Author’s Accepted Manuscript

A review on nanostructured carbon quantum dots

and their applications in biotechnology, sensors,
and chemiluminescence

M.J. Molaei

www.elsevier.com/locate/talanta

PII: S0039-9140(18)31309-2
DOI: https://doi.org/10.1016/j.talanta.2018.12.042
Reference: TAL19390
To appear in: Talanta
Received date: 24 August 2018
Revised date: 11 December 2018
Accepted date: 13 December 2018
Cite this article as: M.J. Molaei, A review on nanostructured carbon quantum
dots and their applications in biotechnology, sensors, and chemiluminescence,
Talanta, https://doi.org/10.1016/j.talanta.2018.12.042
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 A review on nanostructured carbon quantum dots and their applications in

biotechnology, sensors, and chemiluminescence

M.J. Molaei*

Department of Chemical and Materials Engineering, Shahrood University of Technology,

Shahrood, Postcode 3619995161, Iran

*corresponding author e-mail: m.molaei@shahroodut.ac.ir

ABSTRACT

Carbon quantum dots (CQDs) are a member of carbon nanostructures family which have

received increasing attention for their photoluminescence (PL), physical and chemical stability

and low toxicity. The classical semiconductor quantum dots (QDs) are semiconductor particles

that are able to emit fluorescence by excitation. The CQDs is mainly referred to

photoluminescent carbon nanoparticles less than 10 nm, with surface modification or

functionalization. Contrary to other carbon nanostructures, CQDs can be synthesized and

functionalized fast and easily. The fluorescence origin of the CQDs is a controversial issue

which depends on carbon source, experimental conditions, and functional groups. However, PL

emissions originated from conjugated π-domains and surface defects have been proposed for the

PL emission mechanisms of the CQDs. These nanostructures have been used as nontoxic

alternatives to the classical heavy metals containing semiconductor QDs in some applications

such as in-vivo and in-vitro bio-imaging, drug delivery, photosensors, chemiluminescence (CL),

1
and etc. This paper will introduce CQDs, their structure, and PL characteristics. Recent advances

of the application of CQDs in biotechnology, sensors, and CL is comprehensively discussed.

Graphical Abstract:

Keywords: Carbon quantum dots; biomedical; bioimaging; drug delivery; sensors;

chemiluminescence

2
1- Introduction

CQDs have been the focal point of interest of many worldwide researchers in the recent years,

due to their unique properties such as small size (best for some bio-applications),

biocompatibility, PL properties, high-temperature stability, chemically inert structure and the

easy routes of functionalization [1]. CQDs are carbon nanoparticles which are usually surface

passivated and functionalized with organic or biomolecules. CQDs have a high cross-section for

two-photon excitation and are also nonblinking and water-soluble which besides nontoxicity that

makes them superior candidates in bioimaging [2]. The size of these clusters is usually <10 nm

and still is better to be <5 nm for some biological applications.

The semiconductor QDs with the sizes below 10 nm are synthesized from the groups II-VI or

III-V elements of the periodic table. In QDs, all three dimensions are below a certain critical size

that quantum confinement effect can occur and the mobility of the internal electrons is confined

in any directions. The conventional QDs are made from almost heavy metals. Many of the

conventional QDs are composed of cadmium and selenium [3]. Semiconductor QDs as two-

photon fluorescence materials (like CdSe and related core-shell QDs struc,tures) have been used

extensively in different in vivo and in vitro bioimaging [4]. The CQDs have water solubility,

acceptable biocompatibility, high fluorescence emission intensity, resistance to photobleaching,

neglectable cytotoxicity, and are chemically inert. While the synthesis of semiconductor QDs is

costly, the CQDs can be synthesized on a large scale and inexpensive [3]. The CQDs may have

functional groups such as hydroxyl, carboxyl, carbonyl, and epoxy that can result in their water

solubility. The functional groups on the CQD surface can bring them the potential for organic,

biological or polymeric functionalization [5]. Therefore, the CQDs can be considered as superior

alternatives to conventional semiconductor QDs in order to overcome problems such as

3
expensive synthesis, toxicity, and environmental problems concerns which are accompanied with

semiconductor QDs [3].

There are some other almost new carbonaceous materials with fluorescent properties. The

fluorescent carbonaceous materials include graphene quantum dot (GQD) [6-14], polymer dots

(PDs) [15, 16], carbon nanotube dot [17, 18], graphene oxide (GO) [19-22], nanodiamonds

(NDs) [23-31] and CQD [4, 32-44]. The NDs are composed of carbon atoms with sp3

hybridization in the core and carbon atoms with the graphitic structure on the shell [45]. The PDs

are dots with bright fluorescence composed of aggregated polymers or π-conjugated polymers

with a typical particle size of less than 100 nm that consist of discrete discontinuous phase in

water or other low molecular-weight liquids as a continuous medium [46].

Although the CQDs and GQDs are dots that consist of carbon atoms and the whole QD is

covered with functional groups, they differ in structure, synthesis methods, properties, and

applications. Graphene is a 2D sheet of carbon atoms which has a honeycomb structure with sp2

hybridization. The shape, size, and thickness of graphene sheets can have a strong influence on

its properties. The GQDs have quantum confinement and edge effects [47]. Graphene can be

considered as a semiconductor which has a zero bandgap and infinite exciton Bohr diameter.

Therefore, it is expected to confinement effects can be exhibited in any fragment of graphene

sheet; however, the typical size of GQDs might be supposed below 20 nm. Electronic transport

in all three dimensions of a GQD is confined. The GQDs with a non-zero bandgap, show

luminescence phenomenon. The bandgap in GQDs can be tuned through altering the surface

chemistry and changing the size of GQDs fragments. What should be noted is that the PL

bandwidth of GQDs is wider than that of semiconductor QDs. Furthermore, by increasing the

excitation wavelength in GQDs, their PL maximum undergoes a red-shift and decreases [6].

4
Similar to graphene, the GQDs have carboxylic acid moieties on their edges and hence, this

makes them water soluble and helps for an easy functionalizing with organic, inorganic,

biological, and polymeric species. The GQDs have better surface grafting through a π-π

conjugated network of surface groups [48]. The GQDs usually have a crystalline structure and

also are anisotropic with larger dimensions in basal plane and smaller dimensions in height.

The CQDs differ from other carbon dots such as GQDs that have been the focus of several

researchers over the past 20 years. The GQDs have the structure of graphene lattice within the

dot while the CQDs have crystalline or amorphous structure. The GQDs are composed of one or

a few layers of graphene sheets, while the CQDs are quasi-spherical discrete carbon

nanoparticles typically below 10 nm in diameter [49]. The carbon atoms in CQDs and GQDs

have sp2 bonding. Based on the fringes seen via HRTEM, the CQDs have a fringe spacing of

0.34 nm corresponding to the (002) interlayer spacing of graphite. The fringe spacing for GQDs

is 0.24 nm corresponding to the (100) interlayer spacing of graphene. Therefore, the GQDs are

graphene fragments (with the thicknesses less than 2 nm) [5].

The GQDs are synthesized through nanolithography or by chemical breakdown of GO [38].

The CQDs can be synthesized via different top-down or bottom-up synthesize procedures from

organic or inorganic starting materials. Using organic ingredients such as fruit juice [42] might

result in lower toxicity for the synthesized carbonaceous dots. CQDs can be used in several

applications including photovoltaic cells to bioimaging (Fig. 1).

In this research we will focus mainly on the CQDs; however, for PL mechanisms we will

discuss GQDs, as well. The fluorescence in CQDs arises from the defects and in GQDs is caused

by defects and/or isolated π domains of graphene sheet [50].

5
 The carbon-related PL is originated from the passivated surface defects which act as excitation

energy traps or is originated from conjugated π-domains. The CQDs can also show two-photon

excitation in NIR [4]. In single- and multi-walled carbon nanotubes (CNTs), fluorescence arises

from passivated surface defects. The fluorescence in CNTs occurs in a wide range of excitation

wavelengths from UV to NIR. The CNTs fluorescence inspired the origin of fluorescence in

CQDs. Since CQDs are nanoparticles of carbon with numerous surface defects, they might also

emit fluorescence by surface-passivated defects [50].

This review is intended to survey the recent advances in the fast-evolving field of CQDs

research and aims to update biomedical, sensors and CL applications of CQDs in order to place

emphases on challenges and future perspectives for their development.

2- Different types of photoluminescence emissions in CQDs

The exact fluorescence mechanism in the CQDs is not clear yet and has been a controversial

issue among scientists. Although there have been the proposed mechanisms for the origin of the

PL in the CQDs, there are not adequate experimental examinations confirming the theoretical

models. Generally, two models have been proposed for the PL mechanism in the CQDs. These

two models are the CQDs fluorescence emission originated from conjugated π-domains and/or

surface defects that are discussed below.

2-1- Photoluminescence emissions originated from conjugated π-domains

Size-controlled PL emission of semiconductor nanocrystals is one of the most attractive

properties of these materials [51]. Quantum size effects [52] results in increasing the band gap of

the semiconductor nanocrystals as their size decreases. For example, for CdSe QDs, the emission

6
color of PL shifts from red (centered at 650 nm) to blue (centered at 450 nm) with a decrease in

QD size. PL quantum yield (QY) which is a measure of PL brightness of semiconductor

nanocrystals, strongly depends on the synthesis method and varies from synthesis to synthesis

[53]. Unfortunately, the reproducibility, as well as the stability of the PL are not predictable [54].

There have been several attempts for surface modification of QDs to enhance their luminescence

efficiency and colloidal stability. Passivation of both anionic and cationic surface sites using

organic ligands is not an easy process. Therefore, dangling bonds cannot be removed completely.

Several inorganic surface modification methods have been applied in order to passivate both

anionic and cationic surface sites [55]. For example, CdSe QDs have been covered with CdS

[56-58] or ZnS [59] in them the band gap energy of the core stands within the band gap energy

of the shell and the photogenerated electrons. This core/shell structure of semiconductor QDs can

tolerate chemical degradation or photo-oxidation to some higher extent [55].

GQDs belong to the fluorescence carbon materials such as nanodiamonds, fluorescence CNTs,

and fullerene. Studying the PL mechanism of GQDs as a simple model system can help us to

understand the PL mechanism of other fluorescence carbon nanostructures [60]. Similar to

semiconductor QDs, the electrons are confined in conjugated π-domains of graphene sheets.

Therefore, we can name them graphene quantum dots (GQD), knowing that the electron

confined π-domains are not real dots. PL color dependence on the π-domain size of graphene

sheets is manifested to a lesser extent in comparison to semiconductor QDs. CQDs are

photoactive, with the π-plasmon absorption covering UV/Vis and NIR spectral regions [61].

Graphene sheet has an extended π-network which can be considered as a large planar aromatic

molecule. Graphene, however, has different electronic transitions in comparison with aromatic

molecules. The π-domains are isolated as sp2 hybrid islands which are rich in π-electrons and are

7
created through reduction of graphene oxide (reduced graphene oxide (rGO)). Graphene oxide is

obtained by harsh oxidizing conditions applied on graphite flakes (Hummers method) and this

condition exfoliates the graphite into single-layer sheets of GO. There is no connection between

sp2 islands of graphene sheets. In fact, if there are any π-connections between sp2 islands of

graphene sheets, interisland quenching of fluorescence emission occurs [33, 62]. Bandgap

fluorescence requires preserving a single-layer configuration after partial conversion to rGO or

applying other methods for inducing isolated sp2 islands. In an effort [63] with the aim of

fluorescence emission, oxygen plasma etching was applied to treat graphene sheet. However, in

spite that single layer sheets emitted fluorescence, multiple layers did not emit due to the

quenching.

GQDs with a single layer of carbon and functional groups on the surface and edges have a

chemically similar structure to GO which includes oxygen-based functional groups on the

graphene plane or its edges. Therefore, sp2 domains in GO are between C-O sp3 domains of

epoxy and hydroxyl groups [64]. It has been reported that in graphene oxide (GO) thin films

deposited via exfoliated suspensions, the isolated sp2 clusters within the carbon-oxygen sp3

matrix results in electron-hole pairs localization and radiative recombination of small clusters.

The optoelectronic properties of carbon materials including sp2 and sp3 bondings is dictated by π

states of sp2 sites. The π and π* electronic levels of sp2 clusters is lying localized between σ and

σ* states bandgap of the sp3 matrix. These sp2 domains act as luminescence centers as a result of

recombination of electron-hole pairs. The bandgap is affected by the fraction of sp2 domains,

their size, and shape. Based on calculations, in chemically derived GO, the sp2 clusters of

conjugated repeating units leads to a bandgap corresponding to blue emission [19]. The PL

8
spectrum of GO varies from visible to NIR. This wide emission spectrum of GO is due to the

wide size distribution of sp2 domains that have different band gaps [64].

The PL spectrum of GQDs can be considered the transition from the lowest unoccupied

molecular orbital (LUMO) to the highest occupied molecular orbital (HOMO). The bandgap of

HOMO-LUMO depends on the GQDs size and decreases as the GQDs size increases. Therefore,

different mixtures of GQDs with different sizes, have different PL spectra [48]. Kwon et al. [65]

synthesized GQDs through the amidative cutting of tattered graphite in the range of 2 to 10 nm,

easily with changing the amine concentration. They observed that by increasing the size of the

synthesized GQDs the energy gap decreases and the PL changes from blue to brown. Tan et al.

[66] used electrochemical exfoliation of graphite in K2S2O8 and showed that red fluorescence

GQDs are isolated sp2 domains with the size of 3 nm. The domains were generated by SO4-

radicals as scissors to cut graphene to isolated sp2 domains.

Synthesize of CQDs with different size and nitrogen content resulted in CQDs which generate

RGB luminescence with a stable and bright emission [67]. However, most of the times the PL

color of CQDs can be tuned via surface groups rather than size. Therefore, it is not efficient to

control the PL color in CQDs by controlling their size [64]. On the other hand, the PL is not

exclusively affected by the CQDs size; but is affected by functional groups, edge, and size in a

synergic manner [60].

2-2- Photoluminescence emissions originated from surface defects

Many distinctive fluorescences in graphene materials cannot be explicated via emission caused

by sp2 islands. Functionalized surface defect sites in GQDs can facilitate strong blue emission

and high upconverted photoluminescence. Surface passivation in GQDs results in higher

9
fluorescence performance and upconversion properties [68]. It has been reported that surface

defects formed by surface oxidation would be as capturing spots of excitons and this, in turn,

results in the surface-state-related fluorescence. More defects on the surface of CQDs forms by a

higher degree of surface oxidation. This leads to narrowing energy levels and red-shift [69]. The

surface defects can be any site that has not a perfect sp2 domain and acts as an energy trap. The

functionalized surface defects as well the sp2 and sp3 carbons that exist in the CQDs could

contribute to multi-color emission [33].

Functional groups on the CQDs could have different levels of energy that results in different

emissive traps. By illuminating the CQD with a certain excitation wavelength, the emission is

dominated by surface state emissive trap. If the surface oxidation degree is higher or if some

modifications are made, more surface defects forms which result in red-shift emission [64].

Wang et al. reported that in CQDs and GQDs the common origin of green luminescence

emission centers is assigned to the edge states that are composed of carbon atoms on the edge of

carbon backbone and functional groups that include C=O like carbonyl and carboxyl groups.

They suggested that the competition between emission centers (edge states) and traps can

conquer the optical properties of these structures [70].

Furthermore, it has been claimed that quasi-molecular fluorescence of GO arises by carboxylic

acid groups coupled electronically by the adjacent atoms of the graphene sheet which forms

quasi-molecular fluorophores similar to polycyclic aromatic compounds [71]. Strong and

spatially uniform PL across the flakes can be induced in single-layer graphene sheet using an

oxygen plasma treatment. The PL is connected to elastic scattering spectra distinctly different

from those of gapless pristine graphene [63]. The mentioned quasi-molecular fluorescence and

graphene PL after plasma treatment are non-bandgap PL which are attributed to the defect size in

10
the graphene sheets. As discussed in the previous section, being a single sheet is required for

occurring PL in bandgap related emissions of graphene in order to suppress substantial interlayer

quenching. However, being a single sheet is not required for PL occurred via defect-derived

origin ones [62].

Some defects on the graphene sheets and on the CQDs are similar. Therefore, it expected that

these two carbon structures have common PL mechanism. The emission mechanism of CQD

which is adopted in recent years is a radiative recombination of electron-hole pairs that are

confined on the surface. The electron-hole pairs are generated by photo-induced charge

separations in CQDs. Passivation of the dot surface by organic or inorganic compounds creates

more stable surface sites for the effective radiative recombination [62]. Surface passivation of

CQDs has a strong effect on PL performance. Passivation of CQD using oligomeric

poly(ethylene glycol) diamine (PEG1500N) molecules, results in green fluorescence emissions

with QY near to 20% which with further processing with the aim of better surface passivation the

QY reaches to 50% [2]. Passivation of CQD by a combination of doping with nanoscale

semiconductors and organic functionalization, coupled with gel column fractionation to harvest

the most fluorescent carbon dots, showed a high QY of 78% (Fig. 2) [43].

Changing of surface chemistry in GQDs can alter or suppress the emission from surface

defects. The surface chemistry of GQDs can be altered through reduction or modification and as

a result, the green luminescent emission of the GQDs would change to the blue. During the

reduction of GQDs, the epoxy, carbonyl, and amide groups change to -OH groups. In fact, the

chemical structure changes by reduction or modification via replacing of -COOH and epoxy

groups which induce non-radiative recombination of localized electron-hole pairs. This

11
suppresses non-radiative recombination and enhances the integrity of surface π electron network.

Therefore, in reduced GQDs the intrinsic state emission dominates the defect state emission [72].

In another work on the effect of functional groups of CQDs on their fluorescence, samples of

CQDs with similar size distribution and graphite structure and with different surface state and

different degree of oxidation showed red-shift in emission from 440 to 625 nm. The red-shift in

these samples was attributed to the gradual reduction in bandgaps by increasing of oxygen

species in the structure of the CQDs surfaces. Their work showed that the energy bands depend

mainly on the surface structure and functional groups, not on the CQDs size [73]. The PL tuning

via amino functional groups is also has been reported [10, 74, 75]. Dong et al. which synthesized

CQDs in the range of the 4-10 nm and functionalized with branched polyethylenimine found that

the fluorescence emission of the synthesized CQDs is excitation wavelength independent. Since

the surface state of the synthesized CQDs was similar and the CQDs sizes were different,

therefore, the fluorescence emission could be mainly due to the surface state CQDs [76].

The PL shift of GQDs can occur as a result of charge transfer between GQDs functional

groups. For example, Jin et al. showed that the GQDs band gap and hence, PL can be tuned by

changing electron density in GQDs which occurs via applying functional groups on them [75].

Functionalizing of GQDs does not always give result in direct bandgap changes, but can form

energy levels within the bandgap. First-principles calculations on amino-functionalized GQDs

showed that amine edge termination (NH2) forms an interband within the bandgap of GQDs

which is responsible for tunable PL emission. The additional interband within the bandgap is due

to the hybridization of p orbital of C–N atoms at the edge sites [74].

The PL in GQDs can also be tuned by changing the pH. The PL shift as a result of changing in

pH could be due to the protonation/deprotonation of functional groups. Experiments and

12
calculations based on density functional theory (DFT) confirm that electron-donating and

electron-withdrawing of the functional groups applied on the GQDs can tune the bandgap which

this, in turn, causes a PL peak shift [75]. Yuan et al. synthesized GQDs which have different

colors of fluorescence in different pH values from 1 to 14 [77]. The fluorescence of the CQDs

which their surfaces were capped with branched-polyethyleneimine (BPEI) was dependent on

the pH. The fluorescence activity of the BPEI-capped CQDs decreases by increasing pH more

than 9.0. This pH dependence has been attributed to the protonization of the amino groups on the

capped CQDs surfaces. Below the pH of 9.0, the BPEI is charged positively and hence, the

stability and fluorescent activity of the CQDs increases by decreasing pH due to their

electrostatic repulsion. The fluorescent activity again decreases in the acidic media (pH < 4) that

is probably because of the high positive charges carried by the BPEI which might inhibit the

excitation process of CQDs [76].

3- Applications of CQDs

CQDs have been the subject of numerous researches in several fields such as biomonitoring,

sensors, photocatalysis, drug and gene delivery, solar energy conversion and LEDs. However,

still more researches are needed in order to lead to their development in these applications. Some

of the CQDs applications will be discussed in the following sections. Table 1 summarizes

examples of the CQDs applications in bioimaging, drug delivery, gene delivery, sensor, CL, and

their synthesis methods and achieved quantum yields.

13
 3-1- Biomonitoring

Real-time dynamic observation of bio-molecules in live cells can elucidate many hazy

phenomena in cell biologies such as molecules translocation, interaction with partners, and

response to environmental cues [93]. Single particle tracking (SPT) is a technique which is

enabled to track single bio-molecules with high resolution [93, 94]. By using brighter probes,

like semiconductor QDs in SPT, actual molecular dynamics can be monitored. Photo-physical

properties of semiconductor QDs depends on chemical composition, shape, size and surface

modifications. Semiconductor QDs advantages such as wide absorption spectra, narrow emission

band and being orders of magnitude more photo-stable than organic dyes have made them as

superior candidates in live cells biomonitoring for long tracking trajectories [93]. Apart from the

conventional semiconductor QDs which suffer from toxicity due to the presence of the elements

such as Cd and Pb in their structure, other nanostructures such as CQDs capable of showing

bright and colorful fluorescence emission have been recently introduced for biomonitoring [50].

CQDs have potential bioimaging applications in several fields which are described in the

following sections.

3-1-1- Cell imaging in vitro

The CQDs have some advantages such as physicochemical stability, non-blinking,

biocompatibility and aqueous solubility that makes them suitable for bioimaging. CQDs can be

readily taken by cells and enable cell imaging via both one and multiple photon excitations [50].

Sun et al. synthesized CQDs with the possibility of using them for cell imaging and beyond. The

CQDs synthesized with laser ablation of a carbon target (baked and cured graphite powder and

cement mixture) in the presence of water vapor by using a carrier gas. The non-emissive CQDs

14
showed PL after acid treatment and passivation by attaching organic species such as PEG1500N

to the surface of the dots (Fig. 3). The PL was also observed using confocal microscopy after

incubation of E. coli ATCC 25922 cells with the treated CQDs [95].

Bhunia et al. [78] reported the application of chemically synthesized CQDs for biological

labeling and imaging. Fig. 4 shows the TAT peptide- or folate-functionalized CQDs which were

mixed with cell culture medium, and after incubation for several hours were imaged with a

fluorescence microscope. The CQDs had controlled emissions in colors such as blue, green,

yellow and red. The QY for the synthesized CQDs was in the range of 6-30% [78].

The intensity of the CQD PL is dependent on the doped nitrogen content. Nitrogen doping can

be used for improving emission characteristics. For example, nitrogen-doped CQDs with a core-

shell structure of a carbon core and the oxygen-containing shell were used for cell imaging. After

2 h of incubation of the nitrogen-doped CQDs with HeLa and HepG2 cells, the cells illuminated

with multicolor emissions when excited with 405, 488, and 543 nm laser pulses. It was observed

that nitrogen-doped CQDs were concentrated in the cytoplasm and infiltrating into the cell nuclei

was not remarkable [96]. In another research, cell imaging using nitrogen-doped CQDs which

was prepared by bombyx mori silk and via hydrothermal procedure was investigated on human

lung cancer (A549) cell lines through CKK-8 assay. It was observed that the major part of the

CQDs reaches into the cell nucleus and illuminate the whole cell. The experiment showed that

PL intensity does not reduce even after excitation for a long time. In fact, it has been suggested

that the synthesized CQDs are alternative candidates for organic dyes (which are easy to photo-

bleach) and semiconductor QDs (which have bio-toxicity concerns) [97]. Fluorescence

15
microscopy of MCF-7 cells which were incubated with nitrogen-doped CQDs (with QY of

46.2%) for 24 h, resulted in colorful PL with no substantial change in shape and viability of the

cells [88]. Ray et al. synthesized CQDs with a diameter of 2-6 nm and QY of about ∼3% through

oxidation of carbon soot with nitric acid. It is claimed that the CQDs have graphitic structure and

nitric acid oxidation incorporates nitrogen and oxygen atoms into the CQDs which results in

water solubility. In order to study cell labeling of CQDs, Ehrlich ascites carcinoma cells (EAC)

collected from the peritoneal cavity of adult female mice after 7 days of inoculation and the

suspension was mixed with CQDs solution incubating for 30 min. Imaging under UV blue

excitation resulted in illuminated cells with bright blue-green and imaging under blue excitation

resulted in illumination in yellow. Control samples with no CQDs were colorless under UV

excitation [37].

Surface passivation of CQDs makes them strongly photoluminescent in solid state or in a

solution. In this case, the spectral features of CQDs would be similar to surface-oxidized silicon

nanocrystals [95]. In fact, the emission is due to the trapped surface energy on the CQDs surface.

As an example, surface passivated CQDs were used as wavelength-tunable optical nanoprobe to

target HeLa cell line cancer cells. Passivation was done with polyethylene glycol (PEG) chains,

polyethylenimide-co-polyethylene glycol-co-polyethylenimide copolymer, and 4-armed PEG

molecules and the CQDs conjugated with transferrin. It is assumed that surface passivation leads

to more absorbing centers on the CQDs [98]. PEG1500N-capped surface passivated CQDs with

an average diameter of 1.5–2.5 nm were applied as bioimaging agents for labeling of E. coli

cells. These cells were covered thoroughly with the CQDs and the dots could emit PL using

excitations from a broad range of wavelengths. The CQDs internalized in murine P19 progenitor

16
cells as well. Photo-stability of the used CQDs was high and accompanied by low photo-

bleaching and no blinking [99].

In most of the reported cell imaging using CQDs, it has been observed that CQDs are

internalized by the cell through endocytosis, while remarkable infiltration to the cell nucleus is

not observed [33]. Zhang et al. synthesized CQDs via one-pot hydrothermal oxidation of

nanodiamond and used them for cell imaging. Cell internalized CQDs excited by 405 and 458

nm wavelengths, emitted green and green-yellow fluorescent emissions. The images confirmed

that CQDs could uptake by the cells and accumulate in them. In the confocal laser scanning

microscopy (CLSM) images, numerous dark areas were seen that might be cell nucleus. In fact,

CQDs could translocate into the cells and locate at cytoplasm [100]. In another attempt for cell

imaging, it was seen that CQDs with an average diameter of 5 ± 2 nm, synthesized from coffee

grounds were localized in the cell membrane as well cytoplasm of LLC-PK1 cells [101]. Ehrlich

ascites carcinoma cells (EAC) were incubated with an aqueous solution of CQDs for 30 min. It

was seen that CQDs enter into the cells which as a label can be detected using a fluorescence

microscope [37]. CQDs exhibited a uniform distribution in the cytoplasm when MCF-7 cells

were incubated with 3-4 nm hydrothermally synthesized CQDs for 24 h. Outstanding

luminescence of the CQDs in the cells was observed with excitation at a wavelength of 405 nm

[102]. Cell membrane and cytoplasm and areas surrounding cell nucleus had the most emission

in an in vitro cell imaging of CQDs incubated with HeLa cells [103]. The cellular uptake

assessments of the synthesized CQDs from the carbon source of sodium alginate via

hydrothermal carbonization method showed that both caveolae- and clathrin-mediated

endocytosis pathways are included in the cellular uptake of CQDs/plasmid DNA (pDNA)

complexes. The pDNA finally enters the cell nucleus while the CQDs remains outside the cell

17
nucleus [104]. CQDs and Cy5-labeled DNA (DNA-Cy5) were incubated with A549 cells and

were observed at different time intervals. NR12S was used for labeling cell membrane (Fig. 5). It

was observed that the blue color of CQDs fluorescence could be detected after 1 h incubating

and the fluorescence intensity increases with increasing incubation time. The red fluorescence is

almost restricted to the outside of the cells. On the other hand, it can be concluded that

CQDs/DNA-Cy5 complexes disassembled in the cells and released DNA molecules have weak

fluorescence which cannot be detected [105].

The reported fluorescent carbon nanoparticles for using in cell imaging is not confined to the

CQDs. Larger hollow carbon nanoparticles can also show fluorescence properties and can be

used for bioimaging. Fang et al. [106] used cross-linked hollow fluorescent carbon nanoparticles

(HFCNs) without the modifier/surface passivation agent as a bioimaging material. They reported

that no remarkable decrease in the fluorescent intensity observed (>95% normalized intensity in

5000 s) that means the HFCNs have suitable photo-stability. Comparison of cellular imaging

photo-stability of the HFCNs, CdTe QDs and the organic dye (fluorescein isothiocyanate (FITC),

Hoechst)) elucidated that the cells containing HFCNs were detectable after 25 min, while those

labeled with CdTe QDs, FITC, and Hoechst almost were not detectable with the same

conditions. Extended laser exposure up to 100 min resulted in almost no change in the green

fluorescent emission of HFCNs [106].

One of the advantages of the CQDs for bioimaging is their photostability and resistance to

photobleaching. For example, The CQDs that were synthesized from pyrolysis of the waste

plastic residue were employed for fluorescence imaging of MDA-MB 468 cells. The CQDs had

18
high photostability. The CQDs showed low photobleaching and the fluorescence intensity

observed from the cells was stable for 1 h after constant excitation [89].

The CQDs can also be used in multifunctional fluorescence imaging/magnetic resonance

imaging (MRI) drug delivery systems. For example, Fe3O4@CQDs coated CNTs were used for

photodynamic and photothermal therapy (PTT) with the aid of 808 nm laser irradiation. The

synthesized platform was also loaded with doxorubicin (DOX) to be used in drug delivery. The

platform was conjugated with a sgc8c aptamer. The resulted nanovehicle was used for targeted

fluorescence imaging/MRI. When the nanovehicle was incubated with lung cancer cells and was

irradiated with a laser, was able to kill most of the cancer cells. This phenomenon was attributed

to the generation of OH· and ·O2 and simultaneous DOX release and heat generation [107].

Dual-modal fluorescence imaging and MRI has been also reported by using Gd(III)-doped CQDs

synthesized through hydrothermal method. Incorporation of Gd into the solid matrices results in

tumbling of the Gd complex. Therefore, the r1 relaxivity will be augmented [108]. Other multi-

functional therapy and/or diagnosis systems based on the CQDs such as CQDs doped with Gd,

Mn and Eu for fluorescence imaging and MRI [109], gold/Gd-doped CQDs for simultaneous

MRI and photothermal ablation (PTA) therapy [110], FeN@CQDs conjugated with folic acid

and riboflavin for simultaneous photodynamic therapy (PDT) and PTT [111], gadolinium oxide–

iron oxide core with mesoporous silica sell gated with CQDs for drug delivery, fluorescence

imaging, and MRI [112] have also been used.

Food, fruit juices and natural precursors can be used for the synthesis of CQDs. Using natural

precursors may result in lower toxicity for the synthesized CQDs which is beneficial for

bioimaging and other biomedical applications. As an example, Citrus sinensis and Citrus limon

peels were used to synthesize CQDs through carbonization route. The CQDs were used for in

19
vitro imaging. The cell viability for the cell lines that were incubated for 48 h with 400 μg/mL of

the synthesized CQDs was above 90% [113]. The CQDs that were synthesized from carbonized

walnut shells as a natural precursor did not show toxicity on MC3T3 cells in an MTT assay with

an exposure time of 72 h and a concentration of 100 μg/mL [114].

3-1-2- Cell imaging in vivo

The fluorescent nanomaterials have been used as contrast agents in bioimaging in vivo. The main

requirements for application of nanomaterials for in vivo bioimaging are high fluorescence

intensity, biocompatibility and nontoxicity. The fluorescent nanomaterials should also resist

photobleaching for in vivo bioimaging. The application of QDs instead of conventional organic

dyes for in vivo bioimaging has been proposed in the literature. CQDs can be used for in vivo

cell imaging due to the excellent fluorescence properties and null toxicity [115].

Yang et al. first reported using of CQDs for optical imaging in vivo. The results revealed that

CQDs could act as a brightly fluorescent contrast agent in live mice. CQDs and ZnS-doped

CQDs which was passivated by PEG diamine were used for in vivo imaging. The injected CQDs

diffused relatively slowly and the emission faded at ∼24 h post-injection. ZnS-doped CQDs had

brighter green fluorescence and were used to track the migration through lymph vessels. QDs

like CdSe/ZnS migrate to axillary lymph nodes in minutes. However, the CQDs migration was

slow due to the small sizes (< 5 nm) and due to functionalization with PEG chains which protein

resistance characteristics might reduce interactions of the CQDs with lymph cells [115]. In a

tissue imaging experiment, it was observed that the CQDs can be uptaken by the stomach and

reach to liver and kidney by blood circulation and be used for imaging of liver and kidney [116].

20
 The in vivo imaging is preferred to be done at longer wavelengths due to the better photon

tissue penetration. For example, the CQDs have been synthesized by harsh oxidation of MWNTs

and were injected subcutaneously into a nude mouse at three different locations. By using blue,

green, yellow, orange, red, deep red, and NIR light excitations in vivo imaging performed. The

signal-to-background separation was better for the images taken under longer-wavelength

excitation (595 nm and beyond). As it is evident in Fig. 6, at longer wavelengths the fluorescence

emission of CQDs is weaker. However, at longer wavelengths excitations (red and NIR) signal-

to-noise increases due to the decrease in the tissue auto-fluorescence background. In fact, due to

the photon tissue penetration as well as decreased background auto-fluorescence, in vivo

imaging is preferred to be performed at longer wavelengths (NIR region) [117].

The pH in physiological conditions is an important parameter for controlling and diagnosis of

different diseases. If the pH deviates by 0.10–0.20 pH units from a normal pH of 7.40, can result

in cardiopulmonary and neurological problems such as Alzheimer. Conventional down-

conversion fluorescent materials that absorb a higher-energy excitation photon and emit one

lower-energy fluorescence photon (such as semiconductor QDs and organic dyes) are not

preferred for pH evaluation in living cells since the application of high energy photons can cause

problems such as auto-fluorescence of biological samples and in some cases introducing

damages to the cells. CQDs can be used as pH probes in the living cells. CQDs based two-

photon fluorescent probe with high photo-stability and low cytotoxicity were used for two-

photon imaging and biosensing of pH gradients in tissues and living cells. Through this

approach, real-time imaging and biosensing of pH have been executed in living human lung

21
cancer A549 cells, mouse LLC-MK2 cells, and tumor tissues generated by implanting tumor

cells [118].

The CQDs can be used for nucleus imaging as well. The nucleolus is the site for ribosomal

RNA (rRNA) production and ribosome factory of the cell. It was shown that the CQDs can be

used for fixed cell nucleolus imaging and also tracking of the nucleolus-related behaviors of the

living cells. The CQDs after cellular internalization have a rapid movement toward the nucleus

within 5 min of incubation while kept localized even after 24 h. This indicates that CQDs can be

used as dyes for nucleus fluorescence imaging. The mechanism of nucleolus-targeting is

selectively binding of the CQDs to RNA (instead of DNA) after nucleus entrance. The

conjugation of the CQDs with protoporphyrin IX (PpIX) photosensitizer and application for in

vivo experiments showed effective tumor accumulation and retention which might be due to the

extended blood circulation due to the negative charge, small size, augmented cellular uptake and

good targeting for nucleus [119].

3-2- Drug delivery systems

Recent advances in nanomedicine have resulted in drug delivery systems that are capable of

targeting and delivery of the drug to the specific parts of the body. The drug delivery systems are

sometimes conjugated with fluorescent nanomaterials for imaging. The QDs with small sizes,

various surface chemistry, and at the same time fluorescence properties have been used in

therapeutic applications as an effective drug delivery vehicle. The nanovehicle localization can

be done in vitro or in vivo using methods such as high-performance liquid chromatography

(HPLC) and by the aid of fluorescence emission properties of some of the drugs which are time-

consuming methods [120]. QDs have been used for developing numerous drug delivery systems

22
in recent years [121-126]. The CQDs which are mainly composed of C, N, O and H atoms are

excellent candidates for drug delivery systems as well. The CQDs with small sizes less than 10

nm have attracted attention for drug delivery systems due to their superior properties such as

fluorescence emission, facile preparation, easy functionalization, biocompatibility, aqueous

solubility, no toxicity, and chemical inertness [127].

The DOX is one of the most used model anticancer drugs in drug delivery systems. The DOX

has also been loaded on CQDs for drug delivery. The possible mechanism for DOX loading on

the CQDs is functional groups that make bonding between the CQDs and DOX. On the other

hand, the electrostatic interaction between positively-charged DOX and negatively-charged

CQDs as well as hydrophilicity of the CQDs which promotes hydrogen bonding between DOX

and CQDs are the main proposed mechanisms for observed enhanced drug loading on the CQDs

[83]. Different steps of the drug delivery of CQDs-DOX include a) CQDs-DOX entry into the

cells (through endocytosis) and forming vesicles, b) transporting CQDs-DOX vesicles into the

lysosomes and c) release of the protonated DOX (in lysosomes acidic environment) and entry

into the cell nuclei [128]. By the aid of electrostatic interactions, DOX was loaded on CQDs that

were anchored onto the heparin (an auxiliary medicine) to make a CQDs-heparin-DOX pH

sensitive nanovehicle for drug delivery [129]. Mitomycin drug can also be loaded on CQDs via

hydrogen bonding and then could be released through the breaking of this bond in the acidic

environment of the tumor [130].

Monitoring of the CQDs fluorescence in the delivery systems and checking the location of

emission (regarding the cell nucleus) can determine living and apoptotic cancer cells. CQDs

were incorporated into hydrogels (with/without 5-Fluorouracil, an anticancer drug) to be uptake

by A549 cells. Fluorescence microscopy observations revealed green emission from CQDs and

23
blue emission from cell staining dye Hoechst 33342 using an excitation wavelength of 360 nm.

The green emission from CQDs was concentration dependent and increased with increasing

CQDs concentration in the gel. Living cells could be characterized by nucleus which is deprived

of fluorescence. However, it was observed that cell size reduction shifts the location of the

fluorescence from cytoplasm to nucleus [131].

The application of CQDs in drug delivery systems could result in a more localized drug-loaded

CQDs in tumor cells compared to the using drug alone. CQDs that were synthesized

hydrothermally from milk were used for DOX delivery to cancer cells. It was observed that

DOX-loaded CQDs were more toxic to the adenoid cystic carcinoma cell line (ACC-2)

compared to the mouse fibroblast cell line (L929). The fluorescence imaging showed that

compared to the DOX alone, the drug delivery system of DOX-loaded CQDs was more localized

in the tumor cells nuclei with a faster rate of apoptosis in the ACC-2 cells [83]. In another in vivo

test, cancer cell growth inhibition of DOX conjugated CQDs showed a better progress compared

to the free DOX injection. In order to verify the DOX conjugated CQDs activity in the body,

these delivery systems were incubated with HepG2 and MCF-7 cells to investigate their

pharmaceutical and imaging characteristics. The MTT cell proliferation assay revealed that the

cytotoxicity of DOX conjugated CQDs in cancer cells (HepG2 and MCF-7) is more than their

cytotoxicity in normal cells (CHO-K1 and COS-7). The DOX conjugated CQDs were excited

with a wavelength of 380 nm via a two-photon laser scanning confocal microscope (Fig. 7).

Almost no background fluorescence was seen for HepG2 cells. By 24 h incubation with HepG2

cells, the fluorescence of DOX conjugated CQDs was detected in the cytoplasm, while the free

CQDs translocated into the nuclei. This has been attributed to the smaller size of the free CQDs

24
compared to those which are DOX conjugated. The bare CQDs had superior photo-stability even

after 240 h (aqueous conditions) as well as low cytotoxicity (2 mg mL-1) [132].

Deng et al. developed a multifunctional Nitric oxide (NO)-delivery platform with target

directing, light-controlled NO delivery and fluorescence tracking. In this platform, ruthenium

nitrosyl and folic acid molecules were bonded covalently on CQDs. The platform can recognize

certain cancer cells via FA–folate receptor binding and the fluorescence emission of CQDs

makes this platform trackable in the cellular environment [133].

In another research, the nanogel network as a functionalizable non-fouling matrix was used for

drug loading and CQDs were responsible for the fluorescence signals in real-time imaging. The

labeled dextran, encapsulated in nanogels could release in a controlled manner. The studies on

this vehicle demonstrated that the folic acid-conjugated nanogel via the folate receptor could be

internalized into the cancer cells, missing normal tissue cells. This makes the vehicle as a

superior targeted delivery system with the ability to be monitored via the CQDs emission [134].

Hollow CQDs have been also used for drug delivery systems that take advantage of rapid

uptake by the cells. The hollow CQDs does not affect drug activity and can be used for the pH-

controlled release of the drug. In an attempt, hollow CQDs with a diameter of 6.8 nm and QY of

7% that were synthesized via solvothermal reaction of bovine serum albumin, were used as a

delivery system for DOX. The DOX loads and get physisorbed on hollow CQDs through

interactions such as van der Waals, π-π stacking and hydrophobic. DOX was loaded up to 6 wt%

on the hollow CQDs. The CQDs-DOX solution did not aggregate, was stable for several weeks,

and was able to emit red fluorescence under UV. In vitro experiments determined that about 4%

and 70% of DOX releases at pH 7.4 and pH 5.0, respectively. The conditions of pH 7.4 and pH

25
5.0 is a simulation of the extracellular environment and intracellular lysosomes, respectively.

Incubation for 24 h resulted in CQDs-DOX systems to reach to the cell cytoplasm and to

surround the nuclei. On the other hand, CQDs-DOX were able to be internalized by A549 cells

and localize in the cytoplasm. The fluorescence of DOX showed that the drug could reach to the

cell nuclei [128].

CQDs can be used in polymer-based nanovehicles. The polymer dendrimers with three-

dimensional architecture and numerous functional groups on the outer side of the dendrimer can

be used as a suitable platform for drug delivery to them CQDs as fluorescence agents can be

attached. CQDs with anionic terminus noncovalently combined via self-assembly to cationic

acetylated G5 Poly (amidoamine) dendrimers and encapsulating chemo-drug epirubicin (EPI)

inside the dendrimer branches were used as a therapeutic vehicle for cancer treatment. CQDs

fluorescence improves in the vicinity of amine groups of the dendrimers and is used for tracking

the distribution and cytotoxic effects of the drug. Apoptosis-inducing ability of the mentioned

complex in breast cancer (MCF-7) cells was confirmed [135].

CQDs have been used for delivery of neurological diseases drugs as well. Dopamine

hydrochloride (DA), the inotropic vasopressor agent in neurological diseases was conjugated

with CQDs for controlled release in vitro. The DA/CQDs was biocompatible against Neuro 2A

cells. The conjugate can easily penetrate into the blood capillaries because of its small size. The

increased penetration of the conjugate results in the enhanced permeability of the drug. The

conjugate does not show toxic effects on the weight of mice during the observations for 45 days

[136].

26
 3-3- Gene delivery

Gene delivery i.e. introducing of foreign DNA into the cells has been developed using

fluorescent nanomaterials. Gene delivery vehicles might be viral or non-viral vectors. Viral

vectors have enhanced transfection efficiency, however, high likelihood of mutagenesis or

carcinogenesis results in some limitations for their applications. The non-viral vectors (e.g.

cationic polymers, cationic liposomes, and inorganic nanoparticles) have the benefit of being

safer, accompanied by high transfection efficiency. Multifunctional vectors with low toxicity,

enhanced transfection efficiency, and simultaneous imaging can result in a more trusted gene

delivery treatment while non-viral vectors miss possessing the ability of self-tracking [137].

CQDs are promising candidates for multifunctional vectors with the ability of fluorescence

imaging in gene delivery. The transfection studies of the CQDs/pDNA complexes illustrated that

the transfection efficiency analogous to the Lipofectamine2000 (positive control) efficiency and

much better than other positive controls (like semiconductor QDs) could be achieved. Due to

lower toxicity, the CQDs were also preferred for gene delivery over cationic transfection reagent,

PEI, 25 kDa. Condensation effects on pDNA suppress pDNA enzymolysis during transport

which increases the transfection efficiency of the synthesized CQDs [104]. Cationic CQDs were

synthesized from citric acid and PEI via microwave pyrolysis and were used for delivering

plasmid DNA or small interfering RNA (siRNA) to different cell lines. The transfection

efficiency and cytotoxicity for the CQDs were analogues to those of the PEI, the raw material

which the CQDs were synthesized from. The CQDs were efficient for siRNA delivery to the

cells. A 55% specific gene silencing for CQDs/siRNA weight ratio of 12 and 85% gene

knockdown for weight ratios of 50-100 was achieved [105]. The cationic CQDs/gene plasmid

SOX9 (pSOX9) nanoparticles showed better transfection efficiency than the PEI-CQDs/pDNA

27
complexes while the PEI as a polymer gene carrier attaches to the cells easily and possess high

transfection efficiency. The pDNA attachment to the cell membrane could be improved by the

aid of the CQDs with fine particle size and no cytotoxicity [137] .

RNA interference (RNAi) technology by siRNA or double-stranded RNA (dsRNA) triggered

post-transcriptional gene silencing is an environment-friendly approach for insects control. Das

et al. compared CQDs, chitosan and silica nanoparticles in conjugate with dsRNA in order to

target mosquito genes (SNF7 and SRC) with the aim of controlling Aedes aegypti larvae. The

investigations shed light that compared to chitosan and silica nanoparticles, CQDs were a more

efficient carrier for dsRNA retention, delivery and hence, gene silencing and mortality in Ae.

aegypti [138].

CQDs as the fluorescent nanoparticle in conjugate with quencher nanoparticles can be used for

monitoring the complexation and dissociation of polyplex in the cytoplasm. Kim et al. used

CQDs for monitoring of association/dissociation of polymeric carrier/pDNA complex during

transfection. The delivery complex was synthesized as follow: CQDs and gold nanoparticles

were modified with a cationic polymer, PEI and then were treated with pDNA. The fluorescence

of CQD-PEI quenches through dynamic quenching of Au-PEI. Finally, the fluorescence

quenches statically when CQD-PEI and Au-PEI completely form complexes with pDNA. It can

be assumed that pDNA as a glue keeps the CQD-PEI and Au-PEI in an intimate contact.

Dissociation of the complex might restore fluorescence emission of CQD-PEI. For fluorescence

recovery, the charge interaction should be decreased. Using a high concentration of salt (NaCl)

for destabilizing the charge interaction leads to the dissociation of the complex. This, in turn,

results in fluorescence recovery which has been attributed to the increase of the distance between

CQD-PEI and Au-PEI on the complex [139].

28
 The PEI molecule can passivate the surface of the CQDs and at the same time could play as a

polyelectrolyte to condense DNA. CQD-PEI exhibited bright multicolor fluorescence and

showed superior photo-stability. CQD-PEI mediated gene transfection in COS-7 and HepG2

cells with high efficiency [86]. In order to visualize gene expression, Hu et al. [102] used

branched PEI-based CQDs (PCD) with QY of 54.3% for gene delivery. The DNA/PCD

complexes with different DNA/PCD weight ratios prepared through mixing. As the DNA/PCD

weight ratio decreased, the fluorescence intensity increased. It was concluded that the PCD

fluorescence can be used as a proper labeling agent for gene delivery. However, some of the

PCDs fluorescence does not superimpose with the reporter gene of EGFP (enhanced green

fluorescent protein) fluorescence. This phenomenon occurs since broken PEI chains on the

CQDs miss the capability of acting as a gene carrier [102].

3-4- Optical sensors for metal ions

The CQDs can be used in sensors and biosensors due to their PL characteristics, low

cytotoxicity, cell internalization (useful for biosensors), chemically inertness, fast and easy

synthesis and functionalization. The fluorescence emission quenches in the presence of metal

ions (e.g. Hg2+) because of the charge transfer process. Fig. 8 is the schematic illustration of the

heavy metal ions detection mechanism in which the CQD fluorescence quenches in the presence

of the Hg2+ ions. The CQDs show fluorescence in an aqueous solution. If certain ions are added

to the solution, then the fluorescence might be quenched because of the charge transfer. The

fluorescence in the CQDs is due to the radiative recombination of excitons (similar to other

semiconductor QDs). The metal ions (such as Hg2+) can cause non-radiative electron-hole pair

recombination annihilation because of effective electron transfer process [140]. The fluorescence

29
emission of the CQD is affected by its surface state; i.e. the change in the environment and

surface state would result in the change in the fluorescence emission [141].

Heavy metals, which are metallic elements with much higher density compared to water, have

arisen globally ecological concerns on environment pollution due to increasing application of

these elements in different industries and agricultural districts. The environmental pollution in

the vicinity of mines, foundry factories, smelters and etc. is the main concern of these production

plants [142]. The QDs fluorescence has been used for detection of heavy metal ions, extensively.

However, the conventional semiconductor QDs are expensive to be synthesized and are toxic to

the environment in some cases which suppress their usage in a detector system. CQDs can be

used instead of conventional semiconductor QDs since can be synthesized from organic and bio-

friendly ingredients and hence, are less toxic. For example, Yu et al. [143] synthesized CQDs

from a plant (Jinhua bergamot) as a carbon source. The CQDs were water-soluble with a QY of

50.78%. The PL of the hydrothermally synthesized CQDs quenched by using Tris–HCl buffer

solution for Fe3+ and HAC–NaAC solution for Hg2+. Using the CQDs, the detection limits of

0.075 μmol L-1 for Fe3+ and 5.5 nmol L-1 for Hg2+ were achieved.

The detection limit of heavy metals measurements in aqueous solutions can decrease to less

than μmol L-1 and nmol L-1 range, by application of CQDs fluorescence in the detection system.

The best-reported detection limit for the CQDs synthesized through reflux method of

poly(ethylene glycol) (PEG), applied for detection of Hg2+ ions in the samples from the lake,

river, and tap water was 1 fmol L-1 [140]. The detection limit among 15 different metal ions

including Hg2+ was 2 μM. Between the investigated ions, only the detection of Fe3+ had

interference with Hg2+. The low toxicity of the synthesized CQDs showed that they can be used

for probing of Hg2+ in the living cells as well [144]. The detection limit for Hg2+ using the CQDs

30
sensor synthesized through the hydrothermal method of apple juice was 2.3 nmol L-1[145].

Amino-functionalized CQDs synthesized from anhydrous citric acid (carbon source), sodium

borohydride (reducing agent) and ammonia (surface passivation agent) could be quantitatively

quenched in the presence of Hg2+ in an aqueous environment. The detection limit of this sensor

reaches to 20 nmol L−1 [146].

The sensor systems of CQDs and heavy elements ions can be engineered to be used with an on-

off molecular switch. In these types of sensors, one ion quenches the fluorescence of the CQDs,

while the other recovers it. As an example, the on-off sensor for detection of Hg2+ and I− has

been developed. The fluorescence of CQDs quenches if Hg2+ exists in the environment and

addition of I− to the CQDs/ Hg2+ dispersion, results in fluorescence recovery. The detection limit

for Hg2+ is 0.201 μmol L-1 and that of I− is 0.234 μmol L-1 [147]. CQDs/Hg2+ system sensor has

also been applied for cysteine, glutathione, and histidine which works based on the fluorescence

recovery of CQDs/Hg2+ suspension [148].

The cysteine has been used in conjugate with Hg2+ for on-off sensors in some of the research

experiments. For example, the magnesium and nitrogen co-doped CQDs were used for the

detection of Hg2+ and cysteine. The Hg2+ ion quenches the CQDs fluorescence and cysteine

recovers it. The recovery is because of the stronger affinity of Hg2+ to cysteine than to CQDs.

This system can be used for detection of both Hg2+ and cysteine [149]. In another attempt, an on-

off CQDs sensor was developed for detection of Hg2+ ions with a detection limit of 0.017 μM. l-

cysteine used to recover the fluorescence of CQDs after quenching by Hg2+ ions [150]. Nitrogen-

doped CQDs with a QY of 35.4% which are quenched in the presence of Hg2+, completely

recover with the addition of L-cysteine to the solution. The detection limit for this on-off sensor

can be in the order of 1.48 nmol L-1 with a linear range of 0-10 μmol L-1. The complex can also

31
be used as an on-off sensor of L-cysteine with a detection limit of 0.79 nmol L-1 and a wide

linear range of 0-50 μmol L-1 [151].

Detection of other elements such as Cu2+, Pb2+, Pt4+, As3+, etc. is also possible with the aid of

CQDs fluorescence. Wang et al. used CQDs for detection of Cu2+ which the quenching effect

could be recovered with the addition of ethylene diamine tetraacetic acid. The CQDs probes can

reach a detection limit of 0.0295 μmol L-1 and response time of 3 s for Cu2+ ions. The probe

works in the range of 0.25-10 μmol L-1 [152]. The detection limit for detecting Cu2+ ions by

CQDs synthesized from prawn shells is 5 nmol L-1 [153]. By using CQDs which were

synthesized from chocolate by a hydrothermal method, a sensor for detection of lead ion (Pb2+)

in the water was developed. The quenching in this sensor is due to special chelation between the

lead ion and the hydroxyl group of the CQD surface. The detection limit of the CQD sensor for

lead ion reaches 12.7 nmol L-1 [154]. CQDs which are functionalized with poly(amidoamine)

(PAMAM-NH2) dendrimer were used as a chemosensor for detection of Pt (IV) ion in water. The

detection limit for Pt (IV) ion sensor was 657 nmol L-1 and had a sensitivity of 78 nmol L-1 in the

range of 6–96 μmol L-1 of the dissolved platinum ions [155]. A Cu2+ ion detection sensor which

applied branched-poly(ethylenimine) (BPEI) functionalized CQDs had a detection limit of 6

nmol L-1 and a dynamic range of 10 to 1100 nmol L-1. By capturing the Cu2+ via amino groups of

the BPEI, the CQDs fluorescence quenches [156]. CQDs have been used for a colorimetric dual

mode sensor of arsenic [As (III)] and glutathione with the naked eye. The detection limit for As

(III) reaches the low value of 32 pmol L-1. The synthesized CQDs can detect glutathione among

other biothiols like homo-cysteine and cysteine. The detection limit can reach to 43 nmol L-1,

even in blood plasma [157].

32
 CQDs based sensors can recognize a certain ion in a solution containing several ions. CQDs

optical sensor could recognize Fe3+ among other ions such as Na+, Ni2+, Co2+, Ag+, Mn2+, Cd2+,

Pb2+, Hg2+, K+, Zn2+, Al3+, Cu2+, and Fe2+ with a linear relationship of emission intensity versus

the concentration in the range of 0 to 20 μmol L-1 [158]. As another example of detection of a

certain ion among several ions, CQDs synthesized via laser ablation of carbon targets immersed

in water and functionalized with NH2–polyethylene-glycol (PEG200) and N-acetyl-l-cysteine,

experience fluorescence quenching upon presence of Hg2+ or Cu2+ in the environment; while no

fluorescence quenching observes in the presence of Cd2+, Ni2+, Zn2+ and Ca2+ ions. For Hg2+,

25% decrease and for Cu2+, 13% decrease in fluorescence emission observes via the addition of

2.69×10−6 mol L-1 metal ions [159]. In another research for detecting several metal ions, it was

revealed that most of the added metal ions of Cu (II), Cr (II), Co (II), Ni (II), Al (III), Ca (II), Pb

(II), Zn (II), Sn (II) and Hg (II) have quenching effect on CQDs based sensor. While Zn (II), Hg

(II) and Ca (II) ions showed the lowest quenching effect, that of Cu (II) and Pb (II) ions were

significant [160].

The optical sensors which work with the aid of CQDs can be designed by application of optical

fiber to make their usage easy. It is important to immobilize the CQDs in a permeable matrix to

be able to interact with the surrounding environment, while must prevent leaching. CQDs

immobilized in a sol-gel matrix at an optical fiber tip and factionalized with PEG200 and N-

acetyl-l-cysteine can reach a detection limit of submicron molar concentrations for Hg2+ in

aqueous solutions [161].

Other researchers have used CQDs for detection of Hg2+ [162-178], Fe3+ [172, 178-196], Fe3+

ions in human blood, urine and water samples [113], Fe2+ [197], Ag+ [198-201], Au3+ [202, 203],

Al3+ [204], Cr6+ [205-208], Cr3+ [172], Co2+ [209], Cr2O72− [210], Pb2+ [172, 178, 211, 212], Zn2+

33
[211], Cd2+ [213], Mo6+ [214], Pt2+ [203] Eu3+ [172], Cu2+ [172, 175, 215-220], Cu2+ in rat brain

[221], selenite (SeO32–) [222], and Li+ in water samples [223].

3-5- Optical sensors for other molecules

Fluorescence is one of the most used methods in biosensing of biomolecules. Organic dye and

protein-based fluorophores which are used for this purpose have disadvantages such as narrow

absorption window, photobleaching, self-quenching at high concentrations and short excited

state lifetime. Therefore, various fluorophores have been synthesized to overcome these

drawbacks. Colloidal luminescent semiconductor QDs have been considered as alternatives to

the organic and protein-based fluorophores [224]. However, the semiconductor QDs have some

drawbacks such as complexity of production procedure and application prohibition due to

toxicity concerns [225]. CQDs with appropriate resistance to photobleaching and null toxicity

might be preferred to organic dye and protein-based fluorophores and semiconductor QDs.

Fluorescence resonance energy transfer (FRET) is a phenomenon occurs between two

chromophores which one is a donor and another one is an acceptor. For occurring FRET, donor

emission and acceptor absorption spectrums should overlap. The donor chromophore could

transfer energy to the acceptor one, through a non-radiative interaction. This phenomenon is

extremely distance-dependent and is used for probing complex intermolecular interactions.

CQDs can play the role of a chromophore in this mechanism and can be used for sensors with

superior detection limit. Kundu et al. used CQDs for detection of riboflavin (RF, known as

vitamin B2) in aqueous solutions. The absorption spectrum of RF and emission spectrum of the

used CQDs have an overlap which indicates the possibility of a FRET interaction that can occur

from the CQDs (as the donor) to the RF (as the acceptor). By increasing the RF concentration,

34
the fluorescence emission intensity of CQDs decreases with a blue shift, and that of RF

increases. The hydroxyl and carboxyl groups found on the surface of the functionalized CQDs

strongly attract >C=O and –NH groups of the RF, resulting in hydrogen bonds formation which

leads to fluorescence quenching. The detection limit for vitamin B2 via the CQDs sensor is 1.2

nmol L-1 [226]. CQDs were used for a sensor of 2,4,6-trinitrotoluene (TNT) explosives residues

in water that works based on the FRET mechanism. The fluorescence of the CQDs can be

selectively quenched in the presence of TNT via FRET mechanism. The detection limit is as low

as 0.213 μmol L-1 [227].

FRET mechanism was also applied for detecting glutathione by CQDs. Glutathione has a

strong effect on cellular functions and abnormal levels of this protein molecule cause different

clinical diseases. Therefore, detection of glutathione with an excellent detection limit is critically

important. For detecting glutathione, a nanocomposite of MnO2 nanosheets/CQDs was

synthesized through an in-situ method by Cai et al. [228]. The CQDs in the as-synthesized

nanocomposite are quenched because of the FRET. If the glutathione is present in the

environment, MnO2 nanosheets will be reduced to Mn2+ ions which results in releasing of CQDs

and sufficient recovery of its fluorescence. The detection limit for glutathione through this

approach would be down to 300 nmol L-1 and has a sensitive response in analyzing human serum

samples [228]. Another sensor for glutathione has also established based on the degree of the

surface passivation of the CQDs [229].

Gold nanoparticles can be used as a quencher for the sensors that use CQDs and performs

based on the FRET mechanism. The gold nanoparticles have a larger extinction coefficient and

broader absorption spectrum that have an overlap with the emission spectrum of the CQDs. In an

experiment, it was observed that the fluorescence quenching of the CQDs via gold nanoparticles,

35
based on the FRET mechanism, can be recovered by the aid of thiocholine (produced from

acetylthiocholine via hydrolysis of butyrylcholinesterase (BChE)) that cause the gold

nanoparticles to aggregate due to the Au–SH interaction. Organophosphorus pesticides (OPs) can

inhibit the catalytic activity of BChE and therefore, the recovery process will be diminished. The

variations in the fluorescence intensity can be used as a measure for OPs determination [230].

Gold nanoparticles have also been used as fluorescence quencher and colorimetric reporter of a

mixture of CQDs and gold nanoparticles that have been used as a sensor. Protamine can induce

gold nanoparticles to aggregate and therefore, the fluorescence emission of the CQDs no longer

coincides with the absorption spectrum of the aggregated gold nanoparticles and would not be

quenched. Aggregation of gold nanoparticles results in a color change from red to blue that can

be used as a colorimetric reporter. The FRET mechanism has been used for a protamine sensor

with a detection limit of 1.2 ng·mL−1 [231]. The FRET, based on the amino-functionalized CQDs

and gold nanoparticles was also applied for detecting of melamine in milk samples. By

introducing of melamine to the gold nanoparticles solution before addition of CQDs, the amino

group of the melamine molecules covalent interaction with gold nanoparticles prevents the

interaction of CQDs and gold nanoparticles. On the other hand, by addition of melamine to the

gold nanoparticles solution, fewer CQDs have the possibility of absorption onto the gold

nanoparticles surfaces. Therefore, the FRET effect hinders and fluorescence intensity increases.

The FRET-based mechanism of the melamine detection is shown in Fig. 9 [225].

The quenching mechanism of hydrogen bonding seen in the work of Kundu et al. [226] was

observed in the detection of carboxylated multiwalled carbon nanotubes (c-MWCNTs) in water

by a CQDs sensor. The detection limit for sensing c-MWCNTs was 0.37 mL−1. By the addition

36
of other carbogenic nanoparticles in the water, it was concluded that the interaction of the CQDs

sensor with other carbogenic species is almost absent, especially, nonoxidized nanoparticles.

This, in turn, implies that CQDs may interact with c-MWCNTs by hydrogen bonds instead of the

electronic surface [232].

CQDs can be used for monitoring certain drugs in the body. For example, 6-Mercaptopurine (6-

MP) as an anti-cancer drug can be monitored in the human serum by application of CQDs based

sensors. Carboxyfluorescein-DNA macro-molecules through π–π stacking were conjugated on

the CQDs. The resulted complex could be used as a sensor for 6-mercaptopurine. An enhanced

emission can be detected from carboxyfluorescein. The interaction between Hg2+ and DNA

forms T-Hg2+-T (T: thymine base) complex which destroys the conjugate system of CQDs, DNA

and 6-mercaptopurine and results in fluorescence quenching. The detection limit for Hg2+ reaches

to 1.26 nmol L-1 through this mechanism [233].

The inner filter effect (IFE) which occurs by overlapping of the absorption spectrum of the

quencher with fluorescence excitation/emission spectra of the donor and is accompanied by a

decrease in the fluorescence intensity [234] has been used in some CQDs-based sensors. For

example, the IFE between CQDs and hematin (in human red cells) that occurs due to the

fluorescence quenching as a result of absorption of the excitation and emission spectrum of the

CQDs by hematin has been used for developing a hematin sensor. The CQDs quenching is

influenced by the hematin concentration and hence, this linear dependence has resulted in

developing a sensor with superior detection limit of 0.25 μmol L-1 [235]. CQDs have also been

used in a nanosensor which works based on the IFE for imaging of the apoptosis. Fluorescence

imaging by the aid of CQDs has been used for detection of cytochrome c (Cyt c) which acts as a

biomarker in the early stage of apoptosis. The CQDs-based nanosensor applies fluorescence

37
imaging of the Cyt c release. The nanosensor has also been utilized for visualization of Cyt c in

the living zebrafish. Fluorescence quenching due to the IFE was suggested as the main

quenching mechanism of the CQDs fluorescence by the Cyt c [236]. IFE has also been the

mechanism for the CQDs-based fluorescence sensor for detection of methotrexate [237].

The CQDs could act as oxidizing or reducing agents in the sensors since they are great electron

donors and electron acceptors. The functional groups on the CQDs surface such as carboxy and

hydroxy groups have a key role in the CQDs ability for reduction which can make them as

nucleation centers for metallic nanoparticles growth. In a sensor for detection of arginine based

on CQDs, when arginine is mixed with HAuCl4 solution, the formation of Au/CQDs composite

is restricted before addition of CQDs. The CQDs act as reducing agents and stabilizer to result in

Au/CQDs composite via carboxy and hydroxy groups on the surface of CQDs. The designed

sensor has a detection limit of 450 nmol L-1 through fluorescence spectroscopy [238].

CQDs have also been applied for detection of iodide (I–) [169, 174, 239], K+ [240], F– [241],

phytic acid [242], ascorbic acid [195, 207, 243-245], ascorbic acid in rat brain [246], uric acid

[247], boric acid and hydroxylamine hydrochloride [248], hyaluronic acid and hyaluronidase

[249], picric acid [250], HClO [251], biothiols [200, 252-254], proteins in phosphate buffered

saline [255], adenosine triphosphate [188], β-galactosidase [256], α-glucosidase [257, 258],

2,4,6-trinitrophenol [259], trinitrotoluene (TNT) in water [260], pyrophosphate anions and

alkaline phosphatase [261], polypeptides and Deoxyribonuclease I [262], hydrogen peroxide

[263-265], double strand DNA detection [266], miRNA detection [267], proteins [268],

tuberculosis [269], folic acid in human serum [270], neurotoxin quinolinic acid in human serum

[271], cholesterol [272], pollutants such as 2,4-dinitrophenol and 2-amino-3,4,8-trimethyl-3H-

imidazo[4,5-f]quinoxaline [273], nitrobenzene [265], sinapine [274], promethazine

38
hydrochloride [275], hematin in human red cells [235], selenite in water [276], amoxicillin (the

drug) [277], tiopronin [177], flumioxazin [278], phenolic carbofuran [279], dopamine [179, 247,

280], DNA [281], hypochlorite (ClO−) [282], histidine [283], cysteine [199, 284], L-cysteine

[187], hydrazine [192], arsenite [285], tetracycline [265, 286, 287], prilocaine [288], aflatoxin

B1 [289], vitamin B12 [290], NO2– in water [291, 292], nitric oxide (NO) [293], phosphate anions

[294], alkaline phosphatase [295], and organophosphorus pesticides [296].

3-6- Chemiluminescence

Chemiluminescence (CL) is the light emission due to relaxation of electronically excited

intermediate or product state to the ground state in which the excited state is caused by a

chemical reaction between reagents. The CL has application in analytical chemistry because of

high sensitivity and simple instrumentation. Luminol as well as potassium permanganate,

lucigenin and peroxalate are frequently used and studied CL reagent in analytical chemistry due

to their acceptable CL intensity. However, the used reagents are expensive and poisonous and

suffer from excellent selectivity. Therefore, developing other CL systems with strong emission

intensity and green approaches is essential [297].

CQDs can enhance the CL effect through several routes. CQDs can act as a reaction catalyst or

can concentrate the excited CL emitter and enhance the emission. The CQDs can also impart in

CL reaction and the CL emission occurs by the annihilation of the hole-injected and electron-

injected CQDs [298].

The reaction between potassium permanganate (KMnO4) and CQDs and reduced state CQDs

(r-CQDs) in an acidic environment can result in CL. In the CQDs-KMnO4 system, the KMnO4

has the role of hole injection into the CQDs and by the interaction with electrons of CQDs, high

39
energy state electrons are produced which makes excited CQDs*. The CQDs* relaxation leads to

the emission. At the same time, Mn (II)* excited state is generated which relaxes to the ground

state by emission. In the r-CQDs-KMnO4 system, the excited state of CQDs* produces from the

reaction of KMnO4 with the r-CQDs including hydroxyl groups. Returning of the CQDs* excited

state to the ground state results in CL. Furthermore, r-CQDs reduces KMnO4 and produces

excited state of Mn (II)* which relaxes with CL emission [299].

The CL of the CQDs can be applied for detection of analytes with a high sensitivity. The CL

has the potential to be used as a tool for rapid spectroscopic technique in characterization

techniques as well [91]. For example, Lin et al. [298] showed that CQDs enhance the CL in

NaNO2– H2O2–Na2CO3 system. (CO2)2* is an energy donor to the CQD that converts it to an

excited state (CQD*) which returns to the ground state via CL emission. The annihilation of hole-

injected and electron-injected CQDs also result in CL emission. This method was used for

sensing nitrite in tap water with proper accuracy. Although, the CL can be used for determining

the oxygen states (O-states) of the CQDs. The O-states of the CQDs have an influence on their

optical properties. It has been reported that the C–O group-related O-states of the CQDs have

influence on the CL intensity of the CQDs in presence of peroxynitrite (ONOO−) that this can be

used as a probe for characterization of O-states of the CQDs [91]. CL has been used for DNA

detection on the paper analytical device. CQDs dotted nanoporous gold employed as signal

amplification label. The detection limit of 8.56×10−19 mol L-1 has been achieved for the target

DNA [300]. The CQDs were also used as a fluorescence component in chemically initiated

electron exchange luminescence. The CQDs-based peroxyoxalate CL results in a linear

dependence between hydrogen peroxide (H2O2) concentration and PL intensity that can act as a

probe for H2O2 determination in the range of 10–1000 μmol L-1 [301]. The CQDs have been used

40
 in CL systems for detection of adenosine [302], ranitidine [303], thiourea or tannic acid [304],

bromate [305], gallic acid in food samples [306], Mn2+ [307], m-phenylenediamine [308], and

metronidazole [309].

Zhao et al. [310] discovered that CL can be generated by the only injection of a strongly

alkaline solution into the CQDs, while no CL reagent of oxidants or CL system is used. Using a

high concentration of NaOH solution with CQDs resulted in a prompt CL response. The

suggested mechanism for this phenomenon was “chemical reduction” of CQDs in high

concentration alkaline solution. The single orbital detected by electron paramagnetic resonance

(EPR), acts as electron traps. Thermally excited generated holes annihilate with the electrons

which are injected by chemical reduction and the energy releases in the form of CL.

CL is observed in CQDs factionalized with BPEI as well. The mentioned CL obtained from

CQDs as a probe in alkaline solution can be applied for detection of iron (III) ions. The proposed

mechanism for CL says that iron (III) is selectively captured by the surface groups of BPEI and

injects holes into the BPEI functionalized CQDs as the oxidant, and as a consequence, CL

emission is generated. Fig. 10 is a schematic illustration of the CL and fluorescence emissions in

BPEI functionalized CQDs/NaOH/Fe(III) system [92].

By the aid of polymer-surfactant interaction on the surface of CQDs, a selective CL probe was

designed for Co(II). The system can determine Co(II) in HepG2 cells [311].

The CL of luminol can take place by using CQDs acting as catalyst, without adding oxidant to

the system. The π-rich electronic structure of the CQDs cause formation of the activated complex

[CQDs…luminol] via charge transfer between luminol (donor) and CQDs (acceptor). It was

observed that by application of 3-aminophthalate as the luminophore, the CQDs in the system

accelerate the electron transfer processes and catalyze the decomposition of the dissolved oxygen

41
and this leads to the generation of superoxide radical anion in the luminol solution. The CL

emission occurs as a result of the reaction of superoxide radical anion with luminol. The catalytic

activity of CQDs is influenced almost by surface states, while CQDs size misses a considerable

effect on it. Therefore, by engineering the functional groups, one can tune the catalytic activity of

CQDs [90].

3-7- Electrochemiluminescence

Electrochemiluminescence (ECL) or electrogenerated chemiluminescence is a process in which

species generated at electrodes experience high-energy electron-transfer reactions and therefore

excited states forms and light emits. Generally, luminescent processes include

photoluminescence (PL), bioluminescence (BL), electroluminescence (EL),

radiochemiluminescence, sonoluminescence (SL), CL and ECL. In both ECL and CL, species

undergo high energetic electron-transfer reactions and consequently, light emission. Mixing of

necessary reagents and controlling of fluid flow can initiate and control luminescence in CL.

However, in ECL, change in electrode potential can initiate and control the luminescence [312].

In recent years several QDs such as CdSe, CdTe and CdSe/ZnSe have been used in ECL

investigations. However, especially for biological applications, the metal-based QDs have raised

cytotoxicity concerns. CQDs with much lower cytotoxicity have received researchers’ attention

[313].

The ECL of the oxidized CQDs is mostly affected by surface state, not particle size, as in other

QDs. The ECL can be obtained in CQDs without surface passivation. Oxidized CQDs without

surface passivation were used as ECL luminophores in pH 7 of phosphate buffer solution (PBS).

The ECL signal of the CQDs was observed both in negative and in positive potential regions.

42
Without CQDs, ECL signal was not detected in the system. In the absence of co-reactants, both

cationic radical CQD (R•+) and anionic radical CQD (R•-) should cooperate for ECL signal. ECL

of CQDs occurs by the annihilation of (R•+) and (R•-) radicals. The (R•+) and (R•-) radicals

transfer charge at colliding and form the excited state CQD* [314].

The wavelength of the maximum ECL emission shows a red-shift from the wavelength of the

maximum PL. This has been attributed to the smaller energy separations of the CQDs surface

states (for ECL) compared to the CQDs band gap in PL [313].

The CQDs can be used in ECL immunosensors for detection of tumor markers. The detection

of trace changes in the tumor markers is essential for cancer diagnosis and treatment since, a

small change in their concentration can be correlated to the cancer occurrence, development, and

palindromia. For the synthesis of a nanomaterial designed as a tumor marker ECL

immunosensor, graphene was used as nanocarrier and perylenetetracarboxylic acid and CQDs as

luminophores. The resulted immunosensor with a detection limit of 0.00026 fg mL-1 can be

applied for versatile cancers’ sample detection [315].

The K2S2O8 is used as the co-reactant in most of the CQDs cathodic ECLs. The ECL

mechanism by the K2S2O8 as the co-reactant is as follow: electro-generation of CQDs• − radicals

is accelerated through functional groups of CQDs; SO4• − radicals are produced by S2O82−

electrochemical reduction; resulted SO4• − radicals react with CQDs• − radicals through electron-

transfer annihilation and excited-state of CQDs (CQDs*) forms for light emission (ECL) [316].

It has been reported that when K2S2O8 (10 mmol L-1, as an oxidative reactant and a hole donor)

is added to the ECL system of N-doped CQDs/K2S2O8, the ECL emission is strong, while no

ECL emission is observed when K2S2O8 is used without CQDs. It can be concluded that K2S2O8

43
acts as coreactant (or a hole donor) and the N-doped CQDs are ECL luminophores in this system

[317].

In spite of that S2O82- is the mostly used co-reactant in CQDs ECL, sulfite (SO32-) has also been

suggested for this purpose. For cathodic ECL signal of the CQDs, by potential cycling, SO32-

oxidizes electrochemically and SO3• − radical in the anodic polarization process forms. The

electro-generated SO3• − in the presence of dissolved oxygen produces sulfate radical SO4• −.

CQDs electrochemically reduces through cathodic polarization process and negatively charged

CQDs• − forms which react with SO4• − and results in an excited state of CQDs (CQDs*). The

excited CQDs then returns to its ground state by emitting light [318].

CQDs can be used for enhancing ECL of the semiconductor QDs. It has been reported that

CQDs have improved the ECL of CdSe QDs with co-reactant of dissolved O2. The low electron-

transfer resistance and surface states of the CQDs facilitate the formation of electron-injected

QDs which results in an increase in ECL emission. The QDs were assembled on poly

(diallyldimethylammonium chloride)-functionalized carbon nanospheres (PFCNSs) and the

complex was used for detection of oxidase substrates. The biosensor was designed by

immobilizing the enzyme on the QDs/PFCNSs complex. The detection limit for hypoxanthine

was 5 nmol L-1 [319].

is a classic metal-organic which generate ECL emission by application of analytes

as co-reactants. This complex has the capability of covalent bonding to other co-reactants and

forms self-enhanced ECL complexes which show high luminous efficiency. For example, PEI

capped N-doped CQDs were used as co-reactant of nanosheets as the luminophore.

Furthermore, reduced graphene oxide introduced into the complex for benefit of electron

transferring and ECL signal amplifying. The resulted complex on glass carbon electrode showed

44
nearly 69 fold better ECL signal intensity in comparison with just nanosheets on

glass carbon electrode. The produced sensor had a detection limit of 10 nmol L-1 with a linear

range of 0.01–50 μmol L-1 for sensing of dopamine [320]. In another work, N-doped CQDs were

used as co-reactant and for enhancement of a ECL sensor signal. The sensor was

able to detect bisphenol A (BPA) via quenching effect of Ru(bpy)3+2/CQDs with the linear

relationship in the range of 0.03–1.0 μmol L-1 and detection limit of 10 nmol L-1. In this sensor,

CQDs react with electro-generated and produce an excited state of

which shows the ECL signal. Addition of BPA results in quenching and inhibition of ECL. The

electron transfer from the excited state of to BPA oxidation product may be

responsible for inhibition mechanism [321]. as a donor and amorphous carbon

nanoparticles (ACNPs) as an acceptor in a -labeled antibody and ACNP-antigen

conjugate resulted in ECL quenching of . The target antigen (when is present)

competes with ACNP-antigen for -labeled antibody and hence, ECL quenching

decreases. The system can detect mouse IgG with a detection limit of 0.35 ng mL−1 [322].

Ru(bpy)32+/CQDs/polyvinyl alcohol system was also applied in an ECL sensing platform for

detection of sophoridine [323].

ECL resonance energy transfer (ERET) can be used for the production of highly sensitive

immunosensors. Nitrogen-doped CQDs as ECL luminophores and aminated graphene (NH2-G)

as quenching labels of secondary antibody were incorporated in an ECL immunosensor. The

NH2-G have the ability to quench the ECL of CQDs on electrodes due to the ECL resonance

energy transfer (ERET). A detection limit of 3.3 pg mL−1 with the linear relationship in the range

of 0.01–100 ng mL−1 was achieved, using alpha-fetoprotein as a model for analytical

performance assessment [324].

45
 CQDs were also used in ECL based sensors for selective detection of MCF-7 cancer cells

[325], selective detection of cancer cells via functionalized CQDs and graphene nanosheets (as

signal amplification agents) [326], aptasensor for thrombin based on CQDs-capped gold

nanoflowers [327], a probe for the evaluation of CD44 expression on breast cancer cells [328],

detection of microRNAs based on a DNA functionalized CQDs [329], carcinoembryonic

antigen immunosensor [315, 330], carcinoma antigen with CdTe@CQDs-labeled secondary

antibody and primary antibody on the surface of the Fe3O4 nanoparticles [331], detection of 8-

hydroxy-2′-deoxyguanosine using CQDs coated Au/SiO2 core-shell nanoparticles [332],

detection of chlorinated phenols by CQDs immobilized on graphene [333], detection of human

IgG using nitrogen-doped CQDs as luminophore and K2S2O8 as co-reactant [334], and detection

of Cu2+ with oxidized CQDs and K2S2O8 system [335].

4- Challenges and prospective

In this review, we introduced the CQDs and different properties and applications of these

nanostructures were discussed. Different types of PL emissions in CQDs were explained and

their mechanisms were clarified. The versatile applications of CQDs in drug delivery, gene

delivery, in-vivo and in-vitro bioimaging, optical sensors, chemiluminescence, and

electrochemiluminescence illustrated.

The increasing need for QDs with tunable band gap has resulted in extensive researches on

different kinds of semiconductor QDs. However, the classical semiconductor QDs have mostly

complex production methods and the disadvantages such as expensive raw materials and toxicity

confine their use in certain fields such as biomedical applications. However, the CQDs can have

economical and easy production procedure with minor toxicity. Several top-down and bottom-up

46
methods have been applied to produce CQDs with the sizes below 10 nm. Surface passivation

and doping have great influence on fluorescence properties of these structures.

There are still some obstacles that need to be conquered by further research before the

development of CQD in the aforementioned districts. For biomedical applications of fluorescent

QDs, the need for high QY and intensive brightness is vital for imaging applications.

Furthermore, the QDs should have uniform size and hence, uniform emission properties. For CL

reactions, low QY and weak intensity of the emitted light of the most used structures is an

obstacle to the development of high-performance CL sensors. Furthermore, poor selectivity is

another drawback that hinders the application of these sensors for some species. Except for some

limited cases that high QY of the synthesized CQDs has been achieved; other synthesized CQDs

suffer from low QY. Therefore, further researches must be accomplished in order to overcome

low QY, low intensity and non-uniform optical properties of the CQDs. Still, more research

should be done to increase fluorescence intensity in the NIR region which is essential in certain

biomedical applications. Since the surface chemistry and impurities doping of the CQDs plays an

important role in their properties, studies should focus on the effect of these factors on CQDs

properties.

It seems that by passing these obstacles within a few next years, CQDs can be used

commercially in various areas and compete with traditional semiconductor QDs. The minor

toxicity and low price can lead to substitution of CQDs instead of semiconductor QDs in the

biomedical application in the near future.

Conflicts of interest
There are no conflicts of interest to declare.

47
Acknowledgment
The author would like to appreciate Shahrood University of Technology and Iranian

Nanotechnology Initiative Council for financial support of this project.

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 Figure captions

Fig. 1: Different applications of CQDs.

Fig. 2: Photographs of CQDs coated with ZnS (CZnS) and CQDs coated with TiO2 (CTiO2)

solutions compared with fluorescein in ethanol (fluorescence QY is about 80%) under sunlight

(upper) and under the monochromated light, xenon arc source, (lower). Reprinted with

permission from [43]. Copyright 2011 Royal Society of Chemistry.

Fig. 3: The aqueous solution containing CQDs which are surface passivated by PEG1500N; a)

excited at 400 nm and photographed using different wavelengths band-pass filters (indicated on

image) and b) excited at the indicated wavelengths and photographed without a filter. Reprinted

with permission from [95]. Copyright 2006 American Chemical Society.

Fig. 4: CQDs used as fluorescent cell label. CQDs are incubated 3-6 hours with HeLa cells.

Images are prepared under bright field (BF) and fluorescence (FL) mode of a confocal or

Apotome microscope. Reprinted with permission from [78]. Licensed under a Creative

Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License,

http://creativecommons.org/licenses/by-nc-nd/3.0/.

Fig. 5: Confocal laser scanning fluorescence microscopy from CQDs/DNA-Cy5 complexes

incubated with A549 cells at different time intervals (1, 4, and 24 h); a) Excitation wavelength =

488 nm (NR12S); b) Excitation wavelength = 405 nm (CQDs); c) Excitation wavelength = 635

nm (DNA-Cy5); d) merged images, (all scale bars: 10 μm). Reprinted with permission from

[105]. Copyright 2015 Elsevier Ltd.

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 Fig. 6: a) In vivo fluorescence images of a CQDs injected mouse; the excitation wavelengths

are 455-704 nm indicated on the image. Fluorescent signals of CQDs and the tissue auto-

fluorescence are red and green, respectively; b) Signal-to-background separation of the image

(excitation wavelength: 704 nm) which confirms that the signal (fluorescence from CQDs) is

well distinguished from the background (tissue auto-fluorescence). Reprinted with permission

from [117]. Copyright 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Fig. 7: Fluorescence images that were taken by confocal microscopy of HepG2 cells incubated

for 24 h with a) bare CQDs (G-tag) and b) DOX conjugated CQDs (T-tag) via excitation with a

wavelength of 380 nm, and schematic showing location for c) bare CQDs and d) DOX

conjugated CQDs in nucleus and cytosol of cancer cells, respectively. Reprinted with permission

from [132]. Licensed under a Creative Commons Attribution-NonCommercial- ShareAlike 3.0

Unported License. http://creativecommons.org/licenses/by-nc-sa/3.0/.

Fig. 8: Schematic illustration of the heavy metal ions detection mechanism via CQD

fluorescence quenching in a) absence and b) presence of Hg2+ ions. Reprinted with permission

from [140]. Copyright 2013 Elsevier Ltd.

Fig. 9: The FRET-based mechanism for melamine detection; a) The CQDs fluorescence

quenches in the presence of gold nanoparticles, b) the CQDs fluorescence enhances if melamine

is incubated with gold nanoparticles before addition of CQDs. Reprinted with permission from

[225]. Copyright 2014 Elsevier B.V.

Fig. 10: Schematic illustration of the CL and fluorescence emissions in BPEI functionalized

CQDs/NaOH/Fe(III) system. Reprinted with permission from [92]. Copyright 2014 The Royal

Society of Chemistry.

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Table 1: examples of the CQDs applications, precursors for synthesis, synthesis method, optical

properties and details of the applications

synthesis quantu details of referenc

application precursors
method m yield application e

carbohydrate, chemical
incubation of HeLa
octadecylamine, carbonizatio 5-60% [78]
and other cells
octadecene n

diammonium chemical
incubation of HeLa
bioimaging hydrogen citrate, carbonizatio 46.4% [79]
cells
urea n

microalgae
hydrotherma incubation of
powder, 4.3% [80]
l MCF-7 cells
formaldehyde

CQDs as imaging

probe, RGD
citric acid,
peptide as active
diethylenetriamin pyrolysis 25.5% [81]
targeting ligand,
drug delivery e
and cisplatin(IV) as

prodrug

pyrolysis delivery of
citric acid, urea 14.0% [82]
(microwave) phototrigger

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 conjugated

anticancer drug,

bonded to the

surface of CQDs

drug delivery of
hydrotherma
milk - doxorubicin [83]
l
(DOX)

delivering plasmid
pyrolysis
citric acid, BPEI 20-30% DNA or small [84]
(microwave)
interfering RNA

transfection
sodium alginate,
hydrotherma experiments with
gene delivery hydrogen 12.7% [85]
l plasmid TGF-β1
peroxide
/CQDs complexes

glycerol,
pyrolysis gene expression of
phosphate 54% [86]
(microwave) plasmid DNA
solution

hydrotherma
chitosan 31.8% Hg2+ ions detection [87]
l

dihydronicotinamid
sensor
alanine, hydrotherma e adenine
46.2% [88]
ethylenediamine l dinucleotide

detection

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 chemical
waste polyolefin 4.84% Cu2+ ions detection [89]
oxidation

CL of luminol with

acid CQDs as the

activated carbon 2-11% [90]
treatment catalyst
chemiluminescenc

e (CL)
microwave screening of O-
citric acid, urea [91]
treatment states in CQDs

citric acid, BPEI pyrolysis 42.5% detection of Fe3+ [92]

Highlights

1. Carbon quantum dots (CQDs) posses photoluminescence (PL) properties.

2. PL originates from conjugated π-domains and surface defects.

3. The CQDs can be used for bioimaging, drug, and gene delivery.

4. The CQDs can be used in optical sensors, chemiluminescence and

electrochemiluminescence.

5. The CQDs are non-toxic alternatives to semiconductor quantum dots.

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