A R T I C L E S
DeWit and Gillies
bone, and many environmentally mediated cleavage events are
required to completely degrade the polymer.
Another interesting class of molecules that is under develop-
ment is stimuli responsive polymers. For example, polymers
based on N-isopropylacrylamide (NIPAM)25 or oligo(ethylene
glycol) methacrylates26,27 have been demonstrated to be ther-
mally responsive, with high aqueous solubility below their lower
critical solution temperature (LCST) and precipitation above
the LCST. Polymers containing pendant amines or carboxylic
acids are typically responsive to pH, being soluble within
specified pH ranges.28-30 In addition, hydrophobic groups and
drugs have been appended to polymer backbones by pH-
sensitive acetals,31,32 hydrazones,33 or photochemically cleavable
linkages,34,35 such that the solubilities of the polymers are
significantly altered upon the removal of these groups. Other
systems responsive to stimuli such as sugar concentration36,37
and redox potential38-40 have also been reported. These stimuli
responsive polymers have increasingly been used in recent years
to prepare assemblies such as micelles, vesicles, and nanopar-
ticles that are capable of releasing molecules in response to
changes in environmental conditions.34,35,38,40–47 However, the
design of systems capable of responding within the relatively
narrow range of biologically accessible conditions is still a
significant challenge.
Figure 1. Schematic of a cascade degradable linear polymer, where removal
of a stabilizing end-cap initiates a cascade of reactions leading to
depolymerization.
is intact, but upon removal of the end-cap via a single bond
cleavage, a functionality is revealed at the polymer terminus
that initiates a cascade of intramolecular reactions leading to
complete depolymerization from end to end. This concept was
initially introduced in dendritic systems that upon removal of a
focal point group were demonstrated to degrade by an intramo-
lecular cascade, releasing multiple molecules from the dendrimer
periphery.48,49 Such systems were then further developed to
provide for the simultaneous release of multiple different drug
molecules, the incorporation of tumor targeting groups, and focal
point groups that were sensitive to reducing conditions or
enzymes.50-53
The application of this concept to linear cascade degradable
polymers has the potential to dramatically expand their utility.
Such materials may be used for the assembly of supramolecular
aggregates such as micelles, vesicles, and nanoparticles or for
the fabrication of medical devices or tissue engineering scaf-
folds, where they can impart several unique and advantageous
properties. For example, the use of end-caps responsive to
different conditions could allow the degradation of a single
polymer to be triggered under a wide range of conditions, while
the composition of the polymer backbone itself would determine
the rate of degradation. By tuning the length of the polymer
backbone, the time required for polymer degradation can
potentially be controlled, as a longer polymer should take longer
to completely depolymerize than a shorter polymer. In addition,
due to the end to end degradation mechanism resulting in a
controlled and gradual reduction of polymer molecular weight,
the physical properties of the polymer should be retained longer
during the degradation process in comparison with a traditional
degradable polymer such as a polyester, where a single cleavage
event may decrease the molecular weight by up to 50%. Despite
these attractive features, only one cascade degradable linear
polymer backbone has been reported to date.54,55 This backbone
was a polycarbamate based on 4-aminobenzyl alcohol deriva-
tives, which degrades entirely by intramolecular 1,6-elimination
reactions via iminoquinone methide intermediates. It has been
demonstrated that by using enzyme sensitive end-caps this
backbone can be used as an amplifying sensor,54 or to release
A new and attractive concept for the design of materials that
are both degradable and stimuli responsive is end-capped
cascade degradable polymers. As illustrated in Figure 1, these
polymers comprise a backbone that is stable when the end-cap
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