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ABSTRACT: Inspired by the spontaneous cyclization of ornithine in peptides, polyesters containing protected ornithine (Orn) side chains along the backbone were synthesized and shown to degrade rapidly upon deprotection through intramolecular cyclization. A new ornithine-based poly(ester amide) PEA 1 and a lysine-based control PEA 2, both bearing the light-sensitive protecting group o-nitrobenzyl alcohol (ONB), were synthesized. Tert-butyl carbamate (Boc)-protected versions 1-Boc and 2-Boc were also synthesized for proof of concept. GPC confirmed that 1-Boc degrades over 40 times faster than 2-Boc following deprotection into the designed intramolecular cyclization products. Finally, TEM visualization of particles made from 1 encapsulating iron oxide nanoparticles reveals complete disruption of nanoparticles and release of payload within a day upon UV irradiation. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 3783–3790Journal of Polymer Science Part A Polymer Chemistry 09/2013; 51(18):3783-3790. · 3.54 Impact Factor
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ABSTRACT: Biological systems rely on recyclable materials resources such as amino acids, carbohydrates and nucleic acids. When biomaterials are damaged as a result of aging or stress, tissues undergo repair by a depolymerization-repolymerization sequence of remodelling. Integration of this concept into synthetic materials systems may lead to devices with extended lifetimes. Here, we show that a metastable polymer, end-capped poly(o-phthalaldehyde), undergoes mechanically initiated depolymerization to revert the material to monomers. Trapping experiments and steered molecular dynamics simulations are consistent with a heterolytic scission mechanism. The obtained monomer was repolymerized by a chemical initiator, effectively completing a depolymerization-repolymerization cycle. By emulating remodelling of biomaterials, this model system suggests the possibility of smart materials where aging or mechanical damage triggers depolymerization, and orthogonal conditions regenerate the polymer when and where necessary.Nature Chemistry 07/2014; 6(7):623-8. · 23.30 Impact Factor
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ABSTRACT: Self-immolative polymers (SIPs) are unique macromolecules that are able to react to multiple types of environmental influences by giving amplified response outputs. When triggering moieties installed at SIP chain ends are activated by their corresponding stimuli, a spontaneous head-to-tail depolymerization ensues, often involving multitopic release of small molecules. SIP designs have evolved a high degree of modularity in each of their functional components, enabling a broad range of utility and applications-driven tuning. In this Perspective, we summarize and discuss recent progress in this nascent area of research, including (i) synthesis of different types of SIPs, (ii) design and evaluation of triggering moieties, (iii) depolymerization mechanisms and kinetics, (iv) applications of SIPs, and (v) outlook and challenges facing the field.Macromolecules 09/2012; 45(18):7317-7328. · 5.93 Impact Factor
Wenxin Wang and Cameron Alexander*
cascade reactions · diagnostics · drug delivery ·
polymers · sensors
The investigation of synthetic
polymers for biological applica-
tions is increasing as assembly
techniques for generating well-
defined macromolecules from ar-
tificial building blocks become
techniques have now evolved such
that a wide variety of functional
groups can be tolerated by polymerization catalysts, and a
fascinating and diverse range of macromolecular and poly-
meric materials has resulted.[1–3]These synthetic polymers are
now beginning to resemble natural counterparts in terms of
molecular architectures, suprastructures, and functions.[4,5]
However, although there has been enormous progress on
synthesis and assembly, there has been much less emphasis on
the controlled depolymerization or disassembly of polymers.
The limited interest in depolymerization is perhaps surprising
when one considers that natural polymers are put together,
modified, and dismantled with equal ease. Indeed, living
systems show extraordinary abilities to move forwards and
backwards along reaction pathways, and are incredibly atom-
efficient in doing so. The repeated generation, processing, and
hydrolysis of spider silk proteins is but one example amongst
many in nature of this ability to assemble and disassemble
polymers.The search is on, therefore, for wholly artificial
functional materials that are assembled easily yet broken
down in an equally facile manner to switch between states of
differing (biological) activity. One step along this road is to
make polymers that are programmed through their synthesis
to disassemble in ways that might be triggered environ-
mentally to yield products that are biologically important.
In recent years, the research group headed by Doron
Shabat at Tel Aviv University has made significant strides in
this direction, with a series of publications describing “self-
immolative” systems. Of particular interest is a study
published earlier this year by Sagi et al.,who described
the sequential disassembly of a linear main-chain polymer by
a single triggering reaction (Scheme 1).
The self-immolation system is based on an ingenious
design philosophy: Polymers are prepared with architectures
that enable the exploitation of neighboring-group interac-
tions, 1,6-elimination, and decarboxylation reactions. The
blocked isocyanate used for the polymer-assembly reactions
underwent homopolymerization in the presence of a catalyst
to generate polyurethanes, which were finally capped with a
trigger group. By connecting up the constituent repeat units,
or monomer fragments, by the urethane linkage through para
positions of an aromatic ring and with a benzylic-carbon-atom
spacer, the polymers are, in effect, set up to collapse the
moment the end group is removed. This triggering effect is
analogoustothe removal ofa keystonefrom an arch, whereby
the whole structure is destabilized and the arch collapses,
except that in this case the “keystone” group is at the end of
the polymer “arch” rather than in the middle.
What is especially exciting about the recent research by
Sagi et al. is the demonstration of cleavage cascade reactions
with applications which extend well beyond programmed
polymer degradation. In the first example, the single reaction
to cleave the polymer chain end was used for enhanced-
sensitivity protein detection. By capping the polymer with 4-
hydroxy-2-butanone, a substrate for b elimination by the
common protein bovine serum albumin (BSA), a protein
sensor was installed at the head of the polymer chain. Careful
monomer design enabled a fluorogenic group to be installed
in the main chain. This unit exhibited low fluorescence-
emission intensity when present in the carbamate form (i.e. in
the polyurethane chain), but high emission intensity when
released as the free amine. The incubation of the butanone-
capped polymer with BSA resulted in the removal of the
polymer head group, liberation of the terminal amine, and
subsequent unzipping of the polymer to release the substi-
tuted 4-aminobenzyl alcohol, which in turn reported the
reaction cascade through enhanced fluorescence (Scheme 2).
In essence, an amplification event occurs, in that a single
signal, that is, hydrolysis of an end group, gives rise to multiple
outputs, in this case the release of fluorescent reporter
Scheme 1. General structure of a main-chain self-immolating polymer.
[*] Dr. W. Wang, Dr. C. Alexander
School of Pharmacy, University of Nottingham
Nottingham, NG7 2RD (UK)
[**] We gratefully acknowledge funding from the UK Engineering and
Physical Sciences Research Council (EPSRC) (grant EP/E021042/1).
? 2008 Wiley-VCH Verlag GmbH & Co. KGaA, WeinheimAngew. Chem. Int. Ed. 2008, 47, 7804–7806
molecules. One could thus envisage a very powerful detection
technology, the signal-to-output ratio of which could in
principle be tuned simply by altering the degree of polymer-
ization, as the higher the number of repeat units in the
polymer, the higher the output from the initial chain-cleavage
event. Furthermore, as the reporter output is independent of
the type of event that leads to the uncaging of the polymer, a
platform of sensor materials can be generated from a single
polymer by using a range of end groups that are substrates for
different enzymes. There is, of course, the usual caveat when it
comes to the detection of enzymes and enzymatic activity. A
single active enzyme molecule amongst a pool of inactive
species is still capable of initiating multiple signaling events,
and this method, like any others that rely on reactive species,
can not distinguish between the active and inactive constit-
uents. In most cases, it is not
necessary to make this dis-
tinction, as for biochemi-
cally important enzymes, it
is nearly always the specific
activity of the enzyme that
one needs to detect. How-
ever, there are some speci-
alized cases (e.g. immune
response) in which the ab-
solute protein concentra-
tion is required, and very
low levels of an immuno-
genic component would not
be picked up by this and
other methods of protein
The recent study by
Sagi et al. also represents
an important extension to
the self-immolation strat-
Shabat research group have
applications, again by using
chemical reactions of the
type that can be triggered
stimuli (Figure 1).
mechanisms by which ther-
apeutic agents are released
have included nucleophilic
that lead to stable cyclic
species, quinone methide
rearrangement, and self-
elimination reactions. The
key factor underlying all
these systems is that the
triggering group can be var-
ied such that it is activated
by a very wide range of
stimuli. Because of the po-
lymer design, the type of
end group that can be installed is highly flexible, yet the
reactivity profile can be tuned to be very substrate specific.
The overriding requirement is that the triggering reaction
caused by a biochemical or other trigger results in the
generation of an active nucleophile, such as an aromatic
amine or activated phenol. To date, the end groups have been
designed to undergo activation upon the action of acids or
bases, catalytic antibodies, amidases, and now esterases.
However, in all cases, the stimulus and trigger reaction serve
to expose a caged nucleophile, which then commences the
cascade reactions that cause the polymers to disassemble
In biomedical terms, this strategy is of considerable utility,
although fully biocompatible self-immolative polymers and
monomers have yet to be prepared. Nevertheless, the ability
Scheme 2. BSA-induced cleavage of a self-immolative polymer composed of potentially fluorogenic units. The
reaction cascade following removal of the protecting group on the head-group amine is shown and results in
the release of fluorescent reporter molecules. Increased fluorescence (lex=270 nm, lem=510 nm) is observed
(left-hand Eppendorf tube) relative to that of the polymer in the absence of BSA (right-hand tube).
Figure 1. Self-immolation strategy for a) linear polymers and b) dendrimers. A single activation event induces
a cascade of self-elimination reactions that lead to the complete dissociation of the linear polymer or
dendrimer into its separate building blocks and the release of side chains or end groups.
Angew. Chem. Int. Ed. 2008, 47, 7804–7806? 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
of a specific biological trigger to promote a wide range and
large number of cleavage reactions leads to some important
therapeutic advantages. If the cleavage products are drug
compounds, they can be held on the caged polymer to await a
site-specific stimulus. For anticancer compounds, which are
typically highly cytotoxic, the ability to hold the drugs on a
polymer backbone until they reach a tumor prevents their
release into nondiseased cells and thus leads to greatly
reduced side effects. The strategy of self-immolative polymers
has been used previously to release the DNA topoisomerase
inhibitor, doxorubicin, in leukaemia cell lines, with either the
catalytic antibody 38C2 or penicillin G amidase as the
trigger.[11,12]Cell-growth assays with the dual-triggered poly-
mer–doxorubicin conjugates showed that dose-dependent
growth inhibition and complete suppression of growth
occurred when the self-immolative polymers were used at a
prodrug concentration of 10–100 nm. The new main-chain-
cleavage methodology described by Sagi et al. could be even
more advantageous in this context, for the amplification
inherent in the polymer design and disassembly should enable
very high drug loading. For some anticancer compounds, the
major challenge is to deliver enough of the cytotoxic agent to
the cell that tumor-cell kill is guaranteed. Conventional
polymer therapeutics often suffer from poor overall drug
payload, as the drug molecules are typically conjugated to a
small proportion of the polymer side chains. If the self-
immolative polymers can be engineered to contain solubiliz-
ing groups as well as drug compounds in their main chains, it
may be possible to reach the high level of cytotoxic payload
needed for resistant tumors.
Another factor that can be exploited in medical applica-
tions of this class of polymer is that the release mechanisms
can be tuned to be complementary or orthogonal to existing
processes already developed for drug release. Biochemical
triggers used in drug-delivery systems to date include acid-
labile polymer–drug conjugates that become reactive at the
comparatively low pH values (between 7.4 and approximately
5.6) in endosomal compartments,[18–20]and reducing agents,
such as glutathione, present in the cytosol to degrade
polydisulfides.Although not demonstrated in the current
study, the installation of acetals, ketals, and hydrazones as
triggering groups would generate polymers that should be
effective in biostimulated release.
A further intriguing possible application of the new
materials could result from the sequential nature of the
disassembly process. The head-to-tail unzipping of the
polymer was shown elegantly by the installation of a 4-
nitroaniline reporter at the tail end of the polymer to enable
the monitoring of total polymer degradation by reversed-
phase HPLC. The evolution of 4-nitroaniline took place over
10 h in the presence of BSA. The results indicated that the
reaction proceeded by the progressive sequence of amine
formation, 1,6-elimination, and decarboxylation along the
chain. It is not difficult toforesee polymer sequencinganalysis
by such a process by using different reporter groups at varying
points along a chain.
In summary, the recent study by the Shabat research
group points the way towards a new family of polymers, the
assembly and disassembly of which are inextricably linked.
The significance of this research is wide-reaching. First, the
way in which the polymers are assembled, that is, by urethane
synthesis, is amenable to modification; thus, many different
types of substitution in the main and side chains are possible.
Second, the degradation of the polymers is sequential and
again could be tuned by the appropriate choice of chemical
reactions to occur at different rates and thus enable delayed-
release profiles if required. Finally, the triggering step is very
versatile, so that the activation event can be fine-tuned to
implicate any of a wide range of physical, chemical, or
biological stimuli. Therefore, the range of possible applica-
tions is very broad.
By using a detailed knowledge of physical organic
chemistry and exploiting efficient nucleophilic and cascade
reactions, Sagi et al. have developed a novel class of materials
that might function in areas as diverse as analytical probes
and diagnostics through to drug-delivery vehicles and medical
devices. Advances in organic chemistry can truly lead to some
fascinating and useful materials.
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