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FEATURE ARTICLE
acidic endosomes and lysosomes. The advances in the design of acid-degradable polymers and drug
delivery systems have been summarized and discussed in this review article. Various acid-labile groups
such as acetals, orthoester, hydrazones, imines and cis-aconityl, that can undergo cleavage in slightly
acidic conditions, have been employed to create polymer architectures or polymerdrug conjugates that
www.rsc.org/chemcomm
can degrade under lysosomal and endosomal conditions, triggering the fast release of drugs or DNA.
Introduction
Polymers are a popular choice for the design of drug delivery
carriers. The use of polymer therapeutics has evolved into a
broad discipline, employing a wide range of architectures either
at the macroscale (gels and hydrogels) or nanoscale (polymer
drug conjugates, polymeric micelles, nanogels and cross-linked
particles, polyplexes for DNA delivery, etc.). Particularly, the
development of multifunctional nanoscale devices has drawn a
lot of attention. The versatility of modern synthetic chemistry
as well as recent developments of very ecient click reaction
enabled the careful design of polymer-based therapeutic agents
with engineered characteristics such as colloidal stability, tunable sizes with narrow distribution, protection of drugs during
circulation, and transportation to targeted organ or tissue.
In summary, controlled release of encapsulated therapeutics
is an active research field. A few strategies have been developed
including bioconjugation with cell-targeting biomolecules for
specific delivery and the use of stimuli-responsive polymers to
create intelligent polymer therapeutics.
Stimuli-responsive polymers are defined as polymers that
undergo relatively large and abrupt, physical or chemical
changes in response to small external changes in the environmental conditions. These stimuli could be classified as either
physical (temperature, electric or magnetic fields, mechanical
stress) or (bio)chemical (pH, ionic strength and chemical
agents) stimuli. The response of a polymer can be defined
in various ways, from a reversible change in their chain conformation or their degree of intermolecular association to more
Centre for Advanced Macromolecular Design, (CAMD), The University of
New South Wales, Sydney NSW 2052, Australia. E-mail: m.stenzel@unsw.edu.au
2082
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to suitable carriers through acid-sensitive bonds is one way of
ensuring the triggered release of the drug in an acidic environment. These acid-degradable systems have been quite popular
for the design of smart drug delivery devices in the past decade,
and surprisingly poorly reviewed except some reports on polymeric prodrugs79 or micellar systems.10,11 Moreover, the multitude of names or keywords coined for acid-degradable,
including acid-labile, acid-cleavable, acid-sensitive,
pH-dependant, makes them dicult to track in the literature.
The aim of this review is to highlight the dierent strategies
based on acid-degradable polymeric systems that have been
developed in the past decade and their application. Acidsensitive polymers have been utilized in various drug delivery
devices such as degradable linear polymers and hydrogels,
cross-linked particles, self-assembled particles, polymerdrug
conjugates, and polyplexes (Fig. 1). For each strategy, the
performances of various systems such as degradation time or
drug release will be compared.
Sandra
Binauld
studied
materials science and polymer
chemistry at the National
Institute of Applied Sciences
of Lyon (INSA), a French
engineering school. She received
her PhD degree in 2009 from
the
University
of
Lyon
(France), after working with
Prof. E. Drockenmuller and
Prof. E. Fleury on the
elaboration of macromolecular
objects using Click Chemistry.
Sandra Binauld
In 2010, she moved to Australia
to work as a research associate at the Center for Advanced
Molecular Design (University of New South Wales, Sydney)
under the supervision of Prof. M. Stenzel, where she developed
smart drug delivery systems using RAFT polymerization. In 2012,
she joined Prof. B. Charleuxs group (C2P2, Lyon) as a casual
lecturer, and her current research focuses on the development of
nanomaterials using MADIX polymerization induced self-assembly
in aqueous media.
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structure of the bond, makes them candidates of choice for the
preparation of acid-degradable drug delivery systems. The acidsensitive linkers most commonly employed in the literature
include orthoester, acetal, hydrazone, imine, cis-aconytil and
trityl bonds. Their chemical structure and degradation products are given in Fig. 2. The orthoester bond is a functional
group containing three alkoxy groups attached to one carbon
atom that can be prepared by the reaction of nitriles with
alcohols under acid catalysis. They are readily hydrolyzed in
mild aqueous acid to form esters, and therefore usually used as
protecting groups for esters. The acetal bond is a molecule with
two single-bonded oxygen atoms attached to the same carbon
atom (or two carbon-bonded R groups in the case of ketal). In
an acidic solution, one oxygen of the acetal group is protonated,
which activates the neighbouring carbon. This facilitates the
attack of water, resulting in the cleavage of the acetal to the
appropriate aldehyde and alcohol. An imine is a functional
group containing a carbonnitrogen double bond, with the
nitrogen attached to a hydrogen atom or an organic group. If
this group is not a hydrogen atom, then the compound is more
stable and defined as a Schi base. They are obtained by
reaction of an aldehyde or ketone with a primary amine. When
an amine group is attached to the nitrogen, the imine is called
hydrazone. Hydrazones are usually formed by the reaction of
hydrazine on ketones or aldehydes. The cis-aconityl linker is a
derivate of natural aconitic acid that has a carboxylic acid (C-4)
in cis-position to a hydrolytic bond (C-1). This linker undergoes
Martina
Stenzel
studied
chemistry at the University of
Bayreuth, Germany, before
completing her PhD in 1999 at
the
Institute
of
Applied
Macromolecular
Chemistry,
University
of
Stuttgart,
Germany. She started working
as a DAAD postdoctoral fellow
at the University of New South
Wales
(UNSW),
Sydney,
Australia, where she currently
holds the position of full
Martina H. Stenzel
professor and ARC Future
Fellow. Her research interest encompasses the synthesis of
functional polymers with complex architectures such as
glycopolymers and other polymers for biomedical applications,
especially polymers with in-build metal complexes for the delivery
of metal-based anti-cancer drugs. Martina Stenzel has authored
more than 190 peer reviewed papers and 7 book chapters mainly
on RAFT polymerization. She is currently the Honorary Secretary
of the Royal Australian Chemical Institute and a member of the
Australian Research Council (ARC) college of experts. She is an
editor of the Australian Journal of Chemistry and also serves on
several editorial boards (Polymer, Progress in Polymer Science,
Macromolecules, Biomacromolecules, ACS MacroLetters). She
received a range of awards including the 2011 Le Fe`vre Memorial
Prize of the Australian Academy of Science.
Chem. Commun., 2013, 49, 2082--2102
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Fig. 1
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Fig. 2
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Fig. 3
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preparation of
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Also linear polyhydrazone28 and water soluble poly(cis-aconityl)29
have barely been investigated.
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which gelled in situ. Based on the same idea, analogues of
thermoresponsive PNIPAM hydrogels have been designed by
mixing aldehyde and hydrazide-functionalized PNIPAM oligomers. The hydrogels exhibit the same thermal swelling
deswelling responses as conventional PNIPAM hydrogels, but
can be degraded back into the reactive polymer gel precursors
via an acid-catalyzed hydrolysis process.45
However, only a few reports deal with the use of these aciddegradable hydrogels as drug carriers. Tian et al. developed a
new antibody (IgG) releasing system by covalently attaching IgG
to the biodegradable hyaluronic acid hydrogel using the hydrolytically unstable hydrazone linkage with the aim to deliver the
antibody to the injured brain.38 In pH 5 and 6 buer solution,
most of antibody (6080%) was released from the hydrogel
within 8 and 70 h, respectively, whereas the release was much
slower in pH 7.4 buer solution (over 400 h).
Table 1
Half-life time
Cross-linker
Ref.
pH 5.5 (min)
pH 7.4 (h)
11a
11b
12
13
14
15
16
17
18
19
20
46
47
48
49
50
51
51
51
23
52
53
5.5
5.5
1.6
n.a.
60
20
30
30
60
n.a.
14
24
24
6.8
n.a.
>20
>20
>20
>20
25
n.a.
29
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Fig. 5
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Acetal cross-linkers used for the synthesis of acid-cleavable particles by inverse-emulsion polymerisation.
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microemulsion polymerization.58 Acid-labile PNVF nanogels showed
increased stability at neutral pH (pH 7.4; t1/2 > 56 h) compared to
rapid dissolution observed at lower pH (pH 4.7; t1/2 B 10 min).
Using dispersion polymerization and RAFT polymerization, Chan
et al. employed a new bisacrylate acetal cross-linker 14 to create
acid-cleavable coreshell nanoparticles for the delivery of hydrophobic drugs.50 The particles were cleaved in a pH dependent
manner similar to the acid-labile hydrolysis behaviour of the
cross-linker itself. The same group also investigated the degradation of a range of bisacrylate acetal cross-linkers (1417) of
dierent polarities, which were used to prepare PHEMA nanogels
particles.51 Comparison of the hydrolysis half-life of the crosslinkers 14 and 16 leads to the conclusion that the presence of the
hydroxyl group as a p-substituent group on the benzene ring
makes the crosslinker more susceptible to acid-catalyzed hydrolysis compared to the cross-linker with the methoxy group.
Influence of the polarity on the degradation was also discussed.
Nanocapsules
chets group prepared
More recently, Broaders et al. from Fre
acid-degradable microcapsules via interfacial polymerization.
The polyamide was formed by the reaction of acid chlorides
with ketal-containing diamine 18 along the wateroil interface.
Rapid degradation into biocompatible products and complete
release of the encapsulated material was triggered upon exposure to an acidic environment.59 In vitro studies showed that
equivalent non-degradable capsules do not lead to significant
cell death regardless of the toxicity of the encapsulant, whereas
acid-degradable capsules lead to high cytotoxicity when loaded
with paclitaxel. The release of the drug, thus the cytotoxic eect,
was only made possible by the ecient uptake of the nanocapsules by cells. Shi and Berkland reported the synthesis of acidlabile poly(N-vinylformamide) (PNVF) nanocapsules by free radical
polymerization of N-vinylformamide in the presence of crosslinker 13 on the surface of silica nanoparticles.60 The formamide
side group of PNVF was then hydrolyzed by extended exposure to
sodium hydroxide to produce polyvinylamine (PVAm) micro- and
nanocapsules. Both capsule types underwent an increasing dissolution rate as the pH decreased. The extent of cross-linking was
observed to influence the degradation rate of the capsules. For
example, doubling the molar content of crosslinker from 6.5% to
13.2% resulted in a 3-fold increase in capsule half-life at pH 5.0
and produced more gradual degradation kinetics.
Cross-linked micelles
Another popular drug delivery technique involves the use of
micellar systems, which are obtained by self-assembly of amphiphilic copolymers. It is well-accepted that the micellar carriers
potentially allow passive targeting of drugs to tumours via
enhanced permeation and retention eect. However, the one
major drawback is the premature dissociation of these structures
in in vivo conditions due to the high dilution upon exposure to
large volumes of body fluids. To overcome this problem, micelles
are often stabilized by crosslinking. Crosslinking strategies include
core or shell cross-linking, but also crosslinking on the interface
between both blocks is known.61 The use of a stimuli-sensitive
cross-linker is particularly interesting since the disassembly of the
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micelles and subsequent release of the drug can be triggered by
external stimuli, such as pH. Several studies reported the synthesis
of core-cross-linked micelles using an acetal cross-linker in conjunction with RAFT polymerisation.62 Two approaches were investigated: a radical crosslinking process where the acid-degradable
divinyl monomer was copolymerised inside the core of the micelle
to stabilize the structure63 or a post-crosslinking approach, where
the integrity of the micelle was enhanced by employing a difunctional crosslinker.
Zhang et al. used RAFT polymerization to chain-extend a
thermoresponsive block copolymer, poly(acryloyl glucosamine)block-poly(N-isopropylacrylamide), with the commercial orthoestertype cross-linking agent 21 after the block copolymer has been
self-assembled into micelles.64 Chan et al. used a similar approach
and polymerized an acid-cleavable diacrylate cross-linker 14 inside
the core region of the micelles, leading to the chain extension of
the living RAFT end groups. The core cross-linking process was
found to have a minor eect on the original size of the micelle and
the core-segment polarity.65 The same technique was employed by
Bhuchar et al. to generate core cross-linked micelles in a one-pot
process by RAFT polymerization in the presence of a shorter
derivative of the di-methacrylate acetal cross-linker.66
An alternative approach is the stabilisation of micelles using an
acid-degradable difunctional crosslinker. Duong et al. eciently
reacted diamino cross-linker 18 inside a pentafluorophenyl-bearing
micelle core, which was formed by self-assembly of PEB-b-P(vinyl
benzylchloride-co-pentafluorophenyl acrylate) diblock copolymer.67
The same cross-linker was used by Huynh et al. in a reaction
between pendant activated esters at the nexus between micelle core
and shell. The micelle was obtained from a triblock copolymer
of poly(oligo(ethylene glycol)methylether methacrylate)-b-poly(N-hydroxysuccinic methacrylate)-b-poly(1,1-di-tert-butyl-3-(2(methacryloyloxy)ethyl) butane-1,1,3-tricarboxylate), which was
designed for the improved delivery of cisplatin. The acid
degradable crosslinker was directly compared to a non-degradable
crosslinker in their cytotoxicity against cancer cell lines, showing
that the degradable micelle had a much faster mode of action.68
Shell cross-linking is an alternative possibility to enhance micellar
stability against micelle-destabilizing conditions, but it can also
delay the drug release at extracellular pH values. Lee et al. and
Li et al. used diamino cross-linkers 18 and 20 to perform shell
cross-linking of acid-bearing block copolymers.53,69 Tappingmode atomic force microscopy (AFM) was applied as an interesting alternative technology to demonstrate the disassembly of
the acid-labile cross-linked knedel-like (SCK) nanoparticles.53
Finally, cross-linking of some alkynylated micelles was readily
achieved by the alkyneazide click reaction using the azidefunctionalized cross-linker 19.52
pH-induced transformation of
self-assembled systems
Destabilizing micellar systems
One approach to the development of acid-sensitive drug
delivery systems has been to incorporate titratable groups such
as amines and carboxylic acids into the copolymer backbone,
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Table 2
Structure/
ref.
Shell
Core
Acid-sensitive group
Drug
22
PEG
Poly(aspartic acid)
Nile red
n.a.
60
2372
PEGdendritic
polyester
PEG
PNIPAM
Hydrophobic
acetals
P(tNEA)
P(OPD-co-CL)
Trimethoxybenzylidene
acetal
Trimethoxybenzylidene
acetal
Cyclic orthoester
Hydrazone
DOX
12
92
80
Nile red
5-Fu
5
9/20
5
48
100
88
0
76
73
24
2579
a
Time
(h)
Releasea (%)
Drug
loading
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pH 5
pH 7.4
Fig. 7
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Table 3
Composition
Acid-sensitive group
pH 5
pH 7.4
Drug
Drug
loading (wt%)
26
Micelles
PEGpolycarbonate
1000
150
2683
Polymersomes
PEGpolycarbonate
1000
120
2784
2885
Micelles
cd-Particles
PDM-co-HEA
Homopolymer
Trimethoxybenzylidene
acetal
Trimethoxybenzylidene
acetal
Cyclic acetal
Trimethoxybenzylidene
acetal
800
900
167
100
PTX
DOX
PTX
DOX
Nile red
PTX
3/13
3/12
3/7
2/4
n.a.
1
Ref.
82
Releasea (%)
Time (h)
pH 5
pH 7.4
48
68
89
56
56
68
90
42
44
31
37
10
1
48
6
24
Fig. 8
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Their amphiphilic pH-sensitive copolymer poly(PDM-co-HEA)
(Fig. 8, 27) self-assembles into nanoparticles, which were able to
increase in size from nano-scale to almost micro-scale in acidic
environment due to the hydrolysis of the acid-labile acetals.84 Using
a dierent approach, Griset et al. reported the synthesis of expansible nanoparticles, which were prepared using a miniemulsion
polymerization technique. This approach combines high-energy
emulsification and free radical photopolymerization of a trimethoxybenzilidene acrylate monomer.85 The particles based on polymer 28
(Fig. 8) were cross-linked to be able to transform into a hydrophilic
nanogel structure at pH 5. The release of paclitaxel from the loaded
expansible nanoparticle was found to be pH dependent and related
to the hydrophobic to hydrophilic transformation.
Switching the solubility of dextrane particles
An acid-responsive biodegradable material was developed by
chet and coworkers based on acetal-derivatized dextran.86,87
Fre
Nanoparticles obtained from this material can be used as
triggered drug delivery systems thanks to its solubility switching
mechanism. Indeed, masking the hydroxyl groups of dextran as
acetals not only provides a hydrophobic material that can be
easily processed using various emulsion techniques, but also
provides a mechanism for introducing pH-sensitivity. Under
mildly acidic aqueous conditions, the pendant acetal groups
can hydrolyze, allowing a complete dissolution of the dextran
nanoparticles and their subsequent degradation (Fig. 9). Full
dissolution of the particles was observed after 24 h at pH 5,
whereas no degradation was observed at pH 7. This pH-dependent
degradation of Ac-DEX particles is further reflected in the
release profile of a model payload. Further studies on this system
demonstrated its eciency for the delivery of plasmid-DNA
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and Si-RNA.88,89 More recently, the synthesis of ethoxy acetal
derivatized acetalated dextran has been reported, which presents the advantage of degrading into non-toxic products such
as ethanol, acetone, and dextran.90 Like Ac-DEX, Ace-DEX
microparticles have tunable degradation rates at pH 5 (intracellular) that can range from hours to several days by varying
the reaction time. These polymers could not only be used
to deliver traditional anti-cancer drugs but also hydrophobic
silver carbene complexes, which have strong anti-bacterial
properties.91
Polymerdrug conjugates
Besides encapsulation, another way to improve drug delivery is
by covalently attaching the drug to a macromolecular carrier.
Indeed, high molecular weight molecules and nano-sized
particles accumulate in solid tumours at much higher concentrations than in normal tissues or organs due to the Enhanced
Permeation and Retention (EPR) eect. Obviously, the stability
of the drugpolymer linkage is crucial. Based on the stability of
this bond, polymer conjugates may be classified into two broad
categories: permanent conjugates and prodrugs that usually
require the transformation of the prodrug to the drug within
the body to allow therapeutic action. Hence, the system should
be able to release the drug at the target site by using appropriate stimuli-responsive linkers. The literature on the release
of the drug from polymeric prodrugs by cleaving various
chemical linkages (esters, carbonates, carbamates, CN linkage,
and amides) has already been reviewed.92 Systems containing
acid-labile linkers, able to release the drug at slightly acidic pH,
have been quite popular for the design of intelligent carriers of
various architectures. Out of all acid-sensitive bonds, the hydrazone bond formed between the C13 carbonyl group of anthracyclines (i.e. Doxorubicin (Dox), daunomycin (Dau)) and polymer
hydrazides or the amide bond of a cis-aconityl residue containing
spacer is the most commonly used type for the preparation of
polymerdrug conjugates.
Linear polymerprotein conjugates
Fig. 9
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Fig. 10
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Table 4
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Releasea (%)
Ref.
Linker
Spacer (X)
Drug
Mn PHPMA (g mol 1)
Time (h)
pH 5
pH 7.4
96
Hydrazone
DOX
Hydrazone
Hydrazone
97
Hydrazone
102
101
Hydrazone
Hydrazone
Gly
Gly-Gly
Gly-Phe-Leu-Gly
b-Ala
Aminobenzoic acid
Aminohexanoic acid
Aminohexanoic acid
Aminohexanoic acid
99
104
cis-Aconityl
Hydrazone
Gly-Phe-Leu-Gly
(Oxohexyl)methacrylamide
9.5
10.5
10.2
7.6
8.2
7.9
9.5
10.5
6.8
6.8
4.7
2.3
5
6.6
4.4
6.3
25 700
19 600
38 900
33 500
34 200
15 800
25 700
21 100
25 600
38 400
35 700
30 000
41 000
56 000
38 800
21 500
48
106
103
Gly-Gly
Gly-Phe-Leu-Gly
Aminohexanoic acid
Aminohexanoic acid
85
75
80
90
80
85
85
75
71
92
96
93
90
86
75
98
10
5
3
38
5
11
10
6
7
16
5
22
42
50
3
8
DOX
PTXLEV
DTXLEV
DOX
DEXOPB
DEXLEV
DEXOPB
DOX
AHMA
9
24
48
6
24
48
24
Fig. 11
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Table 5
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Releasea (%)
Ref.
Spacer
PEGPAsp
Drug
Time (h)
pH 5
pH 7.4
113
114
1237
1238
67.6%/asp
>31 wt%
65
o200
24
24
115
1240
Gly
125
1215
1235
125
1215
1235
125
1215
1235
1235
533
1235
42
137
85
44
45
40
11
25
43
86
62
44
38
38
259
24
116
ADR
DOX
GDMLEV
PTXLEV
PTXOPB
1 : 1 co-assembly
DOX
25
60
81
57.6
0
44.9
40
57
37
60
65
o30
78
45
45
45
55
58
o5
20
78
29.2
0
34
30
44
17
36
30
o30
39
10
38
28
40
49
Abz
117
118
a
Ester only
4-Acetylbutyric acid
6-Oxoheptanoic acid
7-Oxooctanoic acid
DEX
3PO
37.50%
87.50%
13
2.8
10.4
31.6
4.1
10.9
11.4
8.7
4.6
5.6
4.5
2.08
2.21
48
24
such as the poly(aspartate) block length and the nature of the linker
on the micelles size and release profile was investigated. It appears
that the drug loading was highly depending on the nature of the
drug and the linker. Moreover, the release time of those micellar
systems was overall slower than for the graft copolymers systems
(Table 5), and in general the dierences in release rate between
pH 5.5 and 7.4 was less noticeable. This can be explained by the
presence of the hydrophilic shell that protects the hydrazone linker
from the external media. Particularly, the micellar system designed
for the delivery of the glycolytic enzyme inhibitor, 3-(3-pyridinyl)-1(4-pyridinyl)-2-propen-1-one (3PO), showed only a small dierence
in the release profile at both pH after 3 hours, with a significant
drug release at pH 7.4. These results indicate that the micelles may
retain 3PO in the blood stream (pH 7.4) only for a short time. It is
also interesting to note that the method used for dialysis was found
to have a large influence on the drug release profiles.112 In vitro and
in vivo studies performed on the adriamycin-loaded system show
the eciency of this micellar system including the intracellular
pH-triggered drug release capability, tumour-infiltrating permeability as well as eective antitumor activity with extremely low
toxicity.119 A step further in the design of pH-sensitive polymeric
micelles as drug carriers is the introduction of targeting agents by
modification of the polymer backbone with piloting molecules for
cancer cells targeting. Bae et al. paved the way to such systems by
introducing folate (Fol) at the end of the shell-forming PEG chain to
enhance intracellular transport.120 More recently, Xiong et al. conjugated doxorubicin to poly(ethylene oxide)-block-poly(3-caprolactone)
(PEO-b-PCL) micelles decorated with the avb3 integrin targeting
ligand RGD4C on the micellar surface (Fig. 11c).121 The presence of
the targeting ligand allowed the accumulation of DOX in the
nucleus of sensitive cells and mitochondria of resistant cells.
Moreover, the micellar systems were found to be more eective
than free DOX in vivo in inhibiting the growth of DOX sensitive and
resistant tumours, respectively. The same team also proposed an
improved version of this system by designing a virus mimetic shell
that was conferred by attaching two ligands, i.e., the integrin
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Table 6 Composition and release eciency of cross-linked micellar prodrugs
(structures from Fig. 12)
Ref. Polymer
Drug
Fig. 12 Structures of the polymers and cross-linkers precursors of the crosslinked micellar prodrugs.
In a one-pot reaction, the versatility of PDS groups on amphiphilic PPDSM-b-PHPMA, synthesized by RAFT polymerization,
was used to conjugate doxorubicin and simultaneously crosslink
the micellar assemblies via acid-cleavable hydrazone bonds and
reducible disulfide bonds (Fig. 12b), allowing the system to be
cleaved into unimers in a reductive intracellular environment.
Core-cross-linked biodegradable polymeric micelles composed of
poly(ethyleneglycol)-b-poly[N-(2-hydroxypropyl) methacrylamidelactate] (mPEG-b-P(HPMAmLacn)) were obtained by Talelli
et al. by polymerizing a DOX methacrylamide derivative using
free radical polymerization (Fig. 12c).132 The entire drug payload
was released within 24 h incubation at pH 5 whereas only around
5% release was observed at pH 7.4 (Table 6). Finally, Aryal et al.
proposed an original system for the controlled delivery of cisplatin,
by designing novel acid-responsive Bi(PEGPLA)Pt(IV) polymer
cisplatin prodrug conjugate nanoparticles (Fig. 12d).133 The
resulting particles showed excellent acid-responsive drug release
characteristics and potent cytotoxicity against ovarian cancer.
Polysaccharides
Due to their excellent physicochemical properties, biocompatibility
and biodegradability, polysaccharides have also been investigated
for developing macromolecular prodrugs. More specifically, the
design of derivatives with tuneable bio-responsiveness, targeting
or environmental triggering properties, has raised interest in the
past few years. One of the first examples of chemical conjugation
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Drug
Micelles
Releasea (%)
loading diameter Time
pH 5 pH 7.4
(wt%) (nm)
(h)
11
24.9
56
61
24
24
25
72
14
21
3040
80
24
100
86
24
83
55
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Table 7
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Releasea (%)
Ref.
Linker
System
Drug
134
Hydrazone
Alginate
LMW
HMW
Pullulan particles
Stearic
Acid-g-chitosan micelles
DNM
135
137
Hydrazone
cis-Aconityl
138
139
cis-Aconityl
cis-Aconityl
Glycol-chitosan nanoaggregates
Glycol-chitosan nanoaggregates
DOX
DOX
DOX
ADR
Time (h)
n.a.
48
100150
40
70
106
238
238
48
48
48
48
pH 5
pH 7
63
23
100
42
37
28
9 (pH 4)
26 (pH 4)
3
3
10
31
28
15
2.5
6
Table 8
Composition and release eciency of hyperbranched micellar prodrugs and other nanoparticles
Releasea (%)
Ref.
Linker
Core
Shell
Time (h)
pH 5
pH 7
140
141
142 and 143
145 and 146
Hydrazone
Hydrazone
Hydrazone
cis-Aconityl
Dendritic polyglycerol
Dendritic polyglycerol
PAMAM dendron
PAMAM dendron
PEG
PEG
HPMA
PEG
Hydrazone
Hydrazone
Hydrazone
Hydrazone
Boltorn H40
Gold nanoparticle
Boltorn H40
PDA capsule
PEG-b-PLasp
PEG-b-PLasp
PEG-b-PLGlu
PMA
16.4
183
n.a.
83
18
16
50
2452
4491
300
24
24
24
48
147
150
148
149
5
2.1
11
1/4 18
1/16 8.5
1/32 6.4
16
17
16.2
75
70
90
4
8
24
76
70
85
85
o5
50
5
o1
o1
o1
12
10
10
20
24
24
24
12
PolymerDNA complexes
Gene therapy holds great promise for the treatment of severe
diseases including cancer. In recent years the design of synthetic
carriers for nucleic acid delivery has become a research field of
increasing interest. Viral vectors that have been commonly used
are limited by their cargo loading and, more importantly, may
lead to immune reactions. In this context non-viral carriers for
plasmid DNA and Si-RNA have gained increasing interest in gene
therapy research during the past few years.151 The new trend is
now to design targeting and bio-degradable devices that will
allow improved eciency and lower side eects.
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ChemComm
Ref.
Acid-degradable linker
System
Polymer
pH
153
154
Imine
Acetal
4.5/7.4
5/7.4
155
156
Acetal
Acetal
157
Acetal
Branched PEI
OEIMK
OEIBAA
PEGOEI copolymer
Linear PEI LMW
Linear PEI HMW
Branched PEI
1.1/118
0.25/5
3 min/3.5
n.a.
2.3/21.6
1.9/20.3
2.6/26.4
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5/7.4
5/7.4
2097
ChemComm
Fig. 13
Fig. 14
Also, a monomer-to-polymer approach was used to obtain aciddegradable cationic nanoparticles,163 using an aliphatic monomer with a pendant primary amine group and a cleavable acetal
chets group
linkage, which was developed previously in Fre
(Fig. 14a).48 This approach allows highly flexible nanoparticle
fabrication, resulting in higher transfection eciency by the
degradable nanoparticles than PEI polyplexes at very low concentrations. Micelles that can undergo structural transformations at
low pH value were obtained by Shim and Kwon by self-assembling
DNA with PEG-conjugated poly(ketalized serine) (Fig. 14b).164
2098
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Upon acid-catalyzed hydrolysis of the ketal linkages, poly(kSer) converts to neutral and naturally occurring poly(serine),
resulting in the destabilization of the micelles. In addition, the
study employed core cross-linking via acid-cleavable aminebearing branches to improve the transfection capability.
A dierent approach was proposed by Chen et al. to promote
the transfection eciency of p-DNA by encapsulating the
PEIDNA polyplexes into microparticles of biodegradable
polymers containing acid-labile segments and galactose grafts
(Fig. 14c).165 The presence of galactose moieties also enhanced
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ChemComm
Conclusions
Fig. 16
Mechanism of compaction of nucleic acid AdPVAPEG cargo into stable nanometer-size particles and its degradation.167
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ChemComm
products listed in this review may fail this bill while other
approaches may be too expensive or dicult to upscale. However, this should not discourage the reader to reach into this
toolbox and use this remarkable chemistry. The opportunities
are evident and highly promising.
Acknowledgements
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