to react with
H2O2, Lin et al.693 presented a label-free, resettable, and
colorimetric logic network.
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Sharpe et al.694 reported a portable nanoceria-based assay for

rapid detection of food antioxidants. Immobilized CeO2
nanoparticles changed color after interaction with antioxidants
by redox and surface reactions. The sensor has a number of
advantages including high stability and portability, low cost,
ease of quantication, and high sensitivity. In fact, common
antioxidant compounds including ascorbic acid, gallic acid,
vanillic acid, quercetin, caeic acid, epigallocatechin gallate, and
even real samples (tea and medicinal mushrooms) have been
successfully tested.
Liu et al.695 reported an original method to detect H2O2 and
glucose in serum using a uorescently labeled DNA as a probe.
The uorescence was completely quenched by nanoceria, and
completely recovered immediately after adding H2O2 (Figure
69b). Gel electrophoresis and surface group pKa measurements
conrmed that H2O2 induced DNA release by capping the
nanoceria surface. Taking advantage of the high sensitivity and
low background uorescence, the system was used to develop a
biosensor for H2O2 with a wide linear range (1 mM) and low
LOD (130 nM). By coupling with glucose oxidase, sensitive
assays of glucose with a LOD of 8.9 M in buer were realized.
This study opens a new window for new applications in
biotechnology and medicine.
The half maximal inhibitory concentration (IC50) of

nanoparticles, dened as the critical concentration of the NPs
that can cause the cell culture to lose 50% of total viability after
a given time interval, is another index of the cytotoxicity of NPs
when using the cell viability approach. Li et al.697 reported the
IC50 of NaYF4:Yb,Tm@FexOy nanocrystals as 295 and 190 g
mL1 when incubated with KB cells for 24 and 48 h, which
generally represent the toxicity of Ln3+-based nanoparticles.
8.1.2. Cell Proliferation and Dierentiation. The impact
of NPs on cellular proliferative and dierentiative ability is
another indicator of the cytotoxicity of nanomaterials. Wang et
al.696 investigated the inuence of Eu3+-doped Gd2O3 nanoparticles on the proliferation of human mesenchymal stem cells
(hMSCs) by measuring the number of the attached cells with a
cellular proliferation assay kit, and no loss of proliferative
activity as compared to control was observed. Identication of
dierentiated cells among hMSCs cultured in their corresponding dierentiation induction media also suggested that the
potential of hMSCs to dierentiate into osteogenic, adipogenic,
and chondrogenic cells remain largely unimpaired (Figure
70b,c).
8.1.3. Hemolysis. Nanoparticles that cause signicant
hemolysis are not suitable for bioapplications. In a typical
hemolysis assay, red blood cells (RBCs) extracted from full
blood are suspended in PBS and mixed with the PBS
suspension of nanoparticles. After incubation, the NPs and
intact RBCs are removed by centrifugation, and the absorbance
of hemoglobin released by ruptured RBCs in the supernatant is
measured. For instance, Qu et al. evaluated the toxicity of
BaYbF5:Tm699 and Lu2O3:Gd,Yb,Er nanoparticles700 using this
method, and the results suggest that neither of these NPs
caused signicant hemolysis in human blood (Figure 70d).
8. BIOSAFETY EVALUATIONS OF LANTHANIDE

NANOMATERIALS
Toxicity assessment of nanoparticles is necessary if they are to
be applied in bioapplications. Common evaluation techniques
include in vitro or in vivo methods. In the following section of
this Review, the general assessing procedures involved in both
methods are introduced, and the biosafety of some functional
Ln3+-based nanoparticles based on their evaluation results will
be discussed.
8.2. In Vivo Toxicity Evaluation
8.2.1. In Vivo Toxicity in C. elegans. C. elegans is a

hallmark model organism that has been widely used in
biological research. As a free-living nematode, it is one of the
simplest organisms with a nervous system, whose pattern has
been thoroughly mapped out. Although being a multicellular
eukaryote with primitive yet full-edged digestive, reproductive,
and nervous systems, its simplicity allows a detailed study into
the dierentiation and developmental fate of each and every
one of its cells. Its transparency further facilitates research into
cell dierentiation while simultaneously enabling optical
imaging of its ne structure. These features made it an
excellent model for the toxicology study of nanomaterials.
Yan et al.423 studied the biosafety of NaYF4:Yb,Tm
nanocrystals by assessing their impact on the protein
expression, life span, egg production, egg viability, and growth
rate of C. elegans. Transgenic marker strains of rrIs1[elt-2::GFP]
and JK2868[lag2::GFP], which have nuclear expression of
green uorescent protein (GFP), are utilized for this purpose.
As the NaYF4:Yb,Tm nanocrystals are primarily internalized
through the intestinal tract, nuclear GFP expression in
intestinal cells of intact and nanocrystal-treated worms was
monitored, showing no obvious dierence of expression pattern
and ratio. Despite the worms continuous exposure to the
nanocrystals throughout their life cycle, the life span, daily and
total egg production, egg viability (as characterized by hatching
rate), and growth rate (as characterized by the proportion of
mature worms among larvae) of intact and nanocrystal-treated
worms generally show no statistically signicant dierence
(Figure 71a,b).
8.1. In Vitro Toxicity Evaluation
8.1.1. Cell Viability. The most convenient approach for the

evaluation of the cytotoxicity of Ln3+-based nanoparticles is
considered the studies on the viability of cells cultured in vitro
where the target NPs are involved. Numerous assay kits have
been developed for this purpose, among which the 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
is the most commonly used to evaluate the activity of the
intracellular NAD(P)H-dependent oxidoreductases as the
indicator of cell viability. These enzymes can reduce the
MTT to its insoluble formazan, which has a characteristic
purple color due to its characteristic absorbance. During the
evaluation process, the incubation of the NPs and cells on a
microplate is followed by the addition of MTT, and the
resulting mixture is usually taken in dimethyl sulfoxide
(DMSO) or sodium dodecyl sulfate (SDS) to give a colored
solution, whose absorption is then measured to give
quantitative results of cell viability. This assay has been
employed in numerous research studies to evaluate the
cytotoxicity of Ln3+-based nanoparticles for bioapplications.152,425,487,563,576,583,584,593,601,696702 Other common
assay kits including XTT,703 MTS,704 and CCK-8423 assays
employ a mechanism similar to that involved in MTT assay. All
of these evaluations indicate that, in general, Ln3+-based NPs
exhibit negligible cytotoxicity even when their concentration is
above the threshold required for their respective applications in
a
wide
variety
of
cell
lines152,423,425,487,563,576,583,584,593,601,696704 (Figure 70a).
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Figure 71. (a,b) Toxicity assessment of NaYF4:Yb,Tm nanocrystals in C. elegans. (a) (i) False-colored GFP uorescent and merged images with
bright eld signals of rrIs1[elt-2::GFP] hermaphrodites fed with the mixture of growth media and NaYF4:Yb,Tm nanocrystals or (ii) only the growth
media as control experiment. (iii) The ratio of rrIs1[elt-2::GFP] hermaphrodites with GFP expression (n = 3). (b) Life span (i), egg production (ii),
and egg viability and growth rate assay of hermaphrodites (iii) fed with the mixture of growth media and NaYF4:Yb,Tm nanocrystals or only the
growth media as control experiment. The egg viability was the ratio of the number of total larvae to that of 30 eggs. The growth rate was censused by
the proportion of L4 and adult stage worms among the total larvae. The inset of (ii) shows the total number of laying eggs from day 3 to 7. (c)
Morphological changes at 48 h postfertilization of zebrash embryos injected with LaF3:Yb,Er@SiO2 nanoparticles. (A1, A2) Control group. (B13)
nanoparticles <200 g/mL groups. (C15) nanoparticles 200400 g/mL groups. Abbreviations: b, brain; e, eye; n, notochord; t, tail; ys, yolk sac;
bs, bent spine; tm, tail malformation; oe, ocular edema; pe, pericardial edema; oy, opaque yolk; yes, yolk sac edema; and ynd, yolk not depleted. (a,b)
Reprinted with permission from ref 423. Copyright 2011 Elsevier B.V. (c) Reprinted with permission from ref 403. Licensed under CC BY-NC-ND
3.0.
8.2.2. In Vivo Toxicity in Zebrash. When vertebrates are

concerned, zebrash (Danio rerio) is one the most commonly
used model organisms. It has a fully sequenced genome, and its
developmental stages and behaviors have been thoroughly

documented. Rapid and robust embryonic development can
reduce the time and hardware requirements for experimentaBO
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tion. Most importantly, they demonstrate considerable

similarity to mammalian models and humans in toxicity testing,
making it an ideal model for toxicity evaluation.
The toxicity of LaF3:Yb,Er@SiO2 nanoparticles in early
development of zebrash embryos was studied in detail by Cui
et al.403 LaF3:Yb,Er@SiO2 nanoparticles were injected into the
embryos, and voluntary movement (tail swings) and heart rate
of the embryos were subsequently recorded, and the result
indicates that the nanoparticles showed no signicant eect on
these two factors. However, the nanoparticles did cause the
reduction of the survival/hatching rate of the embryos when at
higher concentrations (>200 g mL1). More importantly, the
injection of nanoparticles caused signicant deformation in
larval morphologies, including shortened body length; nondepleted or malformed yolk; spinal, tail, and caudal n
malformations; pericardial sac or yolk formations; stunted
body or eye growth; and edema of the body cavity, pericardial
sac, or yolk sac regions (Figure 71c). RT-PCR results revealed a
signicant decrease of sepn1 gene expression, which is related
to abnormal notochord development and heart disease, and the
authors attributed the decrease to the possible DNA damage
caused by La3+ ions.
8.2.3. In Vivo Toxicity in Murine Models. Murine
models, including mice and rats, represent the most commonly
used mammalian models for in vivo toxicology assessments.
Common criteria for toxicity evaluation in murine models
include physical and behavioral signs; histological analysis;
hematological and blood biochemistry analysis; and immunotoxicity.
Physical and behavioral signs: Body weight, litter size, and
behavior traits such as eating, drinking, and mating activities
can all be employed to assess in vivo toxicity, and deviation
from control usually indicates disruption of normal physiology
by injected nanoparticles. The eect on physical and behavioral
signs caused by the introduction of a wide variety of
nanoparticles is investigated,425,487,576,583,584,697,699,700 and the
results generally indicate no signicant changes as compared to
control groups (Figure 72a).
Histology: In a typical histological assessment, organs
(typically including heart, liver, spleen, lung, kidney, and
other organs deemed necessary) are harvested from mice or
rats injected with nanoparticles, xed in formalin or ethanol,
embedded in paran, sectioned, stained with hematoxylin and
eosin (H&E), and observed under an optical microscope in
search of possible histological damages including tissue damage,
inammation, and lesions. In the evaluation of the in vivo
toxicity of chitosan-coated Co2+-doped NaYF4:Yb, Tm nanoparticles conducted by Shen et al.,584 heart, liver, spleen, lung,
and kidney from mice injected with the nanoparticles were
harvested and assessed. Microscopic images reveal that organ
structures remained normal, inammation was not observed,
and there were no signicant increases in leukocytes such as
lymphocyte, macrophage, neutrophil, and eosinophil, suggesting no increased immune response. Necrosis was not observed
in all of the tissue sections, and no characteristic pathological
lesions were observed in organ samples (Figure 72b).
Histological analyses of other lanthanide-based nanoparticles
have similar results,425,487,563,576,583,584,697,699,700,705 indicating
general innocuity to tissue histology.
Hematology and blood biochemistry: Hematological indices
are very important indicators of overall physiological well-being,
while blood biochemistry analysis can reect liver and kidney
function by quantifying corresponding liver and kidney
Figure 72. (a) Changes in body weight (A) and litter size (B) of mice
after intravenous administration of 0.9 wt % NaCl solution and
Lu2O3:Gd,Yb,Er nanoparticles. (b) H&E-stained tissue sections from
mice for the control group and the test group, which was injected with
chitosan-coated NaYF4:Yb3+,Tm3+,Co2+ nanorods for 2 h. Tissues
were harvested from liver, kidney, spleen, and lung, respectively. All are
shown at medium magnication, about 400. (a) Reprinted with
Co. KGaA. (b) Reprinted with permission from ref 584. Copyright
2010 Elsevier B.V.
indicators (such as alanine aminotransferase (ALT) for liver

and creatinine (CRE) for kidney). All of these analyses can be
conveniently conducted on standard instruments. Hematological and blood biochemical analyses of murine blood injected
with various lanthanide oxide700,705 and uoride425,487,576,583,584,699 nanoparticles reveal no signicant
hematological irregularities or impairment of organ functions.
Immunological response: The activation of immunological
response by nanoparticles introduced in vivo can be
detrimental to animal physiology, thus introducing toxicity.
Chen et al. evaluated the immune response caused by
Gd2O3,702 Gd2O3:Eu,152 and Gd2O3@SiO2706 nanoparticles.
As an important mediator of immunity, the reactive oxygen
species (ROS) level in blood was rst investigated. Cluster of
dierentiation (CD) marker and interleukin levels were
subsequently analyzed as indicators of immunological activity.
Results indicate that, although these nanoparticles do stimulate
immunological response, the level of stimulation is generally on
par with or slighter higher than Gd-DTPA, currently the most
widely applied MRI contrast agent. Therefore, these abovementioned Gd2O3-based nanoparticles can be regarded as
relatively safe for in vivo bioapplications.
8.3. Autophagy-Inducing Ability of Lanthanide
Nanoparticles
Autophagy refers to the intracellular catabolic process where

the unnecessary or dysfunctional cellular components, for
example, long-lived proteins and damaged organelles, degrade
in lysosomes. The degradation of cellular components provides
the necessary energy to maintain basic cellular function during
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by crystal symmetry, the distance between Gd3+ ions, the

impurities-induced magnetic environment changes, and even
the Gd percentage should be investigated. Although the
relaxivities of dierent Gd3+ systems including oxides, uorides,
oxysalts, and hydroxides have been studied, the most suitable
matrix for T1 relaxation enhancement still remains unclear. (b)
The dierent facets of Gd-based nanoparticles should be taken
into consideration for the design of T1 CAs. In fact, the
adsorption of water molecules on dierent surfaces cannot be
identical, similarly to the selective anchoring of oleates on GdF3
surfaces,110 and the inner-sphere relaxation involving the
adsorption of water molecules to surface Gd3+ mainly
contributes to contrast enhancement. (c) As compared to
Gd3+-based CAs, other Ln3+-based CAs need to be extended
from traditional systems (e.g., oxides and uorides). Prior to
the above addressed issues, further improvements on the
reproducible and controllable synthetic approaches for
monodispersed nanoparticles are necessary. Besides, the
optimized conditions for the coating of water-dispersible layer
on particles are to be explored. Facing clinical applications,
general evaluation of the biocompatibility, pharmacokinetics,
biodistribution, and metabolism of the applied nanoparticles is
necessary.
(2) In recent years, Ln3+-based UCNPs have been
extensively drawing attention in theranostic studies such as
bioimaging due to their ecient NIR triggered emissions with
large anti-Stokes shifts, high detection sensitivity, and excellent
biocompatibility. UCNPs supported biomedical applications
have made considerable achievements in interdisciplinary elds.
Nonetheless, the pending questions include: (a) Monochromatic emissions. Featured by the sharp emission bands, Ln3+based UCNPs are promising for multicolor imaging and
multiplexed detections. The currently used methods for
encoding samples employ the dierences in their upconversion
emission ratios. However, the emission ratio is decided by
various factors including the surface properties of the UCNPs
and the solvents used. UCNPs with monochromatic emissions,
on the other hand, may aord more convenient encoding, but
there is no general synthetic strategy. Eorts toward such
UCNPs should include investigations on tailoring the local
coordination structure and the incorporation of the proper
activators, where the minimization of deleterious crossrelaxations must be considered. (b) Improved luminescent
eciency. UCL from Ln3+ ions are indeed attractive, but their
relatively low quantum yield limits the optical applications of
UCNPs, such as deep-tissue (>2 cm) imaging. The establishment of an eective strategy to signicantly enhance the
eciency of upconversion emissions has always been highly
desirable. So far, there is only one report verifying the feasibility
of the introduction of antenna ligands that can donate energy
to Ln3+ luminescent centers. More investigations should be
conducted to explore the scale of such NIR antenna ligands. (c)
Bioimaging and therapy. The current bioimaging and
therapeutic models are mainly focused on cells (in vitro) and
mice (in vivo). Other biological models including large animals
and plants should also be considered to enrich the UCNPbased bioimaging applications. Moreover, most UCNP-based
bioimaging and therapy studies employed 980 nm laser as the
irradiation source, which can induce signicant overheating
eect. To address the problem, 808 nm NIR light triggered
UCNPs have been developed to minimize tissue absorption. In
addition, current reports on targeted imaging and therapy
mainly focus on folate-modied UCNPs. The use of antibodies
starvation, and the constitutively active basal autophagy allows

the recycling of the degraded cellular components, which is
essential for maintaining cellular homeostasis. Well-regulated
autophagy is usually considered to promote cell survival.
Nonetheless, for cells under constant stressed conditions or
treated with autophagy-inducers, an irregularly elevated level of
autophagy can also promote cell death. In general, autophagy
involves (i) the sequestration of cellular components by
autophagosomes, (ii) the fusion of autophagosomes with
lysosomes, and (iii) the subsequent decomposition of the
engulfed contents by lysosomal enzymes.
Wen et al. have observed that Ln3+-based nanoparticles can
function as autophagy-inducers: both light lanthanide (samarium/europium) oxides and heavy lanthanide (gadolinium/
terbium) oxides can be used to promote autophagy in HeLa
cells.707 The autophagic response of such nanoparticles was
found dependent on the type and concentration of Ln3+, the
time of induction, and possibly the cellular vacuolization caused
by lanthanide oxide nanocrystals. With the aim of applying this
autophagy-inducing eect into therapeutic use, it has been
demonstrated that C60(Nd), C60 containing a neodymium
atom in its cage, can up-regulate the formation of
autophagosomes and sensitize chemotherapeutic killing of
drug-resistant cancer cells.708 Because C60(Nd) cannot
decompose in the presence of lysosome enzymes, this can
disrupt the normal autophagic ux and cause the accumulation
of autophagosomes, making the cancer cells more susceptible to
chemotherapy. In another work, the autophagy-inducing ability
of Ln3+-based nanoparticles was utilized to treat neurodegenerative diseases.709 Eu(OH)3 nanorods have been found
capable of inducing autophagy in various cell lines to promote
the elimination of Huntington protein aggregates, which is a
primary cause for neurodegenerative diseases such as
Parkinsons disease and Huntingtons disease. In another
study on tuning the autophagy-inducing ability of Ln3+-based
nanoparticles,710 they selected a short peptide that can form a
stable coating layer on the surface of lanthanide oxide/
upconversion nanocrystals to eectively weaken their autophagy-inducing capacity, with the variations of the used peptide
for the desired level of autophagy.
9. CONCLUSIONS AND PROSPECTS

In summary, in this Review the main principles and recent
progress of the diagnostic and therapeutic applications of
lanthanide-based functional nanoparticles, covering MRI, CT,
SPECT, UCL imaging, biosensing, PTT, PDT, drug delivery,
antioxidation, and autophagy induction, have been discussed.
The various approaches biosafety assessment of such nanoparticles has also been briey introduced. Conclusions can be
drawn that lanthanide nanoparticles show great promise in
theranostics as they oer numerous advantages over conventional biomarkers and therapeutic agents due to the unique 4f
orbitals of lanthanides, and the biocompatibility brought by the
intrinsic merits of nanoscale materials. Here, we outline some
future directions for research on lanthanide nanomaterials
toward more powerful and integrated functionalities.
(1) As compared to the rapid pace of the development of
iron-based CAs, research on Ln3+-based nanoparticulate CAs is
still in its early stage. The diagnostic application of most of the
reported CAs is still limited to in vitro testing or preliminary
animal studies. For further work, the following aspects should
be concerned: (a) For Gd-based nanoparticulate T1 CAs, the
inuence on the electronic spin properties of Gd3+ ions brought
BQ
Chemical Reviews
Review
for more specically targeted imaging and therapy can be a

promising direction. Last, the enhancement of the detection
sensitivity and spatial resolution to provide more accurate
information for extended therapy is also important.
(3) In this Review, NIR emitting nanoparticles for sensitive
in vivo imaging have been veried. Nevertheless, investigation
on such nanoparticles for bioimaging and therapy is still in its
infancy. The eective modulation of multicolor NIR emissions
and the enhancement of the emission eciency are both
desired, and the development of targeted imaging and therapy
should also be carried out. Moreover, NIR imaging guided
tracking of disease processes should also be considered.
(4) Oxidative stress has been found related to diseases
including cancer, neurological disorders, diabetes, and
ischemia/reperfusion. CeO2 nanoparticles have been recognized as an outstanding antioxidant for therapeutic applications,
yet there are unresolved issues considering their potentials in
clinical applications. It is essential to realize controllable
synthesis and rational surface modication of CeO2 nanoparticles whose bioresponse is determined by the size, shape,
agglomeration state, and surface properties.
(5) The currently obtained results of the biosafety evaluation
of Ln3+-based nanoparticles are based on toxicological research
employing relatively rudimentary and supercial methods, most
of which solely focused on the manifestations but not the
mechanisms. Satisfactory explanations of the nature of the
detected toxicity were rarely presented. Therefore, the
relationship between the characteristics of nanoparticles
(composition, size, shape, suface coating, etc.) and toxicity
needs to be established, especially for long time tracking
studies, to obtain a more profound and systematic understanding of their toxicity.
Shuo-Ren Du received his B.Sc. degree from Nankai University in

2009. He nished his Ph.D. study on organometallic chemistry in
Professor Nick J. Longs group, Department of Chemistry, Imperial
College London, in 2014. Currently he is working as a lecturer in
Peking University. His research interest is focused on the theranotics
using lanthanide nanophosphors.
AUTHOR INFORMATION
Corresponding Authors
Biographies
Xiao-Yu Zheng received his B.Sc. degree in Chemistry from Xiamen

University in 2012. In the same year, he joined the College of
Chemistry and Molecular Engineering, Peking University. He is
currently pursuing his Ph.D. degree under the supervision of Professor
L.-D. Sun and Professor C.-H. Yan, working on the controllable
synthesis and bioapplications of lanthanide-based functional nanomaterials.
Hao Dong received his B.Sc. degree from Zhengzhou University in

2012. He joined the College of Chemistry and Molecular Engineering,
Peking University, as a Ph.D. candidate under the direction of
Professor L.-D. Sun and Professor C.-H. Yan. His research interest is
mainly focused on the synthesis, function tuning, and bioapplications
of lanthanide functional nanophosphors.
Guang-Ming Lyu received his B.Eng. degree in Chemical Engineering

from Inner Mongolia University in 2010. He is a Ph.D. student under
the supervision of Professor L.-D. Sun and Professor C.-H. Yan at
Peking University. He is currently working on ceria-based nanomaterials, ranging from synthesis, surface modulation, catalytic properties,
and biomedical applications.
*E-mail: sun@pku.edu.cn.
*E-mail: yan@pku.edu.cn.
Notes
The authors declare no competing nancial interest.
BR
Chemical Reviews
Review
Chao Zhang obtained his B.Sc. degree in Applied Chemistry from

Beijing Institute of Technology in 2006 and his Ph.D. degree from
Peking University in 2011. He served as a Research Assistant in the
Department of Physics, the Chinese University of Hong Kong, during
2011 to 2013, and is currently working as a lecturer in Peking
University. His research interest is focused on the design and
fabrication of smart optical materials.
Ling-Dong Sun obtained her Ph.D. from Changchun Institute of

Physics, Chinese Academy of Sciences, in 1996. Following a
Postdoctoral Fellowship at the Peking University, she joined the
faculty at College of Chemistry and Molecular Science and
Engineering, Peking University in 1998, and was promoted to a full
professor of chemistry in 2011. Her current research focuses on the
synthesis and applications of rare earth and semiconductor nanomaterials.
Chun-Hua Yan received his Ph.D. in 1988 from Peking University. He

was promoted to a full professor in the Department of Chemistry at
Peking University in 1992. He is currently serving as an Associate
Editor for Inorganic Chemistry (ACS) and the Managing Editor-inChief for J. Rare Earths (Elsevier). He was elected as a Member of the
Chinese Academy of Sciences in 2011, and a Fellow of the Academy of
Sciences for the Developing World (TWAS) in 2012. His main
research elds are rare earth functional materials, and rare earth
separation chemistry and engineering.
Lin-Dong Li received his B.Sc. degree from Peking University in 2013.

He joined Professor L.-D. Sun and Professor C.-H. Yans research
group in Peking University in the same year. He is currently working
on the synthesis, functionalization, and bioapplications of ceria-based
nanomaterials.
ACKNOWLEDGMENTS
This work was supported by the NSFC (nos. 21331001,
21425101, 21321001, 21371011) and MOST of China
(2014CB643800, 2012CBA01204).
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NOTE ADDED AFTER ASAP PUBLICATION

This paper was published ASAP on July 7, 2015, with an error
in Chun-Hua Yans biography. The corrected version reposted
on July 8, 2015.
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Review

Lanthanide Nanoparticles: From Design toward Bioimaging and

Special Issue: Nanoparticles in Medicine

Received: February 11, 2015

9. Conclusions and Prospects

intrinsic paramagnetism of Ln3+ have been reported for

Scheme 1. Schematic Illustration of the Main Topics of This

2. TYPICAL SYNTHETIC PROCEDURES FOR

The thermal decomposition design involves the oxygen-free

thermolysis of Na(CF3COO) and RE(CF3COO)3.54 Except

Also, the nanoparticles synthesized by this method are highly

reaction temperature, and the duration time. On the basis of

nanoowers were obtained with controlled morphology (cubic,

The hydrothermal/solvothermal synthesis refers to the

particles, the hydrolysis of Ln3+ is the key process for the

nanoparticles. The authors also prepared lanthanides doped

As one of the most classical wet chemical synthetic method,

nanoplates, while SmEr and TmLu would form hexagonal

In addition to the aforementioned well-developed synthetic

Tcala (emu mol1 K)

Texp (emu mol1 K)

Tcal = (1/8)gJ2[J(J + 1)].

synthesized by the single microemulsion method, direct

3. LANTHANIDE NANOPARTICLES AS MRI CONTRAST

Nuclear magnetic resonance (NMR) spectroscopy was rst

3.2. Lanthanide-Based Nanoparticles for T1-Weighted MRI

3.2.1. Gd-Based Nanoparticles for T1-Weighted MRI.

coupling (Table 1). As a result, Gd3+ has a relatively long

With this method, Li and co-workers synthesized ligand-free

suitable as host matrixes for luminescent centers, and, as a

Figure 4. (a) Size distribution determined by photon correlation

Figure 5. (a) Confocal and phase contrast image (inset) of GdS:Eu3+

r1 and r2 values at 4.7 T (13.48 and 24.53 mM1 s1,

lized Gd2 (CO3 ) 3:Tb nanoparticles with a narrow size

Figure 6. MR angiography of rabbits within 3 min after being injected

r1total = r1IS + r1SS + r1OS

Gd3+ ions has a reciprocal relationship to the six powers of

longitudinal electron spin relaxation time (T1e) and the rotation

GdF3 nanowires was attributed to the assembly of GdF3

behavior accompanied by size changing possibly exists (Figure

Figure 8. Scheme of size dependence of two parameters (R and S/V)

Nanoparticle shape is another important parameter related to

appeared to be 70 nm at 7 T (r2 190 mM1 s1) and 60 nm

diacid-600 in the order of increasing ligand size were used to

3.3.1. Gd-Based Nanoparticles for T2-Weighted MRI.

not comparable with SPIO for T2 relaxation enhancement at a

Considering the dierences of various imaging modalities in

where a is a constant, d is the diameter of the nanoparticle, D is

modication process can be achieved by ligand exchange,266

With abundant energy levels of 4f electron congurations, Ln3+

the location of the T1 contrast material. As reported by Gao and

4. LANTHANIDE UPCONVERSION NANOPARTICLES

that of Yb3+Er3+ pairs; thus the upconversion eciency in

can be divided into four categories: (a) controlling Ln3+ doping

4.2. Multicolor Modulation of Upconversion Emissions

cross-relaxation process within two adjacent Er3+ ions: 4F7/2 +

red emission. The cross-relaxation between Er3+ and Yb3+ was

and co-workers.277 They reasoned that the interatomic distance

sensitizers simultaneously. Moreover, novel cross-relaxations

Ho3+ and Er3+Tm3+ codoped nanoparticles, multiphoton

through energy clustering at sublattice level in orthorhombic

triggered by NIR excitation. Moreover, the luminescence

As is known, the intracongurational transitions of Ln3+ are

Figure 17. Enhancing upconversion emission eciency by tailoring