Macromolecular

Review Chemistry and Physics

Oxidation-Responsive Polymers: Which Groups

to Use, How to Make Them, What to Expect
From Them (Biomedical Applications)

Enrique Lallana, Nicola Tirelli*

Dramatic physical changes may take place upon the occurrence of oxidation reactions in a
polymer, for example, solubilization or crosslinking. These effects can be used to perform
responsive actions such as modulating the release kinetics of a drug with the extent of oxida-
tion. The relevance of oxidation-responsive applications to the
biomedical/pharmaceutical field is discussed, starting from a
review of chemical groups that can respond to physiologically
occurring oxidants. An overview of the preparative processes
of polymers containing groups such as metallocenes, (poly)
pyridyl metal complexes, polyconjugated sequences, thiols,
thioethers (sulfides), and stannanes is presented, and the
mechanisms of oxidative response are reviewed.

1. Introduction, Scope, and Limitations associated to pathological (inflammatory) phenomena,

Oxidative processes can easily modify the behavior of
materials. Undesired and generally uncontrolled oxida-
tive degradation often causes aging and failure of a mate-
rial;[1] biomedical applications are not an exception: for
example, the oxidative lability of polyurethanes soft seg-
ments was the major cause of failure of vascular grafts in
the 1990s.[2]
On the other hand, oxidative processes such as double
bond peroxidation have been used since the dawn of
times, for example, to control paint rheology (peroxida-
tion-induced hardening of siccative oils and resins[3–5]).
In this review, we specifically focus on the application
of the general concept of an oxidative response in poly-
mers developed for biomedical applications. Oxidants
are extremely common in biology and they are often
E. Lallana, N. Tirelli
School of Medicine, University of Manchester, Oxford Road,
Manchester, M13 9PT, UK
E-mail: nicola.tirelli@manchester.ac.uk
N. Tirelli
School of Materials, University of Manchester, Oxford Road,
Manchester, M13 9PT, UK
where reactive oxygen species (ROS) and reactive nitrogen
species (RNS) can fulfill both roles of signaling and toxic
molecules. Hereafter, we will focus on ROS (hydrogen per-
oxide, superoxide, OH radical, etc.), since they are generally
recognized to be the main contributors to the intra- and
extracellular redox potential and to the associated stress
conditions[6] and signaling cascades,[7] for example, in
diabetes,[8,9] hypertension, and atherosclerosis,[10,11]
cancer[12]; however, many of our considerations can apply
to some RNS too (e.g., peroxynitrite). Scheme 1 summa-
rizes the general paradigm that ROS-responsive mate-
rials could follow in a physiological environment, in a
sequence of events that link molecular, macroscopic, and
biological scales. Typically, the materials would swell/
dissolve or in alternative shrink/harden as a result, for
example, of increased osmotic pressure (oxidation of a
metallic center, thus larger number of counterions), of
increased polarity (oxidative conversion of a low-dipole
moment molecule into a high-dipole moment one), or of
the occurrence of crosslinking or depolymerization reac-
tions. These physical changes could then be translated
into biological effects, for example, through direct biome-
chanical interactions on adherent cells, or by controlling
the release of encapsulated drugs.

Macromol. Chem. Phys. 2013, 214, 143−158

© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim wileyonlinelibrary.com DOI: 10.1002/macp.201200502 143
 Macromolecular
Chemistry and Physics
www.mcp-journal.de
The first point to ascertain is the identity of the mole-
cular components, that is, the oxidation-sensitive groups
that could respond to physiologically relevant oxidants
under physiologically acceptable conditions.
2. Selection of Oxidant (ROS)-Responsive
Groups
ROS comprise compounds characterized by free radical
reactivity and high oxidation potentials (Eo0, left part of
Table 1), whose typical chemical signature is the (per)oxi-
dation of lipids,[13] proteins,[14] and nucleic acids.[15] At high
concentrations, ROS are involved in a number of potentially
toxic/inflammatory processes; at low concentrations, they
can direct behavior of cells, which respond to even very
modest modulations in the redox potential[16]: reducing
intracellular environments (Eo0 > 200 mV) are associated
to proliferation and differentiation phases (as in fetal life),
while even mildly oxidizing ones to apoptosis and necrosis
(Eo0 < 170 mV).
Two main strategies are used in nature to interfere with
ROS: (A) the enzymatic intervention at specific stages of
the free radical chain reactions, for example, superoxide
dismutase and glutathione peroxidase focus, respectively,
on the conversion of superoxide and lipid hydroperoxides
into the less dangerous hydrogen peroxide, which in turn
is the target of catalase; (B) the use of broad-spectrum
antioxidants, for example, vitamins C and E, or glutath-
ione, which typically present oxidation potentials in the
range of +0.2 to −0.5 V (Table 1, right part). The redox
behavior of the latter could be mimicked by synthetic
systems with similar oxidation potentials; in order of
decreasing ease of oxidation, these systems are viologens,
thiols/disulfides, hydroquinones/quinones, metallocenes,
polypyridyl ruthenium complexes, and thioether/sulfox-
ides (Table 2).
Stability and toxicity concerns hinder the biomedical
application of some of these systems: most quinones
Scheme 1. General modus operandi of oxidation-sensitive materials in the perspective of
biomedical applications.
Macromol. Chem. Phys. 2013, 214, 143−158
144 © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
E. Lallana and N. Tirelli
Nicola Tirelli holds a Master’s degree in chemis-
try and a Ph.D. in Industrial Chemistry from the
University of Pisa (Italy), both under the super-
vision of Francesco Ciardelli. After a postdoc-
toral period with Ulrich Suter at the ETH Zurich
in 1998, Nicola joined Jeff Hubbell at the ETH
Zurich as an Senior Staff Scientist, turning his
research interests to the area of biomaterials. In
2002, he moved to Manchester first as a Senior
Lecturer, where he holds the Chair of Polymers
and Biomaterials since 2005. His research
interests include synthetic polymer chemistry,
colloid science, and biomedical applications.
Enrique Lallana received his Master in Chem-
istry in 2004 from the University of Santiago
de Compostela (USC, Spain). He subsequently
obtained his Ph.D. in 2010 from USC under
the supervision of Profs. R. Riguera and E.
Fernandez-Megia for his work on configura-
tional assignment of polyols by NMR and new
bioconjugation procedures for the preparation
of immunonanoparticles. He is now a postdoc-
toral research associate in the group of Prof. N.
Tirelli at the University of Manchester (UK). His
current research interests include bioconjuga-
tion reactions, surface functionalization via
controlled living radical polymerization, and
redox-responsive materials.
are toxic[37] due to both Michael-type reactivity (alkyla-
tion of proteins and nucleic acids) and to their own redox
behavior. Similarly, the rich redox responsiveness of vio-
logen chromophores[38,39] is also at the basis of their tox-
icity (see paraquat herbicides[40]).
The groups characterized by a low oxidation potential,
for example, thioethers, could also be advantageously
employed to interfere only with highly oxidizing situa-
tions to possibly discriminate between biological envi-
ronments according to the gravity of a
ROS-based pathology.
3. Organometallic Polymers
3.1. Metallocenes
Ferrocene is the most popular metal-
locene building block with redox prop-
erties in part due to its stability in air
and in the presence of protic solvents.
However, a few examples exist of mac-
romolecules incorporating other met-
allocenes, such as cobaltocene and
nickelocene centres.[41]
www.MaterialsViews.com
 Macromolecular
Oxidation-Responsive Polymers: Which Groups to Use . . . Chemistry and Physics
www.mcp-journal.de

Table 1. Oxidation half-cell potentials of some ROS and biologi- Metallocenyl-containing monomeric structures have
cally relevant reducing agents.a) also been polymerized via free radical mechanisms, for
System Reduced form Oxidized form E0o [V] example cobaltocenyl acrylates[53] and a variety of ferro-
H2O2 O2 − b)
−0.91[17] and other metallocene derivatives comprehensively
reviewed by Pittman.[54] In recent years, the attention has
oxidants H2O H2O2 −1.35[17]
shifted toward polymers obtained through controlled rad-
(ROS) OH•/H2O H2O2 −0.32[18] ical mechanisms, for example, reverse addition/fragmenta-
H2O OH• −2.31[18] tion chain transfer (RAFT) polymerization,[55] atom-transfer
radical polymerization/single-electron transfer living rad-
ical polymerization (ATRP/SET-LRP),[56] or surface-initiated
α-tocopherol α-tocopheroxyl −0.50[18]
ATRP[57] of ferrocenyl (meth)acrylates, RAFT of ferrocenyl
(vit. E) radical
styrenes,[58] or (2,2,6,6-tetramethylpiperidin-1-yl)oxyl
ascorbate ascorbate −0.28[18] (TEMPO)-mediated polymerization of vinylferrocene.[59]
reductants (vit. C) radical
Finally, it is worth mentioning the anionic polymeri-
NADHc) NAD+ 0.32[16] zation of vinylferrocene,[60,61] which has been recently
GSHd) GS-SG 0.21,[19] improved by the “carbanion pump” method, in order
0.24[16] to cope with the low reactivity of ferrocenyl-based
macroanions.[62]
a)
In all cases, H+ are omitted, and the potentials refer to a water
environment at pH = 7 and 25 °C. Note that the oxidation poten- 2) Use of metallocene-containing initiators/chain transfer
tial values shown here are presented in the form of standard agents; ferrocenyl RAFT agents[63] or cobaltocenyl ATRP
reduction potentials (E0') in the cited references. b)Superoxide can
initiators[64] have been used to introduce the metallo-
behave both as an oxidant (being reduced to hydrogen peroxide,
which is a powerful oxidant in its own right, see next column), cene group as a terminal or central group of styrene or
but can also be oxidized to molecular oxygen (E0o = 0.33[20]-0.36 (meth)acrylic polymers.
V[17]); this behavior is at the basis of the action of superoxide dis- 3) Functionalization of preformed polymers; a number of
mutases; c)NADH: nicotinamide adenine dinucleotide, two-elec- reactions have been used to introduce metallocenes, in
tron process; d)GSH: glutathione, two-electron process.
most cases, as side chain groups or as terminal groups
in dendritic/star structures. We will here mention only
a few cases, starting from early examples of transesteri-
fication on poly(γ-methyl-L-glutamate),[65] to the nowa-
Synthetic routes to macromolecular metallocenes
days more popular hydrosilylation[66] and “click” (Huis-
started being explored in the 1950s with the first attempts
gen cycloaddition)[67] reactions.
of ferrocene (co)polymerization in DuPont,[42] but their
real development dates only from the 1990s and followed Ferrocenyl-containing copolymers with inter-
three main directions: esting self-assembly possibilities have been pre-
pared using sequential anionic polymerizations (e.g.,
(1) Polymerization of metallocene-containing monomers.
poly(vinylferrocene)-block-poly(ethylene oxide)[68]),
The most popular mechanism is the ring-opening po-
using macroinitiators (e.g., SiH-terminated poly(ethylene
lymerization of ferrocenophanes, which is based on the
oxide) (PEO) for the ring-opening polymerization (ROP)
structural strain introduced by short (1–2 atoms) ansa
of silaferrocenophane[69]) or combining end-functional
bridges connecting cyclopentadienyl rings; the corre-
polymers (e.g., through the formation of terpyridine
sponding complexes are referred to as [1] and [2] ansa
metallocenes (Figure 1). ruthenium complexes[70]).

This polymerization method has been pioneered by

Manners in the early 1990s[43] and extensively explored
by his group[44,45]; although boron-,[46] tin-,[47] phos-
phorous[48] [1] ferrocenophanes and the slightly longer
unsaturated[49] and saturated C2-bridged,[50] and tri-
sulfide-[51]containing [2] and [3] ferrocenophanes have
been used, silicon-bridged [1] ferrocenophanes have pro-
vided the best results, leading to high-molecular-weight
polyferrocenylsilanes (PFSs) through a variety of initia-
tions, for example, anionic, photochemical, thermal; a
comprehensive overview of PFSs synthesis has been
recently provided by Bellas and Rehahn.[52]
3.1.1. Ferrocenes as Oxidative Triggers
3.1.1.1. Medicinal Chemistry. Ferrocene is known to have a
particularly low acute toxicity[71] and is therefore regarded
as a particularly benign molecule. On the other hand, its
oxidized counterpart, ferrocenium, has been shown to gen-
erate ROS in physiological environment; this activity has
been linked to a specific toxicity toward tumoral cells.[72]
Particularly interesting is the case of ferrocifen where the
ferrocene unit is derivatized with a tamoxifen-like res-
idue. Tamoxifen is a well-known antiproliferative chemo-
therapeutic agent, whose hydroxylated and demethylated

Macromol. Chem. Phys. 2013, 214, 143−158

www.MaterialsViews.com © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 145
 Macromolecular
Chemistry and Physics E. Lallana and N. Tirelli

www.mcp-journal.de

Table 2. Oxidation potentials of possible ROS-responsive groups.a)

Groups Example Ref. elec.b) E0o [V] Solvent
c) 0.36–0.83e,d)[21] propanol/PBd)
viologen substituted viologens NHE

thiols → disulfides glutathione SHE 0.21d)[19] PB

d)[19]
dithiothreitol 0.32
mercaptoethanol 0.21d)[19]

hydroquinones → geldanamycin derivatives NHEc) 0.06–0.27e)[22] propanol/PBd)

quinones 1,4-naphtoquinone-2- O2/O2•−/ O2/O2•− c) 0.06[23]/0.08e)[22] propanol/PBd)
sulfonate
adriamycin NHEc) 0.34e)[24] H2Od)
substituted benzoquinones SHE (0.2)–(−0.05)e)[25]
(−0.1)–(−0.3)f)

metallocenes ferrocene Ag/AgCl (−0.18)–(−0.21)[26] variousg)/H2O

(−0.43)–(−0.45)[27,28] various/MeCNh)

(poly)pyridine metal various RuNH3/pyridine SCE (−0.25)–(−0.50)[29] p-TsOH/K/H2O

complexes complexes
[Ru(bpy)3]2+ with various Ag/AgCl (−0.96)–(−0.97)[30] TBAPF6/DMSO
counterions

thioethers → sulfoxides methioninei) Ag/AgCl −1.50[31] NaBF4j)

−1.24[31] NaHCO3k)
−1.16[31] Na2CO3l)
diphenylsulfide NHEc) −1.54m)[32] H2O
various aliphatic and aro- Ag/AgCl (−1.50)–(−1.85)m)[33] NaBF4/MeCN
matic sulfides

sulfoxides → sulfones aromatic sulfoxides SCE (−1.73)–(−2.19) [34] NaClO4/MeCN

a)Obtained by cyclic voltammetry unless otherwise indicated. Please note that the oxidation potential values presented in this table are taken

from E0′, E1/2 or half-peak oxidation potentials given in the cited references, and that these data are obtained against various reference elec-
trodes (SHE, NHE = standard and normal hydrogen electrode; SCE = saturated calomel electrode; PB = phosphate buffer); b)In relation to SHE
and NHE (0.00 V) at 25 °C the other reference electrodes are estimated to be: SCE +0.24 V, Ag/AgCl (1 M) +0.23 V and Ag/AgCl (sat) +0.20 V
and O2/O2• − −0.18 V; c)From pulse radiolysis measurements; d)pH = 7.0; e)One-electron oxidation to radical anion; f)Two-electron oxidation
to hydroquinone; g)Measured at pH = 6.96–7.44; h)For a compilation of standard reduction potentials of Fc+/Fc in MeCN at 25.0 °C measured
using different reference electrodes, see ref.[35] For a compilation of standard reduction potentials of Fc+/Fc in different organic solvents meas-
ured using SCE as reference electrode, see ref.[36]; i)Dehydromethionine is proposed as the direct oxidation product, which is then rapidly
hydrolyzed to methionine sulfoxide; j)pH = 2.1; k)pH = 8.2; l)pH = 12.2; m)One-electron oxidation to radical cation.

metabolite (endoxifen) is capable of binding to estrogen
receptors (ER) that are overexpressed in a significant
number of tumours. However, ferrocifen exhibits anti-
proliferative activity also for ER(–) cells and therefore its
cytotoxicity has been attributed to an antenna effect of
the ferrocene group, which allows the formation of toxic
quinonic species (Figure 2)[73,74] via electron transfer from
(deprotonated) phenol[75] or catechol[76] species to tran-
siently formed ferrocenium ions.
This antitumoral (antiproliferative) activity in the
absence of direct interactions with nucleic acids is not
a peculiarity of ferrocene or of structurally similar com-
pounds (e.g., ferrocenophanes are reportedly more active
than ferrocene itself[77]); its occurrence in a number of

Macromol. Chem. Phys. 2013, 214, 143−158

146 © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.MaterialsViews.com

Oxidation-Responsive Polymers: Which Groups to Use . . .
Figure 1. Top: The one-electron oxidation of the metallic center.
Bottom: For several metallocenes, the magnitude of tilt angle
α between aromatic rings is a measure of the structural strain,
which indicates also the propensity to a ring-opening polymeri-
zation. This relationship does not hold for metal centres with few
d electrons, such as Zr, whose energy is substantially insensitive
to the tilt angle.
other organometallic reagents suggests a broad occur-
rence of redox-mediated toxic mechanisms.[78] Studies of
the use of polymeric and/or colloidal carriers, for example,
lipid nanoparticles[79] or micelles,[80] bearing ferrocene
moieties to enhance its antitumoral, redox-mediated
effects have been performed and in general the imple-
mentation of ferrocene as a redox antenna is extremely
promising, although the field is yet in its infancy.
3.1.1.2. Controlled Release. The reversible oxidation of
a metallocene can dramatically change the polarity of
its environment, due to the acquisition of a net positive
charge, but also to the presence of counterions. In a few,
this phenomenon has been used to modulate the inter-
facial properties of amphiphilic compounds, with the
clear perspective application of drug release modulated
by oxidative signaling. For example, ferrocene groups
covalently linked on liposomal surfaces have allowed the
electrochemical modulation of the liposomal membrane
permeability.[81] Similarly, vesicles obtained through the
guest–host interactions between ferrocene- and cyclodex-
trin-functionalized polymers are disrupted and eventually
solubilized upon electrochemical oxidation of the iron cen-
tres.[82] Even more interestingly, amphiphilic cationic PFSs
have shown reversible changes in micellar size in response
to the presence of Fe(III), which allow the release of encap-
sulated payloads and are reversed by reduction with
ascorbic acid.[83]
Similar effects could be shown also in macroscopic
matrices. Ferrocene oxidation can be performed also in
an organogel state and indeed crosslinked hydrophobic
Macromol. Chem. Phys. 2013, 214, 143−158
www.MaterialsViews.com © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Macromolecular
Chemistry and Physics
www.mcp-journal.de
PFSs correspondingly show strong electrochromic
effects.[84] When crosslinked polyanionic PFSs are used,
the color change is accompanied by gel shrinkage, due to
the attraction between the positively charged oxidation
products (ferrocenium ions) and the polymer negative
charges (sulfonates), with a redox-responsive swelling
performance that could be used to design actuators or
responsive drug reservoirs.
3.2. Multidentate (Polypyridine) Coordination Systems
Synthetic polypyridine metal complexes, above all those
based on ruthenium centers, are extensively studied in
supramolecular chemistry for their photophysical prop-
erties and as a means of obtaining reversible linkages at
the basis of polymer structures. These systems have been
object of a number of reviews, and the reader should refer
to them for what attains to the synthesis[85,86] and electro-
chromic/electro-optical/photochemical properties[87–89] of
their macromolecular derivatives. A peculiarity of ruthe-
nium systems is that the strength of the complexation by
polydentate pyridine ligands depends on the oxidation
state of the metal, for example, only a mono terpyridine
complex can be obtained from Ru(III) salts, whereas double,
and possibly asymmetric, complexation can be obtained
by reduction to Ru(II).[90] This opens the way to the prepa-
ration of coordination polymers of ruthenium in this lower
oxidation state,[91] whereas Ru(III)-containing polymers
can be obtained only through side-chain complexation of
the metal centre.[92] It is therefore possible to speculate
that oxidation of Ru(II) coordination polymers may lead to
their depolymerization, and thus to macroscopic changes
in the material properties.
3.2.1. Ruthenium Complexes as Oscillating
Oxidative Triggers
A most interesting case is offered by the introduction of
the Belousov-Zhabotinsky oscillating reaction in polymeric
materials; this has allowed the modulation of material
properties (color, dimensions, etc.) through the oxidation
state of ruthenium in polypyridine complexes.
This Belousov-Zhabotinsky reaction has a complex
mechanism,[93] which in the Field-Koros-Noyes (FKN)
scheme[94] is based on essentially three inter-dependent
processes: (1) the production of bromide (Br−) from malonic
acid (or citric acid), bromate (BrO3−), and an inorganic oxi-
dant such as Ru(III), (2) the oxidation of Ru(II) by bromate
to restore Ru(III) and produce hypobromite (HBrO2), and
(3) the consumption of bromide to eventually produce
bromine (Br2) through various reactions with higher oxi-
dation state bromine species (hypobromite, bromate,
etc.; see Figure 3, top). The different kinetics of the three
steps produce periodic oscillations in the concentration of
147
 Macromolecular
Chemistry and Physics
www.mcp-journal.de
Figure 2. An antenna effect based on the transient oxidation of ferrocene to ferro-
cenium and a charge transfer from (deprotonated) phenol groups is hypothesized to
explain the cytotoxicity of ferrocifen and related molecules. In the insert, the chemo-
therapeutic amoxifen and of its active metabolite endoxifen, whose structures inspired
that of ferrocifen.
bromide, which are mirrored by oscillations in the ratio
between the two oxidation states of ruthenium.
Terpyridyl complexes have been shown to be the best
ruthenium catalysts for this reaction, whereas the activity
of bipyridyl complexes can be detrimentally affected by
ligand exchange phenomena. [ 95 ] Nevertheless, ruthe-
nium tris(bipyridyl complexes) covalently embedded in
N-isopropylacrylamide (NIPAm) gels showed remarkable
stability and the occurrence of the Belousov-Zhabotinsky
reaction determined significant oscillations in the gel
volume, with corresponding changes in mechanical prop-
erties (Figure 3, bottom).[96]
Further, the relation between mechanical effects and
chemical oscillations is bidirectional: compression, hence
variations in the ruthenium concentration but not in
Macromol. Chem. Phys. 2013, 214, 143−158
148 © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
E. Lallana and N. Tirelli
those of soluble reagents, can affect the
reaction producing different optical pat-
terns in the poly(NIPAm) gels.[97] These
phenomena are caused by precipita-
tion/solubilization of polymer chains,[98]
which (a) are determined by the varia-
tions in the ionic strength of swelling
liquid following changes in the charge
of the ruthenium complex, and (b) occur
due to the proximity of the experimental
temperature to the lower critical solu-
tion temperature (LCST) of poly(NIPAm),
effectively reversibly shifting the LCST
below room temperature through the
increase of ionic strength. The last point
has been further confirmed by the use of
terpyridyl ruthenium complexes in gels
of poly(N-ethylmethylacrylamide)[99]:
the latter are characterized by a higher
LCST [56 vs 32 °C for poly(NIPAm)] and
correspondingly allowed to extend this
oscillating behavior to higher tempera-
ture values.
The ruthenium-catalyzed reaction
displays a peculiar behavior under irra-
diation[100]: the excited state of Ru(II)
complexes (<Ru2+>∗ in Figure 3, dotted
box) is particularly effective in the pro-
duction of BrO2, thus increasing the
amount of HOBr and ultimately the con-
sumption of bromide. This sensitivity
has been used to produce complex and
oscillating optical patterns,[101] since
the accelerated conversion of the Ru(II)
complex (intense absorption max at
460 nm) to the Ru(III) one (less intense
absorption at 460, but secondary peak
at 670 nm) is associated to strong color
changes. Most importantly, light of
appropriate intensity can temporarily inhibit the oscil-
lation and this feature has been cleverly used to control
the amplitude and period of oscillations in both color and
dimensions of poly(NIPAm) gels;[102] further it has been
theoretically shown that these features can be used to
determine directional motility of these gels, forcing them
to follow complicated trajectories. [103]
4. Conjugated Organic Polymers
Hereafter, we will refer to highly π-conjugated macromo-
lecular structures characterized by high intrinsic conduc-
tivity simply as conjugated polymers. Most often, these
polymers are synthesized by oxidative polymerization,
www.MaterialsViews.com
 Macromolecular
Oxidation-Responsive Polymers: Which Groups to Use . . . Chemistry and Physics
www.mcp-journal.de

the resulting conjugated polymers; a

number of (bio)molecules[109,110] have
been used as dopants in the application
of conjugated polymers, for example, as
artificial muscles,[111,112] sensors,[113] or
in batteries.[114]
During oxidation conjugated poly-
mers may swell due to capturing of
anions from solution, whereas they
may shrink during reduction due to the
release of these species; the biomedical
applications of such phenomena are the
subject of a number of reviews[115–118]
and here we specifically focus on their
implementation in redox triggered
encapsulation/release of drugs. It is
noteworthy that from the beginning
of this field[119,120] to date[121,122] PPy
appears to be the most popular material
used in these studies, mainly due to its
easy synthesis and rather good biocom-
Figure 3. Top: The Belousov-Zhabotinsky reaction is accomplished by using bromate, patibility. For what attains the active
malonic acid (MA), and a ruthenium catalyst. According to the FKN scheme, three main principles, different strategies have
processes occur concurrently, which in the figure correspond to the three solid boxes. In been developed:
the first from the right, bromide is produced (the intermediate is the 2-bromo malonic
acid, BrMA) and ruthenium is reduced; in the other two processes, the main events are (1) Electrostatic entrapment: Anions
the oxidation of ruthenium to restore Ru(III) and the consumption of bromide to produce can typically be incorporated in the
bromine. Bottom: The Belousov-Zhabotinsky reaction has been implemented in polymer conjugated polymer as dopants dur-
gels, most commonly poly(NIPAm) crosslinked via N,N′′-methylenebisacrylamide
(polymer chains in bold). (LCST = lower critical solution temperature).
ing its electrochemical synthesis,
for example ATP,[123] neurotrophin-3
(NT-3),[124] and RNA.[125] Alternatively,
either chemically (for instance, with FeCl3) or electro- they can replace the dopant originally used in the syn-
chemically, generally in the form of thin films. Most thesis of the conjugated polymer during a redox cycling
often, the product of an oxidative polymerization is a of the polymer in a solution containing the drug. This
positively charged/doped conjugated polymer, which is strategy was pioneered by Zinger and Miller[119] for the
ionically counter balanced by the inclusion of an anionic incorporation of glutamate in PPy upon electrochemical
species (dopant) present in the polymerization environ- reduction/oxidation of the polymer (originally synthe-
ment. Readers are referred to specialized reviews for the sized in the presence of NaClO4) as attempts to polym-
synthesis of commonly used conjugated polymers, for erize pyrrole in the presence of glutamate failed. Simi-
example, polythiophenes,[104,105] polyaniline (PANI),[106,107] larly, this approach has also been used with salicylate,
or polypyrroles (PPy).[108] naproxen, and nicoside anions.[126]

Cations can be incorporated upon redox cycling if

4.1. Redox-Responsive Drug Release
The electrochemical redox cycling of conjugated poly-
mers results in an ingress (p-doping during oxidation)
and an egress (n-doping during reduction) of ions upon
application of a voltage potential. This redox switching
modulates the polymer surface charge, rearrangement of
tethered dopants, and ion flux through the polymer–elec-
trolyte interface, which eventually affects properties such
as conductivity, wettability, actuation, etc. The incorpora-
tion of an appropriate dopant during synthesis is there-
fore of utmost importance to modulate the properties of
large and/or multivalent anionic dopants are used in
the polymer synthesis; such dopants remain embedded
into the polymer film upon electrochemical reduction
due to their relatively slow diffusion kinetics, therefore
prompting smaller cationic molecules to be incorpo-
rated into the polymer/dopant complex to counterbal-
ance its net negative charge; these cationic drugs can be
later released during the oxidation of the polymer film.
A classic example by Miller and Zhou[127] is the loading
and release of dopamine in a poly(N-methylpyrrolylium)/
poly(styrene sulfonate) composite: N-methylpyrrole
was polymerized in the presence of sodium poly(styrene

Macromol. Chem. Phys. 2013, 214, 143−158

www.MaterialsViews.com © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 149
 Macromolecular
Chemistry and Physics
www.mcp-journal.de
sulfonate) to provide a conjugated polymer that could
be reduced (−0.4 V vs SCE) in an aqueous dopamine solu-
tion; the electrostatically bound dopamine could be later
released by stepping the polymer film potential to +0.5 V.
2) Physical entrapment: The active principle is added
in the polymerization environment, being entrapped
within the polymer matrix after polymerization be-
cause of a mixed of steric hindrance and unspecific in-
teractions or coprecipitation. This approach has been
used with steroidal drugs,[122] proteins,[109] and even
living cells.[128]
3) Affinity entrapment: Less conventional approaches
have exploited specialized dopants such as cyclodex-
trins[129,130] or biotin[131] derivatives, which allow the
incorporation of active principles via specific host–
guest supramolecular complexation or ligand–receptor
interactions. This strategy, however, has predominantly
developed in the direction of selective recognition and
sensing,[132–135] rather than in that of redox-controlled
drug release.
Finally, few examples exist where the release of the
drug is driven by a physical change in the conjugated
polymer, for example, actuation and conformational
change. For instance, Martin and co-workers[136] reported
that the release profile of dexamethasone encapsulated in
poly(lactide-co-glycolide) (PLGA) electrospun nanofibers
could be controlled by the electrochemical deposition
of poly(3,4-ethylenedioxythiophene) (PEDOT), showing
a marked release of dexamethasone in solution upon
PEDOT swelling controlled by electrochemical oxidation.
Also redox-responsive changes in the permeability of
conjugated polymer membranes have been used for sus-
tained release of drugs.[137,138]
5. Heteroatom-Containing Organic Polymers
5.1. Polythiols
Here, we will focus only on the interconversion between
thiols and disulfides, although other redox processes are
possible and actually occur under physiological conditions,
for example, nitrosylation,[139,140] oxidation to sulfenic,[141]
sulfinic acids,[142] and possibly beyond, and have been
applied to biomaterials in some cases (e.g., nitrosylation
for controlled NO release[143]); for an exhaustive review
of biological, ROS-mediated redox processes of thiols,
please refer to the excellent reviews of Forman[144] and
Winterbourn.[145]
In Nature, thiol oxidation to disulfides is a classical
response observed in case of redox imbalance and oxi-
dative stress,[146] and can have significant mechanical
effects, for example, when intervening in the interactions
Macromol. Chem. Phys. 2013, 214, 143−158
150 © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
E. Lallana and N. Tirelli
between structural proteins: the formation of disulfides
can improve the mechanical properties of actin fibers,[147]
can strengthen the association of mucus glycoproteins
(mucins)[148] or can (reversibly) inhibit the polymeriza-
tion of microtubules.[149,150] In synthetic systems, since
the thiol oxidative dimerization can occur also by simple
exposure to air, it has specifically attracted attention as
a means to converting liquid precursors into 3D matrices
under extremely mild and cell-compatible conditions. It
must also be stressed that disulfides are dynamic struc-
tures, due also to the relative weakness of the S–S bond
(around 60 kcal mol−1, ≈40% weaker than a C–C bond); in
particular, the presence of free, deprotonated thiols[151,152]
leads to a rapid and continuous exchange of organic resi-
dues between oxidized (disulfide) and reduced (thiolate)
forms. In these equilibria, glutathione has a major role:
not only it is the most common biologically occurring thiol
(intracellular free thiol concentrations of 1–20 nmol per
mg protein[153,154]), but it is also capable of forming mixed
disulfides with protein thiols[155] (Figure 4, top) that are
present in concentrations up to 30 nmol g−1 of tissue[156]),
which can exchange with synthetic thiols providing free
glutathione and disulfide bioconjugates. Since in any given
biological environment thiols and disulfides are always
present at the same time and continuously exchange,
it is therefore almost impossible to consider thiol- and
disulfide-bearing polymers as separate categories.
5.1.1. Thiol-Disulfide Equilibrium and Mucoadhesion
This environmental responsiveness is characterized by
small variations in redox potential, but it is heavily affected
by entropy, for example, the entropic gain associated to the
liberation of lower MW compounds in depolymerization or
side-chain cleavage processes, by the thiol acidity, and by a
number of kinetic factors.[157]
Disulfide groups are most often introduced to provide
responsiveness to conditions characteristic of intracel-
lular environments, and in particular to those encoun-
tered in endocytic compartments, which are mildly
reducing due to the presence of a significant concentra-
tion of glutathione. S-S groups can be introduced in poly-
mers using disulfide-containing initiators,[158–160] which
end up holding a central position in the polymer chain,
but side-chain systems have been used too.[161] In alter-
native, disulfides can be produced from thiol-containing
polymers, typically crosslinking via oxidative dimeriza-
tion of their complexes with a payload, for example, a
nucleic acid.[162,163] The cleavage of disulfide links in these
systems can decrease the structural integrity of a par-
ticle[164,165] or the binding of a polymer carrier to a nucleic
acid,[161,166,167] or exhibit both effects,[168] therefore facili-
tating the release of a pharmacologically active principle
from a carrier only after the uptake of the latter by cells.
www.MaterialsViews.com
 Macromolecular
Oxidation-Responsive Polymers: Which Groups to Use . . . Chemistry and Physics
www.mcp-journal.de

Figure 4 . Top: Biological thiols, for example, glutathione (structure in the insert), can be oxidized to their homodisulfides (left) or can
exchange with other disulfides, for example, inter- or intramolecular disulfides present in proteins, leading to mixed (hetero)disulfides;
since the average oxidation number of the sulfur atoms does not change, formally the exchange cannot be seen as a thiol oxidation reac-
tion. Bottom: In a recent report,[169] Bernkop-Schnuerch has reversed the normal mode of action of thiomers; disulfides particularly prone to
exchange were synthesized by linking a side chain cysteine residues in a mixed disulfide structure with mercaptonicotinic acid; the release
of the latter is particularly favored due the possibility of establishing a keto-enolic equilibrium and is the main driving force for the forma-
tion of mixed disulfides with mucin, and for the resulting mucoadhesion of the polymers.

Thiols are generally introduced in macromolecular
structures through polymer-analogous reactions such as
carbodiimide-mediated amidation/esterification reac-
tions,[163,170,171] or ring-opening reactions, for example,
that of iminothiolane (Traut’s reagent) by primary amines
to provide 3-mercaptoguanidine groups,[162,170] or of
ethylene[172] or propylene sulfide,[173] although the latter
is possibly complicated by their own polymerization
under basic conditions (see later the section devoted
to polysulfides). The thiol-ene coupling of thioacetic
acid onto allyl residues followed by deprotection of the
resulting thioesters[163,174,175] has also been used.
One of the most interesting application of thiol-disulfide
equilibria on polymeric substrates (aka thiomers) is
the formation of mixed disulfides with mucins, whose
supramolecular structures are kept together by a

Macromol. Chem. Phys. 2013, 214, 143−158

www.MaterialsViews.com © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 151
 Macromolecular
Chemistry and Physics
www.mcp-journal.de
network of inter-chain disulfide bonds.[148,176] The forma-
tion of mucin/thiomer heterodisulfides has been shown
to increase mucoadhesion for a variety of macromol-
ecules, for example, poly(acrylic acid),[177] alginate,[178]
or chitosan;[179] the effect is reversed by the addition of
low MW thiols and is more noticeable with larger poly-
mers.[180] Thiol stability upon storage is of paramount
importance, for example, to avoid self-crosslinking of
the macromolecules; in a recent approach, Bernkop-
Schnuerch has addressed this issue by “preactivating” the
thiol groups,[169] which inter alia is another clear example
of the interchangeability between thiol- and disulfide-
polymers: thiomers were prereacted with low MW thiols
to form provisional, reactive disulfides. The reaction of
these groups with protein thiols at the site of application
is entropically favored due to the release of a low MW
thiol, and the resulting thiomer-protein mixed disulfides
finally allow for mucoadhesion (Figure 4, bottom).
5.1.2. Crosslinking and Self-Healing
The group of Prestwich has extensively investigated the
preparation of gels via oxidation of thiolated hyaluronic
acid (HA); the materials can be cured by simple expo-
sure to air, although the use of mild oxidants provides a
higher crosslink density.[171] The disulfide crosslinks did
not alter the excellent biocompatibility and the negligible
cell adhesion that are typical of HA-based substrates, but
substantially decreased enzymatic degradability, possibly
due to the poor diffusion of hyaluronidase into a highly
crosslinked material.[181] Thiolated HA can be used to pro-
duce disulfide-linked materials with other thiolated mac-
romolecules, such as gelatin,[182] or within decellularized
matrices,[183] but can also be crosslinked with multiple
Michael-type acceptors[172,184] or gold nanoparticles.[185]
Prestwich had demonstrated a more rapid gelation
kinetics with the use of more acidic thiols;[171] this is based
on the higher reactivity of deprotonated thiols, which
is to be expected since the preferred path to disulfides
requires the one-electron oxidation of thiolates to thiyl
radicals. Using thiolated star PEGs, we have confirmed
the role of thiol deprotonation and further showed that
the oxidation process can be accelerated using Fenton
chemistry (tens of minutes vs hours).[174] Interestingly,
we noted that storage of the disulfide bonded gels at pH =
10 (above the thiol pKa) eventually caused their solubi-
lization, which occurred without affecting the number
of disulfides; the phenomenon was likely caused by the
presence of residual thiolates, which allowed a conversion
of intermolecular (crosslinking) disulfides into entropi-
cally favored intramolecular ones; this phenomenon was
also applied by Wu et al.[186] for inducing a reorganization
of disulfide-based gels at basic pH. The very similar thiyl
radical-disulfide equilibrium can also occur, for example
Macromol. Chem. Phys. 2013, 214, 143−158
152 © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
E. Lallana and N. Tirelli
when mechanical action, for example, a scratch, leads to
homolytic scission of some crosslinks in a disulfide-based
network; the corresponding mobility increase coupled to
the possibility of thiyl radical recombination has been
cleverly used to confer self-healing properties to polymer
films in a recent work of Balazs and Matyjaszewski,[187]
who employed star structures with peripheral thiols to
facilitate diffusion and reactivity of the macroradicals.
5.2. Polysulfides
A recent review[188] provides an extensive overview of the
possible synthetic strategies for sulfur(II)-containing poly-
mers. Herein, unless otherwise specified, we will predomi-
nantly focus on poly(1,2-alkylene sulfide)s, which are most
commonly prepared through the ring-opening polymeri-
zation of episulfides (aka thiiranes); this is generally per-
formed with a classical anionic mechanism[175,189,190] based
on thiolates both as initiators and propagating species
(Figure 5, top), which, due to their mildly basic character,
allow to carry out the process even in a water environ-
ment, for example, in emulsion.[191]
The presence of disulfide impurities in the initiators is
the only weak point of this technique; following equilibra-
tion with the propagating species (thiolates), disulfides act
as chain transfer agents,[193] affecting both the molecular
weight dispersion (broadening + characteristic dimer peak)
and the control over terminal groups. Our group has reported
the combination of protected initiators and in situ reducing
agents as a suitable means to overcome these effects.[194]
Insertion polymerization using thioester-,[195]
dithioester-[196] or thiocarbamate-[197] containing ini-
tiators (Figure 5, bottom) is a more modern synthetic
method to provide low polydispersity polysulfides with
linear[197] or cyclic structures;[195,196] due to the absence of
free thiols, this technique is possibly less affected by the
presence and action of disulfides.
5.2.1. Oxidation-Responsive Behavior
Thioethers are generally stable under aerobic conditions;
typically, they can react with oxygen only under transition
metal catalysis and in the presence of co-oxidants (e.g.,
aldehydes).[198] On the other hand, these groups readily
respond to powerful oxidants such as ROS; an accurate
review of the oxidation chemistry of natural organosulfur
compounds was provided by Block in 1992 and is yet a
milestone in the field.[199] In Nature, this oxidation can have
a protective function; for example, sulfur(II) compounds
typically present in garlic and onion oils are well known to
have a protective function against, for example, lipid per-
oxidation acting as sacrificial targets for ROS.[200,201] In pro-
teins, the oxidation of methionine to methionine sulfoxide
can also serve to the same scope, protecting more sensitive
www.MaterialsViews.com
 Macromolecular
Oxidation-Responsive Polymers: Which Groups to Use . . . Chemistry and Physics
www.mcp-journal.de

cysteines) were oxidized with hydrogen

peroxide, undergoing a dramatic con-
formational transition from α-helix to
random coil.[204]
The hydrophobic–hydrophilic tran-
sition produced by thioether oxida-
tion has been extensively investigated
by our group, specifically focusing on
poly(propylene sulfide) (PPS): this struc-
ture provides an appropriate combina-
tion of high hydrophobicity in a reduced
state and high hydrophilicity due to
the small aliphatic content in an oxi-
dized one. It is worth mentioning that
PPS is considerably more hydrophobic
than its oxygenated cognate polymer
poly(propylene glycol), and as a result
amphiphilic block copolymers of PPS
have lower critical micelle concen-
trations (CMCs) and show negligible
exchange between micelles, as dem-
onstrated by Förster resonance energy
transfer (FRET) experiments.[205]
The oxidation of PPS by hydrogen
peroxide has allowed the solubilization
of PPS–PEG vesicular aggregates[206]
or the swelling of different forms of
crosslinked PPS nanoparticles.[207–209]
In the latter case, nanoparticles could
be eventually solubilized if degradable
links are present.[209] Thioether oxi-
dation was also used by Almutairi to
uncover degradable groups, therefore
Figure 5. Top: The anionic ring-opening polymerization of episulfides is the best-known
method for the preparation of organic polysulfides; thiolates are obtained via depro- controlling the cleavage of hydrolytically
tonation of thiols, typically with organic bases, or via in situ generation from thioac- sensitive groups through oxidation.[210]
etates. Disulfides can be present as impurities of the initiators or can be generated in These phenomena can be efficiently
the polymerization environment because of oxygen ingress; in both cases, their chain used to liberate encapsulated payloads
transfer activity would lead to non-end-capped polymers featuring terminal or central
proportionally to the concentration of
disulfide bonds. Bottom: The chain extension polymerization mechanism is based on
the addition of episulfides to thioacetates, trithiocarbonates, thiourethanes etc. and it ROS, that is, in an inflammation-respon-
is typically catalyzed by tetrabutylammonium halides. The mechanism hypothesized by sive fashion; this mechanism has been
Nishikubo[192] (A) foresees an initial activation of episulfides followed by nucleophilic repeatedly proved in vitro, also through
attack of the resulting thiolate onto the carbonyl and a 5-centre rearrangement; how- the enzymatic generation of ROS.[211] On
ever, the coordination of the sulfur to tetrabutylammonium ions in the initial step is
the other hand, polysulfides can also be
not proven. An alternative mechanism (B) may foresee the initial attack of the “naked”
chloride, followed by transient formation of a episulfonium ion and its final rearrange- used as sacrificial materials to protect
ment through a four-centre intermediate. sensitive payloads from damage caused
by oxidizing conditions.[212]
The nature of the oxidizing species,
residues from oxidative damage.[202] In some cases, how- however, profoundly influences the polysulfide oxidative
ever, methionine oxidation may be undesired, for example responsiveness, most likely because they are more diffi-
it inhibits actin polymerization and promotes dissocia- cult to oxidize than other responsive groups (see Table 2).
tion of its already polymerized fibers due to the disrup- First, the kinetics of the process can significantly depend
tion of hydrophobic associations at critical sites.[203] A on the solubility of the oxidant in the matrix, which typi-
similar effect was recorded by Deming, when polypeptides cally increases with the degree of oxidation leading to an
based on thioether-containing amino acids (S-glycosylated auto-accelerating behavior;[207] facing ROS with identical

Macromol. Chem. Phys. 2013, 214, 143−158

www.MaterialsViews.com © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 153
 Macromolecular
Chemistry and Physics E. Lallana and N. Tirelli

www.mcp-journal.de

Conversely, it is also possible to extend

PPS sensitivity to molecular signals to
which it is not originally responsive to:
the conjugation of oxidizing enzymes
to PPS-based systems allows to translate
a chemical signal into a redox signal,
and to maximize the PPS response by
colocalizing with the oxidizing system
(Figure 6, bottom). For example, the
decoration of PPS nanoparticles with
glucose oxidase[217] or that of PPS–PEG
micelles with superoxide dismutase[213]
allowed to generate hydrogen peroxide
at the colloidal surface upon exposure,
respectively, to glucose or superoxide,
thus selectively triggering the release
of payloads in a glucose- or superoxide-
responsive fashion.
Finally, it is worth mentioning that
polyselenides exhibit the same kind of
responsiveness to oxidants, which can
trigger hydrophobic–hydrophilic mor-
phological transitions, as it has been
demonstrated using block copolymers
Figure 6. Top: Oxidant-dependent behavior of polysulfides. Aliphatic polysulfones are of PEG and hydrophobic, Se-containing
well known to undergo facile depolymerization at low temperatures, leading to sulfur polyurethanes.[218]
dioxide and olefins.[215,216] Bottom: The oxidation response of polysulfide can be coupled
to enzymatic reactions to generate a signaling cascade, where the physical proximity of
the oxidation-sensitive groups and of the, for example, hydrogen peroxide-generating 5.3. Polystannanes
enzyme is of the essence to maximize the translation of the chemical signal (the pres-
ence and concentration of the enzyme substrate) into a redox one (the oxidation of the Poly(diorganostannanes) have been
polysulfide matrix). recently reviewed by Caseri and

oxidizing power, it is therefore easy to

predict a quicker response to less polar
(hence more PPS-soluble) molecules.
Second, not all oxidants produce the
same effects: for example, when using
xanthine oxidase to generate in situ
both hydrogen peroxide and super-
oxide, PPS was revealed to be com-
pletely insensitive to superoxide.[213]
On the other hand, while hydrogen
peroxide can quantitatively, although
rather slowly, convert PPS thioethers
into sulfoxides, hypochlorite produced
a mixture of sulfoxide and sulfones;
the presence of the latter labilized the
oxidized polymer structure making
it prone to depolymerization and
increasing its toxicity[214] (Figure 6, top). Figure 7. The photochemical lability of Sn-Sn bonds and their homolytic scission can
As a result, the effect of PPS responsive- lead to the final oxidation of tin atoms (Sn(II) to Sn(IV)) through radical reactions that
have been demonstrated with dichloromethane but can in principle occur with a large
ness can be different depending on the variety of organic compounds. Oxidation-sensitive groups can be introduced in polymer
ROS “cocktail” it is exposed to in a bio- materials in the form of metal complexes or simple heteroatoms. The synthesis, key
logical environment. properties and perspective biomedical applications of these materials are reviewed.

Macromol. Chem. Phys. 2013, 214, 143−158

154 © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.MaterialsViews.com

Oxidation-Responsive Polymers: Which Groups to Use . . .
Smith.[219] With the exception of their oxidative conver-
sion to tin oxide at high temperatures in air,[220] strictly
speaking polystannanes do not present responsiveness to
oxidizing conditions, but their light-induced depolymeri-
zation behavior is worth to mention in the context of this
review.
Polystannanes feature Sn–Sn main chains with a sig-
nificant degree of σ conjugation,[220,221] similar to what is
recorded for polygermananes[222] and polysilanes.[223,224]
Upon irradiation in the main absorption band, these poly-
mers have limited stability and easily undergo unzipping
reactions, leading to depolymerization. The scission of
Sn–Sn bonds proceeds through an homolytic mechanism:
radical scavengers are reported to delay the reaction,[225]
and radical-stabilizing structures such as side-chain aro-
matic groups may reverse the degradation by allowing
the recombination of terminal radicals.[226] The scission
may lead to the formation of stable, low MW cyclic stan-
nanes, for example, in toluene; alternatively, the terminal
radicals may react with other molecules through a formal
mechanism of oxidative addition, as it happens in dichlo-
romethane solution[225] (Figure 7), which therefore could
be defined as a mechanism of light-induced oxidative
depolymerization.
6. Conclusion
Most commonly, oxidation reactions cause polymers to
swell/solubilize in a water environment as a result of an
increase in their polarity/number of counterions. More
rarely, depolymerization reactions can be an integral part
of the response, for example, in the irradiation of poly-
stannanes or in the hypochlorite-mediated oxidation of
polysulfides; in these cases, specific attention should be
paid to the toxicology of the process, since the poor control
over the molecular weight may mean a poor control over
the distribution, metabolism, and elimination of the oxida-
tion products.
Correspondingly, most oxidation-responsive mate-
rials are thought to find application in the field of drug
delivery, where the release kinetics of a drug depends on
its diffusion in a matrix, which, in turn, is accelerated by
oxidation-dependent swelling/solubilization phenomena;
due to the role of ROS, inflammation-responsive drug
delivery appears to be the most logical application of this
class of materials.
The most noticeable exception to the above perspec-
tive is presented by thiols, whose oxidative conversion to
disulfides can be used to promote hardening/gelation and
therefore the preparation of injectable matrices in situ and
possibly in response to inflammatory conditions. More
complex is the case of thiol-disulfide exchanges, which are
characterized by rather smaller thermodynamic driving
Macromol. Chem. Phys. 2013, 214, 143−158
www.MaterialsViews.com © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Macromolecular
Chemistry and Physics
www.mcp-journal.de
forces; not surprisingly, depending on the polymer archi-
tecture, the occurrence of these reactions could give rise
to very different phenomena, ranging from crosslinking
(e.g., in the case of thiomers) or self-healing, to solubiliza-
tion when in the presence of excess thiols.
The field is yet in its infancy; for example, a more
coherent integration between electrochemistry, polymer
chemistry and inflammatory cell biology is required. At
the same time, there are plenty of biological applications
that could be solved by appropriately designed oxidation-
(inflammation-) responsive materials, therefore there is
no shortage of motivation!
Received: August 21, 2012; Published online: December 13, 2012;
DOI: 10.1002/macp.201200502
Keywords: conjugated polymers; ferrocene; polysulfides; redox
polymers; stimuli-sensitive polymers
[1] B. Singh, N. Sharma, Polym. Degrad. Stabil. 2008, 93, 561.
[2] J. P. Santerre, K. Woodhouse, G. Laroche, R. S. Labow, Bioma-
terials 2005, 26, 7457.
[3] T. P. Hilditch, Nature 1950, 166, 558.
[4] N. A. Porter, Acc. Chem. Res. 1986, 19, 262.
[5] N. A. R. Falla, J. Coat. Technol. 1992, 64, 55.
[6] V. Adler, Z. M. Yin, K. D. Tew, Z. Ronai, Oncogene 1999, 18,
6104.
[7] M. Genestra, Cell. Sign. 2007, 19, 1807.
[8] I. C. West, Diabetic Med. 2000, 17, 171.
[9] S. Lenzen, Biochem. Soc. Trans. 2008, 36, 343.
[10] R. M. Touyz, E. L. Schiffrin, Histochem. Cell Biol. 2004, 122,
339.
[11] F. Bonomini, S. Tengattini, A. Fabiano, R. Bianchi, R. Rezzani,
Histol. Histopath. 2008, 23, 381.
[12] J. E. Klaunig, L. M. Kamendulis, Annu. Rev. Pharmacol. 2004,
44, 239.
[13] L. G. Wood, P. G. Gibson, M. L. Garg, Eur. Resp. J. 2003, 21,
177.
[14] B. Chakravarti, D. N. Chakravarti, Gerontology 2007, 53,
128.
[15] M. S. Cooke, M. D. Evans, M. Dizdaroglu, J. Lunec, FASEB J.
2003, 17, 1195.
[16] F. Q. Schafer, G. R. Buettner, Free Radic. Biol. Med. 2001, 30,
1191.
[17] W. H. Koppenol, D. M. Stanbury, P. L. Bounds, Free Radic.
Biol. Med. 2010, 49, 317.
[18] G. R. Buettner, Arch. Biochem. Biophys. 1993, 300, 535.
[19] R. P. Szajewski, G. M. Whitesides, J. Am. Chem. Soc. 1980,
102, 2011.
[20] P. Wardman, J. Phys. Chem. Ref. Data 1989, 18, 1637.
[21] R. F. Anderson, K. B. Patel, J. Chem. Soc. Farad. T 1 1984, 80,
2693.
[22] A. Samuni, S. Goldstein, J. Phys. Chem. B 2012, 116, 6404.
[23] Y. A. Ilan, D. Meisel, G. Czapski, Isr. J. Chem. 1974, 12, 891.
[24] T. Mukherjee, E. J. Land, A. J. Swallow, P. M. Guyan,
J. M. Bruce, J. Chem. Soc. Farad. Trans. 1988, 84, 2855.
[25] Y. Song, G. R. Buettner, Free Radic. Biol. Med. 2010, 49, 919.
[26] A. M. Bond, E. A. McLennan, R. S. Stojanovic, F. G. Thomas,
Anal. Chem. 1987, 59, 2853.
[27] D. A. Bohling, J. F. Evans, K. R. Mann, Inorg. Chem. 1982, 21,
3546.
155
 Macromolecular
Chemistry and Physics
www.mcp-journal.de
[28] K. R. J. Thomas, P. Tharmaraj, V. Chandrasekhar, C. D. Bryan,
A. W. Cordes, Inorg. Chem. 1994, 33, 5382.
[29] T. Matsubara, P. C. Ford, Inorg. Chem. 1976, 15, 1107.
[30] N. Fay, E. Dempsey, A. Kennedy, T. McCormac, J. Electroanal.
Chem. 2003, 556, 63.
[31] Sanaullah, G. S. Wilson, R. S. Glass, J. Inorg. Biochem. 1994,
55, 87.
[32] L. Engman, J. Lind, G. Merenyi, J. Phys. Chem. 1994, 98,
3174.
[33] D. P. Riley, P. E. Correa, J. Chem. Soc. Chem. Commun. 1986,
1097.
[34] P. Charlesworth, W. Lee, W. S. Jenks, J. Phys. Chem. 1996, 100,
15152.
[35] V. V. Pavlishchuk, A. W. Addison, Inorg. Chim. Acta 2000,
298, 97.
[36] N. G. Connelly, W. E. Geiger, Chem. Rev. 1996, 96, 877.
[37] J. L. Bolton, M. A. Trush, T. M. Penning, G. Dryhurst,
T. J. Monks, Chem. Res. Toxicol. 2000, 13, 135.
[38] A. Trabolsi, M. Hmadeh, N. M. Khashab, D. C. Friedman,
M. E. Belowich, N. Humbert, M. Elhabiri, H. A. Khatib,
A. M. Albrecht-Gary, J. F. Stoddart, New J. Chem. 2009, 33,
254.
[39] A. Trabolsi, N. Khashab, A. C. Fahrenbach, D. C. Friedman,
M. T. Colvin, K. K. Coti, D. Benitez, E. Tkatchouk, J. C. Olsen,
M. E. Belowich, R. Carmielli, H. A. Khatib, W. A. Goddard,
M. R. Wasielewski, J. F. Stoddart, Nat. Chem. 2010, 2, 42.
[40] R. J. Dinis-Oliveira, J. A. Duarte, A. Sanchez-Navarro,
F. Remiao, M. L. Bastos, F. Carvalho, Crit. Rev. Toxicol. 2008,
38, 13.
[41] M. Rosenblum, H. M. Nugent, K. S. Jang, M. M. Labes,
W. Cahalane, P. Klemarczyk, W. M. Reiff, Macromolecules
1995, 28, 6330.
[42] F. S. Arimoto, A. C. Haven, J. Am. Chem. Soc. 1955, 77, 6295.
[43] D. A. Foucher, B. Z. Tang, I. Manners, J. Am. Chem. Soc. 1992,
114, 6246.
[44] K. Kulbaba, I. Manners, Macromol. Rapid Commun. 2001,
22, 711.
[45] Y. Z. Ni, R. Rulkens, I. Manners, J. Am. Chem. Soc. 1996, 118,
4102.
[46] A. Berenbaum, H. Braunschweig, R. Dirk, U. Englert,
J. C. Green, F. Jakle, A. J. Lough, I. Manners, J. Am. Chem. Soc.
2000, 122, 5765.
[47] F. Jakle, R. Rulkens, G. Zech, D. A. Foucher, A. J. Lough,
I. Manners, Chem. Eur. J. 1998, 4, 2117.
[48] T. J. Peckham, J. A. Massey, C. H. Honeyman, I. Manners,
Macromolecules 1999, 32, 2830.
[49] M. A. Buretea, T. D. Tilley, Organometallics 1997, 16, 1507.
[50] J. B. Gilroy, A. D. Russell, A. J. Stonor, L. Chabanne, S. Baljak,
M. F. Haddow, I. Manners, Chem. Sci. 2012, 3, 830.
[51] P. F. Brandt, T. B. Rauchfuss, J. Am. Chem. Soc. 1992, 114,
1926.
[52] V. Bellas, M. Rehahn, Angew. Chem. Int. Ed. 2007, 46, 5082.
[53] L. X. Ren, C. G. Hardy, S. F. Tang, D. B. Doxie, N. Hamidi,
C. B. Tang, Macromolecules 2010, 43, 9304.
[54] C. U. Pittman, J. Inorg. Organomet. Polym. Mater. 2005, 15,
33.
[55] C. Herfurth, D. Voll, J. Buller, J. Weiss, C. Barner-Kowollik,
A. Laschewsky, J. Polym. Sci. Part A: Polym. Chem. 2012, 50,
108.
[56] S. J. Zhai, J. Shang, D. Yang, S. Y. Wang, J. H. Hu, G. L. Lu,
X. Y. Huang, J. Polym. Sci. Part A: Polym. Chem. 2012, 50,
811.
[57] B. Y. Kim, E. L. Ratcliff, N. R. Armstrong, T. Kowalewski,
J. Pyun, Langmuir 2010, 26, 2083.
Macromol. Chem. Phys. 2013, 214, 143−158
156 © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
E. Lallana and N. Tirelli
[58] M. Shi, A. L. Li, H. Liang, J. Lu, Macromolecules 2007, 40,
1891.
[59] M. Baumert, J. Frohlich, M. Stieger, H. Frey, R. Mulhaupt,
H. Plenio, Macromol. Rapid Commun. 1999, 20, 203.
[60] T. Higashihara, R. Faust, Macromolecules 2007, 40, 7453.
[61] O. Nuyken, V. Burkhardt, C. Hubsch, Macromol. Chem. Phys.
1997, 198, 3353.
[62] M. Gallei, R. Klein, M. Rehahn, Macromolecules 2010, 43,
1844.
[63] N. C. Zhou, Z. B. Zhang, J. Zhu, Z. P. Cheng, X. L. Zhu, Macro-
molecules 2009, 42, 3898.
[64] L. X. Ren, J. Y. Zhang, C. G. Hardy, D. Doxie, B. Fleming,
C. B. Tang, Macromolecules 2012, 45, 2267.
[65] Y. Okahata, K. Takenouchi, Macromolecules 1989, 22, 308.
[66] M. Zamora, S. Bruna, B. Alonso, I. Cuadrado, Macromolecules
2011, 44, 7994.
[67] I. Javakhishvili, S. Hvilsted, Polym. Chem. 2010, 1, 1650.
[68] C. Tonhauser, M. Mazurowski, M. Rehahn, M. Gallei, H. Frey,
Macromolecules 2012, 45, 3409.
[69] R. Resendes, J. Massey, H. Dorn, M. A. Winnik, I. Manners,
Macromolecules 2000, 33, 8.
[70] J. F. Gohy, B. G. G. Lohmeijer, A. Alexeev, X. S. Wang,
I. Manners, M. A. Winnik, U. S. Schubert, Chem. Eur. J. 2004,
10, 4315.
[71] R. A. Yeary, Toxicol. Appl. Pharmacol. 1969, 15, 666.
[72] D. Osella, M. Ferrali, P. Zanello, F. Laschi, M. Fontani, C. Nervi,
G. Cavigiolio, Inorg. Chim. Acta 2000, 306, 42.
[73] A. Nguyen, S. Top, P. Pigeon, A. Vessieres, E. A. Hillard,
M.-A. Plamont, M. Huche, C. Rigamonti, G. Jaouen, Chem.
Eur. J. 2009, 15, 684.
[74] A. Nguyen, A. Vessieres, E. A. Hillard, S. Top, P. Pigeon,
G. Jaouen, Chimia 2007, 61, 716.
[75] P. Messina, E. Labbe, O. Buriez, E. A. Hillard, A. Vessieres,
D. Hamels, S. Top, G. Jaouen, Y. M. Frapart, D. Mansuy,
C. Amatore, Chem. Eur. J. 2012, 18, 6581.
[76] Y. L. K. Tan, P. Pigeon, S. Top, E. Labbe, O. Buriez, E. A. Hillard,
A. Vessieres, C. Amatore, W. K. Leong, G. Jaouen, J. Chem.
Soc. Dalton Trans. 2012, 41, 7537.
[77] M. Gormen, D. Plazuk, P. Pigeon, E. A. Hillard, M. A. Plamont,
S. Top, A. Vessieres, G. Jaouen, Tetrahedron Lett. 2010, 51,
118.
[78] G. Gasser, I. Ott, N. Metzler-Nolte, J. Med. Chem. 2011, 54, 3.
[79] E. Allard, C. Passirani, E. Garcion, P. Pigeon, A. Vessieres,
G. Jaouen, J. P. Benoit, J. Control. Release 2008, 130, 146.
[80] H. Wei, C. Y. Quan, C. Chang, X. Z. Zhang, R. X. Zhuo, J. Phys.
Chem. B 2010, 114, 5309.
[81] D. Correia-Ledo, A. A. Arnold, J. Mauzeroll, J. Am. Chem. Soc.
2010, 132, 15120.
[82] Q. Yan, J. Y. Yuan, Z. N. Cai, Y. Xin, Y. Kang, Y. W. Yin, J. Am.
Chem. Soc. 2010, 132, 9268.
[83] D. Janczewski, J. Song, E. Csanyi, L. Kiss, P. Blazso,
R. L. Katona, M. A. Deli, G. Gros, J. W. Xu, G. J. Vancso,
J. Mater. Chem. 2012, 22, 6429.
[84] K. Kulbaba, M. J. MacLachlan, C. E. B. Evans, I. Manners,
Macromol. Chem. Phys. 2001, 202, 1768.
[85] P. R. Andres, U. S. Schubert, Adv. Mater. 2004, 16, 1043.
[86] M. Chiper, R. Hoogenboom, U. S. Schubert, Macromol. Rapid
Commun. 2009, 30, 565.
[87] R. J. Mortimer, in Annual Review of MaterialsResearch, vol
41, (Eds: D. R. Clarke, P. Fratzl), Annual Reviews, Palo Alto
2011, p. 241.
[88] F. M. Raymo, R. J. Alvarado, Chem. Rec. 2004, 4, 204.
[89] B. Happ, A. Winter, M. D. Hager, U. S. Schubert, Chem. Soc.
Rev. 2012, 41, 2222.
www.MaterialsViews.com

Oxidation-Responsive Polymers: Which Groups to Use . . .
[90] H. Hofmeier, U. S. Schubert, Chem. Soc. Rev. 2004, 33, 373.
[91] S. Kelch, M. Rehahn, Macromolecules 1997, 30, 6185.
[92] N. P. Tzanetos, A. K. Andreopoulou, J. K. Kallitsis, J. Polym.
Sci. Part A: Polym. Chem. 2005, 43, 4838.
[93] R. Toth, A. F. Taylor, Prog. React. Kinet. Mech. 2006, 31, 59.
[94] R. J. Field, R. M. Noyes, E. Koros, J. Am. Chem. Soc. 1972, 94,
8649.
[95] J. Delgado, Y. Zhang, B. Xu, I. R. Epstein, J. Phys. Chem. A
2011, 115, 2208.
[96] S. Sasaki, S. Koga, R. Yoshida, T. Yamaguchi, Langmuir 2003,
19, 5595.
[97] I. C. Chen, O. Kuksenok, V. V. Yashin, A. C. Balazs, K. J. Van
Vliet, Adv. Funct. Mater. 2012, 22, 2535.
[98] R. Yoshida, T. Sakai, S. Ito, T. Yamaguchi, J. Am. Chem. Soc.
2002, 124, 8095.
[99] M. Hidaka, R. Yoshida, J. Control. Release 2011, 150, 171.
[100] S. Kadar, T. Amemiya, K. Showalter, J. Phys. Chem. A 1997,
101, 8200.
[101] M. Markus, Z. Nagyungvarai, B. Hess, Science 1992, 257,
225.
[102] S. Shinohara, T. Seki, T. Sakai, R. Yoshida, Y. Takeoka, Angew.
Chem. Int. Ed. 2008, 47, 9039.
[103] P. Dayal, O. Kuksenok, A. C. Balazs, Soft Matter 2010, 6, 768.
[104] J. Roncali, Chem. Rev. 1992, 92, 711.
[105] R. D. McCullough, Adv. Mater. 1998, 10, 93.
[106] I. Y. Sapurina, S. Jaroslav, Russ. Chem. Rev. 2010, 79, 1123.
[107] S. Bhadra, D. Khastgir, N. K. Singha, J. H. Lee, Prof. Polym. Sci.
2009, 34, 783.
[108] L.-X. Wang, X.-G. Li, Y.-L. Yang, React. Funct. Polym. 2001, 47,
125.
[109] M. J. Higgins, P. J. Molino, Z. Yue, G. G. Wallace, Chem. Mater.
2012, 24, 828.
[110] G. G. Wallace, L. A. P. Kane-Maguire, Adv. Mater. 2002, 14,
953.
[111] T. Mirfakhrai, J. D. W. Madden, R. H. Baughman, Mater.
Today 2007, 10, 30.
[112] R. H. Baughman, Synth. Met. 1996, 78, 339.
[113] J. Janata, M. Josowicz, Nat Mater 2003, 2, 19.
[114] P. Novák, K. Müller, K. S. V. Santhanam, O. Haas, Chem. Rev.
1997, 97, 207.
[115] D. Svirskis, J. Travas-Sejdic, A. Rodgers, S. Garg, J. Control.
Release 2010, 146, 6.
[116] A. Guiseppi-Elie, Biomaterials 2010, 31, 2701.
[117] N. K. Guimard, N. Gomez, C. E. Schmidt, Prof. Polym. Sci.
2007, 32, 876.
[118] A. G. Rylie, B. Sungchul, A. P.-W. Laura, J. M. Penny, Sci.
Technol. Adv. Mat. 2010, 11, 014107.
[119] B. Zinger, L. L. Miller, J. Am. Chem. Soc. 1984, 106, 6861.
[120] L. L. Miller, B. Zinger, Q. X. Zhou, J. Am. Chem. Soc. 1987, 109,
2267.
[121] D. T. Ge, X. D. Tian, R. Qi, S. Q. Huang, J. Mu, S. M. Hong,
S. F. Ye, X. M. Zhang, D. H. Li, W. Shi, Electrochim. Acta 2009,
55, 271.
[122] R. Wadhwa, C. F. Lagenaur, X. T. Cui, J. Control. Release 2006,
110, 531.
[123] J.-M. Pernaut, J. R. Reynolds, J. Phys. Chem. B 2000, 104,
4080.
[124] B. C. Thompson, S. E. Moulton, J. Ding, R. Richardson,
A. Cameron, S. O’Leary, G. G. Wallace, G. M. Clark, J. Control.
Release 2006, 116, 285.
[125] C. L. Recksiedler, B. A. Deore, M. S. Freund, Langmuir 2006,
22, 2811.
[126] K. Kontturi, P. Pentti, G. Sundholm, J. Electroanal. Chem.
1998, 453, 231.
Macromol. Chem. Phys. 2013, 214, 143−158
www.MaterialsViews.com © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Macromolecular
Chemistry and Physics
www.mcp-journal.de
[127] L. L. Miller, X. Q. Zhou, Macromolecules 1987, 20, 1594.
[128] S. M. Richardson-Burns, J. L. Hendricks, B. Foster,
L. K. Povlich, D.-H. Kim, D. C. Martin, Biomaterials 2007, 28,
1539.
[129] D. Bouchta, N. Izaoumen, H. Zejli, M. E. Kaoutit,
K. R. Temsamani, Biosens. Bioelectron. 2005, 20, 2228.
[130] G. Bidan, C. Lopez, F. Mendesviegas, E. Vieil, A. Gadelle,
Biosens. Bioelectron. 1995, 10, 219.
[131] P. M. George, D. A. LaVan, J. A. Burdick, C. Y. Chen, E. Liang,
R. Langer, Adv. Mater. 2006, 18, 577.
[132] M. N. Akieh, S. F. Ralph, J. Bobacka, A. Ivaska, J. Membrane
Sci. 2010, 354, 162.
[133] P. Bauerle, S. Scheib, Adv. Mater. 1993, 5, 848.
[134] M. Holzinger, L. Bouffier, R. Vilialonga, S. Cosnier, Biosens.
Bioelectron. 2009, 24, 1128.
[135] M. J. Marsella, T. M. Swager, J. Am. Chem. Soc. 1993, 115,
12214.
[136] M. R. Abidian, D. H. Kim, D. C. Martin, Adv. Mater. 2006, 18,
405.
[137] I. Stassen, T. Sloboda, G. Hambitzer, Synth. Met. 1995, 71,
2243.
[138] Q. Fan, K. K. Sirkar, B. Michniak, J. Membrane Sci. 2008, 321,
240.
[139] D. T. Hess, A. Matsumoto, S. O. Kim, H. E. Marshall,
J. S. Stamler, Nat. Rev. Mol. Cell Bio. 2005, 6, 150.
[140] J. S. Stamler, D. I. Simon, J. A. Osborne, M. E. Mullins,
O. Jaraki, T. Michel, D. J. Singel, J. Loscalzo, Proc. Natl. Acad.
Sci. USA 1992, 89, 444.
[141] J. M. Denu, K. G. Tanner, Biochemistry 1998, 37, 5633.
[142] S. G. Rhee, H. Z. Chae, K. Kim, Free Radic. Biol. Med. 2005, 38,
1543.
[143] X. B. Duan, R. S. Lewis, Biomaterials 2002, 23, 1197.
[144] H. J. Forman, J. M. Fukuto, M. Torres, Am. J. Physiol. Cell
Physiol. 2004, 287, C246.
[145] C. C. Winterbourn, M. B. Hampton, Free Radic. Biol. Med.
2008, 45, 549.
[146] E. Margittai, P. Low, I. Stiller, A. Greco, J. M. Garcia-Manteiga,
N. Pengo, A. Benedetti, R. Sitia, G. Banhegyi, Antioxid. Redox
Signal. 2012, 16, 1088.
[147] J. X. Tang, P. A. Janmey, T. P. Stossel, T. Ito, Biophys. J. 1999,
76, 2208.
[148] J. Perez-Vilar, R. L. Hill, J. Biol. Chem. 1999, 274, 31751.
[149] L. M. Landino, M. T. Koumas, C. E. Mason, J. A. Alston, Bio-
chem. Biophys. Res. Commun. 2006, 340, 347.
[150] P. J. Britto, L. Knipling, P. McPhie, J. Wolff, Biochem. J. 2005,
389, 549.
[151] A. Fava, A. Iliceto, E. Camera, J. Am. Chem. Soc. 1957, 79,
833.
[152] R. P. Szajewski, G. M. Whitesides, J. Am. Chem. Soc. 1980,
102, 2011.
[153] G. X. Gao, K. Ollinger, U. T. Brunk, Free Radic. Biol. Med.
1994, 16, 187.
[154] T. Muller, S. Gebel, Carcinogenesis 1998, 19, 797.
[155] M. Fratelli, H. Demol, M. Puype, S. Casagrande, P. Villa,
I. Eberini, J. Vandekerckhove, E. Gianazza, P. Ghezzi, Pro-
teomics 2003, 3, 1154.
[156] R. Brigelius, C. Muckel, T. P. M. Akerboom, H. Sies, Biochem.
Pharmacol. 1983, 32, 2529.
[157] K. S. Jensen, R. E. Hansen, J. R. Winther, Antioxid. Redox
Signal. 2009, 11, 1047.
[158] N. V. Tsarevsky, K. Matyjaszewski, Macromolecules 2002, 35,
9009.
[159] N. V. Tsarevsky, K. Matyjaszewski, Macromolecules 2005, 38,
3087.
157
 Macromolecular
Chemistry and Physics
www.mcp-journal.de
[160] M. D. Rikkou, C. S. Patrickios, Prof. Polym. Sci. 2011, 36,
1079.
[161] G. T. Zugates, D. G. Anderson, S. R. Little, I. E. B. Lawhorn,
R. Langer, J. Am. Chem. Soc. 2006, 128, 12726.
[162] S. Kommareddy, M. Amiji, Bioconj. Chem. 2005, 16, 1423.
[163] K. Miyata, Y. Kakizawa, N. Nishiyama, A. Harada,
Y. Yamasaki, H. Koyama, K. Kataoka, J. Am. Chem. Soc. 2004,
126, 2355.
[164] A. N. Zelikin, Q. Li, F. Caruso, Chem. Mater. 2008, 20, 2655.
[165] R. Bird, T. Freemont, B. R. Saunders, Soft Matter 2012, 8,
1047.
[166] R. C. Carlisle, T. Etrych, S. S. Briggs, J. A. Preece, K. Ulbrich,
L. W. Seymour, J. Gene Med. 2004, 6, 337.
[167] T. Schmitz, I. Bravo-Osuna, C. Vauthier, G. Ponchel, B. Loretz,
A. Bernkop-Schnurch, Biomaterials 2007, 28, 524.
[168] J. Blacklock, H. Handa, D. S. Manickam, G. Z. Mao,
A. Mukhopadhyay, D. Oupicky, Biomaterials 2007, 28, 117.
[169] J. Iqbal, G. Shahnaz, S. Dunnhaupt, C. Muller, F. Hintzen,
A. Bernkop-Schnurch, Biomaterials 2012, 33, 1528.
[170] A. Bernkop-Schnurch, M. Hornof, T. Zoidl, Int. J. Pharm.
2003, 260, 229.
[171] X. Z. Shu, Y. C. Liu, Y. Luo, M. C. Roberts, G. D. Prestwich,
Biomacromolecules 2002, 3, 1304.
[172] M. A. Serban, G. H. Yang, G. D. Prestwich, Biomaterials 2008,
29, 1388.
[173] Q. Peng, Z. L. Zhong, R. X. Zhuo, Bioconj. Chem. 2008, 19,
499.
[174] A. Goessl, N. Tirelli, J. A. Hubbell, J. Biomater. Sci. Polym. Ed.
2004, 15, 895.
[175] A. Napoli, N. Tirelli, G. Kilcher, J. A. Hubbell, Macromolecules
2001, 34, 8913.
[176] J. K. Sheehan, D. J. Thornton, M. Somerville, I. Carlstedt, Am.
Rev. Respir. Dis. 1991, 144, S4.
[177] V. M. Leitner, G. F. Walker, A. Bernkop-Schnurch, Eur. J.
Pharm. Biopharm. 2003, 56, 207.
[178] A. Bernkop-Schnurch, C. E. Kast, M. F. Richter, J. Control.
Release 2001, 71, 277.
[179] K. Kafedjiiski, A. H. Krauland, M. H. Hoffer,
A. Bernkop-Schnurch, Biomaterials 2005, 26, 819.
[180] V. M. Leitner, M. K. Marschutz, A. Bernkop-Schnurch, Eur. J.
Pharm. Sci. 2003, 18, 89.
[181] Y. C. Liu, X. Z. Shu, G. D. Prestwich, Biomaterials 2005, 26,
4737.
[182] Y. C. Liu, X. Z. Shu, S. D. Gray, G. D. Prestwich, J. Biomed.
Mater. Res. Part A 2004, 68A, 142.
[183] A. L. Brown, E. M. Srokowski, X. Z. Shu, G. D. Prestwich,
K. A. Woodhouse, Macromol. Biosci. 2006, 6, 648.
[184] A. Skardal, J. X. Zhang, G. D. Prestwich, Biomaterials 2010,
31, 6173.
[185] A. Skardal, J. X. Zhang, L. McCoard, S. Oottamasathien,
G. D. Prestwich, Adv. Mater. 2010, 22, 4736.
[186] D. C. Wu, X. J. Loh, Y. L. Wu, C. L. Lay, Y. Liu, J. Am. Chem. Soc.
2010, 132, 15140.
[187] J. A. Yoon, J. Kamada, K. Koynov, J. Mohin, R. Nicolay,
Y. Z. Zhang, A. C. Balazs, T. Kowalewski, K. Matyjaszewski,
Macromolecules 2012, 45, 142.
[188] C. D. Vo, G. Kilcher, N. Tirelli, Macromol. Rapid Commun.
2009, 30, 299.
[189] C. Bonnansplaisance, G. Levesque, Makromol. Chem. 1986,
187, 2841.
[190] P. Sigwalt, S. Boileau, J. Polym. Sci. Part C: Polym. Sym. 1978,
62, 51.
[191] A. Rehor, N. Tirelli, J. A. Hubbell, Macromolecules 2002, 35,
8688.
Macromol. Chem. Phys. 2013, 214, 143−158
158 © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
E. Lallana and N. Tirelli
[192] A. Kameyama, M. Kiyota, T. Nishikubo, Tetrahedron Lett.
1994, 35, 4571.
[193] G. Kilcher, L. Wang, N. Tirelli, J. Polym. Sci. Part A: Polym.
Chem. 2008, 46, 2233.
[194] L. Wang, G. Kilcher, N. Tirelli, Macromol. Chem. Phys. 2009,
210, 447.
[195] J. H. Schuetz, P. Vana, Macromol. Chem. Phys. 2011, 212,
1263.
[196] H. Kudo, S. Makino, A. Kameyama, T. Nishikubo, Macromole-
cules 2005, 38, 5964.
[197] H. Kudo, K. Sato, T. Nishikubo, Macromolecules 2010, 43,
9655.
[198] M. M. DellAnna, P. Mastrorilli, C. F. Nobile, J. Mol. Catal. A
Chem. 1996, 108, 57.
[199] E. Block, Angew. Chem. Int. Edit. 1992, 31, 1135.
[200] H. Nishimura, O. Higuchi, K. Tateshita, K. Tomobe, Y. Okuma,
Y. Nomura, Biofactors 2006, 26, 135.
[201] M. A. Vazquez-Prieto, R. M. Miatello, Mol. Aspects Med. 2010,
31, 540.
[202] R. L. Levine, J. Moskovitz, E. R. Stadtman, IUBMB Life 2000,
50, 301.
[203] I. Dalle-Donne, R. Rossi, D. Giustarini, N. Gagliano,
P. Di Simplicio, R. Colombo, A. Milzani, Free Radic. Biol. Med.
2002, 32, 927.
[204] J. R. Kramer, T. J. Deming, J. Am. Chem. Soc. 2012, 134, 4112.
[205] P. Hu, N. Tirelli, React. Funct. Polym. 2011, 71, 303.
[206] A. Napoli, M. Valentini, N. Tirelli, M. Muller, J. A. Hubbell,
Nat. Mater. 2004, 3, 183.
[207] V. V. Khutoryanskiy, N. Tirelli, Pure Appl. Chem. 2008, 80,
1703.
[208] G. Kilcher, C. Duckham, N. Tirelli, Langmuir 2007, 23,
12309.
[209] A. Rehor, J. A. Hubbell, N. Tirelli, Langmuir 2005, 21, 411.
[210] E. A. Mahmoud, J. Sankaranarayanan, J. M. Morachis,
G. Kim, A. Almutairi, Bioconj. Chem. 2011, 22, 1416.
[211] B. L. Allen, J. D. Johnson, J. P. Walker, ACS Nano 2011, 5,
5263.
[212] B. L. Allen, J. D. Johnson, J. P. Walker, Nanotechnology 2012,
23, 294009.
[213] P. Hu, N. Tirelli, Bioconj. Chem. 2012, 23, 438.
[214] P. Carampin, E. Lallana, J. Laliturai, S. C. Carroccio, C. Puglisi,
N. Tirelli, Macromol. Chem. Phys. 2012, 213, DOI: 10.1002/
macp.201200264.
[215] Y. Jiang, J. M. J. Frechet, Macromolecules 1991, 24, 3528.
[216] Y. L. Zhao, W. H. Jones, F. Monnat, F. Wudl, K. N. Houk,
Macromolecules 2005, 38, 10279.
[217] A. Rehor, N. E. Botterhuis, J. A. Hubbell, N. Sommerdijk,
N. Tirelli, J. Mater. Chem. 2005, 15, 4006.
[218] N. Ma, Y. Li, H. F. Ren, H. P. Xu, Z. B. Li, X. Zhang, Polym.
Chem. 2010, 1, 1609.
[219] M. Trummer, F. Choffat, P. Smith, W. Caseri, Macromol.
Rapid Commun. 2012, 33, 448.
[220] V. Y. Lu, T. D. Tilley, Macromolecules 2000, 33, 2403.
[221] L. R. Sita, K. W. Terry, K. Shibata, J. Am. Chem. Soc. 1995, 117,
8049.
[222] M. L. Amadoruge, J. R. Gardinier, C. S. Weinert, Organome-
tallics 2008, 27, 3753.
[223] H. Frey, M. Moller, K. Matyjaszewski, Macromolecules 1994,
27, 1814.
[224] M. Fujiki, J. Am. Chem. Soc. 1996, 118, 7424.
[225] F. Choffat, P. Wolfer, P. Smith, W. Caseri, Macromol. Mater.
Eng. 2010, 295, 210.
[226] M. Trummer, T. Nauser, M. L. Lechner, F. Uhlig, W. Caseri,
Polym. Degrad. Stabil. 2011, 96, 1841.
www.MaterialsViews.com