Dual-Responsive Material Based on Catechol-Modified Self-Immolative Poly(Disulfide) Backbones

Article abstract of DOI:10.1002/anie.202108698

Functional materials engineered to degrade upon triggering are in high demand due their potentially lower impact on the environment as well as their use in sensing and in medical applications. Here, stimuli-responsive polymers are prepared by decorating a

Full text of DOI:10.1002/anie.202108698

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Accepted Article
Title: Dual-Responsive Material Based on Catechol Modified Self-
Immolative Poly(Disulfide) Backbones
Authors: Asger Holm Agergaard, Andreas Sommerfeldt, Steen Uttrup
Pedersen, Henrik Birkedal, and Kim Daasbjerg
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
Dual-Responsive Material Based on Catechol Modified
Self-Immolative Poly(Disulfide) Backbones
Asger Holm Agergaard,[a],[b] Andreas Sommerfeldt,[a],[b] Steen Uttrup Pedersen,[a],[b] Henrik Birkedal*,[a],[b]
and Kim Daasbjerg*,[a],[b]
[a]
A. H. Agergaard, Dr. A. Sommerfeldt, Assoc. Prof. S. U. Pedersen, Prof. H. Birkedal, Prof. K. Daasbjerg
Department of Chemistry
Aarhus University
Langelandsgade 140, 8000 Aarhus, Denmark
*
E-mail: hbirkedal@chem.au.dk, kdaa@chem.au.dk
[b]
A. H. Agergaard, Dr. A. Sommerfeldt, Assoc. Prof. S. U. Pedersen, Prof. H. Birkedal, Prof. K. Daasbjerg
Interdisciplinary Nanoscience Center (iNANO)
Aarhus University
Gustav Wieds Vej 14, 8000 Aarhus, Denmark
Supporting information for this article is given via a link at the end of the document.
Abstract: Functional materials engineered to degrade upon triggering
are in high demand due their potentially lower impact on the
environment as well as their use in sensing and in medical
applications. Here, stimuli-responsive polymers are prepared by
interfaces, and a slower disulfide-exchange between backbones
generated new covalent bonds at interfaces.[4]
Polyamines functionalized by polyphenols such as L-3,4-
dihydroxyphenylalanine formed doubly pH responsive hydrogels
based on the acid/base chemistry of the amines and the
pH-dependent metal coordination of the polyphenols.[5,6] Lu et al.
reported a multi-responsive gel capable of actuation by virtue of a
polyelectrolyte backbone, while also possessing the ability to be
photocleaved and photocross-linked through pendant coumarin
groups.[7] Chen et al. presented a multiresponsive system
containing benzoxaborole ester cross-links, responsive towards
decorating
a self-immolative poly(dithiothreitol) backbone with
pendant catechol units. The highly functional polymer is fashioned into
stimuli-responsive gels, formed through pH dependent catecholato-
metal ion cross-links. The gels degrade in response to specific
environmental changes, either by addressing the pH responsive, non-
covalent, catecholato-metal complexes, or by addition of a thiol. The
latter stimulus triggers end-to-end depolymerization of the entire self-
immolative backbone through end-cap replacement via thiol-disufide
exchanges. Gel degradation is visualized by release of a dye from the
supramolecular gel as it itself is converted into smaller molecules.
2 2
pH, ATP, fructose, and H O
.[8]
While the above examples contain high levels of responsivity,
they all leave the intact polymer backbones after triggering
responses; full deconstruction of the polymer system would in
many cases be advantageous. In literature, numerous examples
of polymeric systems with such a property are reported. For
example, disulfide-linked cyclodextrins have been shown to
Introduction
exhibit responsivity toward glutathione, resulting in cleavage of
polymer cross-links.[9] Chain shattering polymers that respond to
either UV or thiols and released drugs/monomeric units upon
exposure to triggering conditions have been reported.[10,11] Zhang
Multi-responsive gels are an attractive class of materials with
applications within areas such as delivery of therapeutics,[1]
actuation,[2] and sensing.[3] The ability to engineer a material to
show a specific response when exposed to certain conditions
such as the presence of a specific molecule or changes in the
local environment eliminates the need for human intervention, as
the system responds autonomously, with a pre-programmed
response. Such materials can consist of two fundamental
components, a polymeric backbone structure and cross-links
responsible for gelation. For delivery of small molecules, a
vanishing gel is attractive as it delivers not only cargo, but also
breaks down to small molecules at the destination of the cargo.
This raises demand for a degradable polymer backbone, capable
of forming a gel.
et al. further reported a poly(thioctic acid) material that could enter
in a recycling loop complete with polymer degradation, monomer
[12]
recycling, and repolymerization.
Recently, self-immolative
polymers (SIPs) have emerged as a unique class of stimuli-
responsive polymers with the attractive trait of controlled
end-to-end depolymerization upon demand.[13]
Reported
[14]
examples include poly(benzyl carbonates) used in sensors,
[15]
poly(benzyl carbamates) in point of care devices, poly(benzyl
[16]
[17]
ethers) utilized for reversible adhesion, in plastics recycling,
[18]
and in antibacterials,
poly(phthalaldehydes) in smart
[19]
composites,
polyglyoxylates exploited in degradable
and poly(dithiothreithol) as vanishing plastic that
depolymerizes into water-soluble small molecules.
Recently, highly functional materials were reported, in which
both the polymer backbone and the cross-links possessed
responsive chemistries. Zhang et al. utilized thermal ring opening
polymerization of thioctic acid and subsequent carboxylate-Fe3
cross-linking to generate a network polymer possessing two
levels of self-healing. Rapid exchange in carboxylate-Fe3+ cross-
links were responsible for fast formation of weak bonds in broken
[20]
packaging,
[21]
In terms of responsive cross-links, dynamic covalent bonds
+
such as boronate esters,[22] imines and Diels-Alder adducts
[23]
[24]
have been explored, contributing to desirable material properties
such as self-healing.[25] Non-covalent cross-links, such as
catecholato-metal complexes, or chelates of carboxylates and
metal ions similarly result in formation of self-healing gels.[
4,26,27]
1
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
Similar properties are also obtained through cyclodextrin
host-guest interactions.[28]
In this study, our aim is to synthesize fully degradable and
dual-responsive gels addressing both the polymer backbone and
compexes.[34] Mono-catecholato-metal species are predominant
at low pH, and tris-catecholato-metal complexes are abundant in
alkaline environments. When catechol is attached to a polymer
backbone, complexation with metal ions results in cross-links to
cross-linking chemistry. As for the choice of responsive backbone, give a pH responsive gel. The gels have desirable properties such
we chose a SIP, given its inherent ability to be depolymerized into
monomeric species in response to specific stimuli. SIP backbones
are a promising class of fully degradable polymers, enabling
reuse of the product at end-of-life. Recently, we expanded the SIP
family with a new member, namely a self-immolative disulfide
backbone, poly(dithiothreitol) (pDTT), end-capped with
thiopyridine-disulfide bonds (see structure in Scheme 1a). An
attractive trait of pDTT is the ease by which it is prepared on gram
scale through simple solid-state synthesis with no need of
rigorously dry and inert conditions. In addition, the backbone of
pDTT has hydroxyl moieties, which are apt for further
as self-healing, owing to the dynamic bond exchange nature of
the catecholato-metal bond.[ The physical properties of the
catecholato-metal complex, e.g. color and rupture force, depend
on the metal ion used and its exact d-electron structure.[6,36]
In this work, we synthesize a dual-responsive polymer and gel,
denoted pDTT-Cat, where the versatile and pH-responsive metal
ion cross-linking chemistry of catechol is merged with the SIP
backbone of pDTT that provides on-demand degradation through
self-immolative depolymerization. We demonstrate how
depolymerization can result in release of Rhodamine 6 G dye from
gels, due to material degradation to small molecules.
Concurrently, gel liquefaction can be achieved when exposing the
material to low pH, where the catecholato-metal cross-links are
broken, resulting in disintegration of the gel, and dye release.
Thus, the two mechanisms of degradation are promoted under
different conditions, either at high pH in a base-catalyzed,
thiol-induced depolymerization, or at low pH through the transition
from tris- to mono-catecholato-metal ion complexes, effectively
reversing cross-linking.
35]
[
21]
functionalization, making pDTT
a strong candidate for a
degradable scaffold in highly functional and responsive polymer
systems. A third prominent feature is its rapid depolymerization in
response to external stimuli. Specifically, adding dithiothreitol
(
DTT) results in uncapping (i.e. initiation of depolymerization)
through thiol-disulfide exchange with the activated thiopyridine-
disulfide bonds of the end-cap moieties (see Scheme 1b).
As for the choice of cross-linking chemistry, we find the
catechol system particularly appealing. Catechol excels with its
inherently versatile chemistry involving interaction through either
hydrogen bonding, π-π stacking or cross-linking through metal ion
chelation.[29,30] Both catecholato-boronate[31] and catecholato
metal complexes[27,29,32] are highly responsive, and have been
utilized as dynamic cross-links in functional materials. The
catecholato-metal complexation with trivalent metal ions is
dependent on the redox state[33] of catechol, and solution pH.
Agergaard et al. utilized both properties to synthesize detachable
polymer brushes, tethered to surfaces through catecholato-metal
Results and discussion
Scheme 1a outlines the protocol for synthesizing catechol-
modified pDTT, pDTT-Cat , where the subscript designates the
x
catechol content which could be adjusted from 0–100%. First,
pDTT was produced using the previously described solid state
synthesis, applying mechanical mixing (i.e. a speedmixer for 3
min) to a mixture of monomeric DTT and a thiol-disufide activating
reagent, 2,2'-dithiodipyridine.[21]
Scheme 1. a) Functionalization of pDTT Using EDC Coupling of Protected Dihydrocaffeic Acid, Followed by Deprotection to Reveal the Catecholic Moiety. b)
Thiol-Induced/Base-Catalyzed Depolymerization of Catechol Modified Poly(dithiothreitol) to Produce Catechol Modified cDTT via Cyclization Reactions Upon
End-Cap Removal.
a)
OH
OR
OH
O
OR
OR
OR
HO
O
O
N
O
O
N
OH
N
Deprotection
S
S
S
S
S
S
S
S
S
S
n
S
S
n
N
O
O
N
O
O
n
EDC, DMAP
in DMF, 3 h
N
OH
pDTT
R = acetonide
or TBS
pDTT-Cat100
OH
OR
OH
OR
b)
OH
OH
OH
OH
OH
O
O
OH
OH
O
HO
HO
OH
OH
O
S
-
SH
n
O
S
OH
O
O
O
OH
O
N
OH
-
S
S
O
-
S
S
S
S
S
S
S
S
n-1
S
S
S
n
Et N
3
OH
O
O
O
O
OH
N
O
O
OH
HS
OH
2
2
N
S
S
OH
OH
OH
OH
OH
OH
2
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
Next, the carboxylic acid group on protected dihydrocaffeic
acid (DHCA) was esterified with the alcohol groups on the pDTT
TBS-DHCA20
information (Figures S3–S8).
,
and pDTT-Cat20
,
please refer to supporting
backbone through
backbone hydroxyl groups was found to be quantitative, when
using 4-dimethylaminepyridine (DMAP) as esterification catalyst
a
Steglich esterification. Conversion of
Figure 1a shows Size Exclusion Chromatography Multiple
Angle Laser Light Scattering (SEC-MALLS) traces of pDTT after
successive catechol functionalization. Upon modification of pDTT
with protected DHCA, the SEC trace shifts to shorter elution times
as expected for larger molecules. The higher the esterification
density becomes, the more unimodal the SEC trace appears,
suggesting that conversion of hydroxyls to esters changes
molecular interactions in terms of hydrogen bonding. Upon
protection group removal, elution volume decreases further,
and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (EDC•HCl) as coupling agent. Protection of
catecholic hydroxyls was essential for achieving clean reactions
in fair yield. Either acetonide (Ace) or tert-butyldimethylsilyl (TBS)
protection groups were used (Figures S1 and S2), abbreviated
TBS-DHCA and Ace-DHCA, respectively. Polymers obtained
x
from this coupling are denoted pDTT-TBS-DHCA and pDTT-Ace-
DHCA , respectively.
x
Specifically, we obtained pDTT-Cat100 via the acetonide route
and pDTT-Cat20 via the silyl ether route. We note that the yield of
the acetonide synthesis of pDDT-Cat100 is low (9%), but we
include pDTT-Cat100 here for the sake of obtaining a clearer
understanding of the polymer analysis. Figure S3–S5 shows the
1H NMR spectra of pDTT, pDTT-Ace-DHCA100 and pDTT-Cat100
respectively. For complete polymer composition analysis of pDTT,
pDTT-Ace-DHCA100 pDTT-Cat100, pDTT-Ace-DHCA20 pDTT-
,
,
,
Figure 2. a) Chemical structure of depolymerization products from pDTT-
Cat100. b) 1H NMR of pDTT-Cat100 (blue) and pDTT-Cat100 depolymerized in
Figure 1. a) SEC-MALLS traces of unmodified pDTT (blue), pDTT-Ace-
DHCA20 (orange), pDTT-Ace-DHCA100 (yellow), and pDTT-Cat100 (purple)
in 0.01 M LiBr/DMF. The small-molecule peak at ~24 min is ascribed to
solvent impurity as confirmed by H NMR (Figure S5). b) SEC trace of
pDTT-Cat100 (blue) and pDTT-Cat100 after addition of 1 equiv. DTT and
presence of 1 equiv. DTT and 0.5 equiv. Et
caps (orange) in DMSO-d . c) Conversion of polymers, pDTT-Cat100 (green)
and pDTT-Cat20 (black), to cyclic monomer in response to adding 1 equiv.
DTT and 0.5 equiv. Et N, along with the response of adding only 0.5 equiv.
N to pDTT-Cat20 (blue), measured by 1H NMR spectroscopy. In all
Et
3
N with respect to polymer end-
6
1
3
3
0
.5 equiv. Et
3
N w.r.t. end-caps (orange) in 0.01 M LiBr/DMF. All sample
measurements the polymer concentration was 1.6 mM. (lines to guide the
eye).
-
1
concentrations were 4 mg mL .
3
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Angewandte Chemie International Edition
10.1002/anie.202108698
RESEARCH ARTICLE
which we attribute to existence of strong intermolecular
report.[21] The progress of depolymerization is indicated by
decrease of the peak at 5.28 ppm, associated with CH-O(CO)- in
pDTT-Cat100, while a new peak at 4.89 ppm is ascribed to the
interactions between different polymer chains through
now-revealed catechol units.[
37]
Such interactions include
bidentate hydrogen bonding and π-π stacking. In the case of
pDTT-Cat20 we were able to substantiate such
2
same proton in the cyclic monomer, cDTT-(Cat) (Figure S14). A
,
peak at 5.23 ppm, assigned to CH-OH in cDTT, originates from
the linear DTT added to remove end-caps (Figures S14−S16
display full spectrum and assignments of depolymerization
products from pDTT-Cat100).
concentration-dependent interchain interactions between
catechol units by comparing SEC traces of pDTT-Cat20 and pDTT-
TBS-DHCA20 at increasing concentrations. While elution times of
pDTT-Cat20 increased at higher concentrations (Figure S9), there
was no such effect for pDTT-TBS-DHCA20 (Figure S10). Figure
S11 shows the SEC-MALLS traces for pDTT, pDTT-Ace-DHCA20
Figure 1b shows corresponding SEC data where a change
occurs from large hydrodynamic radius with elution times of
16−21 min to small molecule fragments with elution time of 24 min
upon uncapping and depolymerization. This signifies that the
self-immolative property of the pDTT backbone is preserved after
modification with catechol. Similarly, degradation of pDTT-Cat20
and pDTT-Cat20, and Table S1 compiles M
parameters for all studied polymers, extracted from SEC data
see Figures S9–S13 for further discussion).
n w
, M , and DP
(
1
was characterized by H NMR (Figure S17 and S18) and SEC
(
Figure S19). Evident from the SEC data, the products obtained
from degradation of pDTT-Cat20 result in several peaks,
corresponding to cDTT (27 min) and cDTT-(Cat) with one
Degradability of modified pDTT
Scheme 1b shows the proposed reaction transforming
pDTT-Cat to small molecules on basis of the already known
depolymerization pathway of pDTT itself.[ This ability to degrade
on demand through a self-immolative process by exposure to
specific stimuli is a key property of the novel multi-functional
polymer. Specifically, by cleaving off the end-caps with a
stoichiometric amount of DTT (i.e. 1 equiv. per end-cap), the
unstable polymer backbone initiates depolymerization through a
1
catechol unit (25 min) along with a peak ascribed to an unknown
solvent impurity (24 min). Figure S19 also shows the SEC trace
of degradation products from pDTT-Cat100, which results in a
21]
2
single peak assigned to cDTT-(Cat) (23 min).
To investigate the possibility of inter-chain disulfide exchange
and macrocycle formation, we studied degradation of unmodified
pDTT in a more concentrated solution (40 mM vs. 1.6 mM in
standard degradation experiments) to promote possible inter-
chain reactions. By adding 0.25 equiv. DTT w.r.t. end-caps, only
every other chain is expected to depolymerize if no inter-chain
depolymerization occurs. SEC traces showed formation of only
small molecules (Figure S20) which indicates that some inter-
chain depolymerization may take place, however without resulting
in larger macrocyclic structures. Most likely, this observation can
be attributed to a situation where the smallest (and thus fastest
diffusing) depolymerizing thiolate ends attack new chains, thus
inducing depolymerization.
cascade of cyclizations. This involves
base-catalysed ring-closing thiol-disulfide exchanges, to form the
thermodynamically stable 1,2-dithiane-4,5-diol cyclic product
a
sequence of
(
cDTT), which is the oxidized and ring-closed form of DTT. To
promote faster thiol-disulfide exchange kinetics, a catalytic
amount of base (0.5 equiv. Et N per end-cap) was added to
3
increase the concentration of the more reactive thiolate species.
Figure 2a,b shows how the transformation of pDTT-Cat100
from polymer to small molecules is reflected in H NMR. Upon
uncapping, the peaks assigned to end-caps all shift downfield
when pyridine-2-thiol is released in accordance with our previous
1
Figure 3. a) pDTT-Cat20, Al3+ and rhodamine 6G in solution and b) after inducing hydrogel formation by addition of NaOH to raise pH. c) Mechanism of gel
3+
3
breakdown, induced either by depolymerization through decapping by addition of 10 equiv. DTT and 5 equiv. Et N w.r.t. end caps (top), or by cleavage of Al -
catecholato cross-links at low pH, by addition of 1 M HCl in MeOH (bottom). d) Resulting liquefaction of the hydrogel and concomitant release of Rhodamine 6G
into solution after 100 min (depolymerization) and 17 min (catecholato-metal crosslink cleavage).
4
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Angewandte Chemie International Edition
10.1002/anie.202108698
RESEARCH ARTICLE
predominantly mono-, bis-, and tris-complexes at acidic,
intermediate, and alkaline pH respectively.[6,39]
Triggered hydrogel degradation
Figure 3c,d demonstrates the stimuli-triggered response of
3
+
gels made from pDTT-Cat20, Rhodamine 6 G dye, and Al , after
addition of DTT/Et N in MeOH or 1 M HCl in MeOH, either of
3
which results in complete gel liquefaction. Importantly, this
confirms successful introduction of dual stimuli-responsiveness
into the gels through the catecholato-metal cross-links and the
self-immolative backbone. Notably, the time scale for these two
types of gel liquefaction is different, in that cleavage of cross-links
is complete within 17 min, while depolymerization takes at least
100 min (Figure S21 and Movie S1 in supporting information). As
such, the two functionalities represent two orthogonal pathways
to hydrogel degradation, working in different time regimes. While
catecholato-metal cross-links addressed by lowering pH respond
relatively fast, the depolymerization triggered by addition of DTT
is, at least, five times slower. We note that the response time is
minutes to a few hours, and thus the translation of a molecular
trigger to a macroscopic response can be considered as rapid.
Compared to previously reported degradable gels based on
breaking disulfides, this depolymerization reaction results in a
swift degradation, with the option for even faster responsivity
through the acid labile cross links.[9,10,40]
Figure 4. Dye release from pDTT-Cat20 gels in different environments measured
as absorbance at 529 nm; 1 M HCl in MeOH (blue), 10 equiv. DTT and 5 equiv.
Et N (with respect to end-caps) in MeOH (yellow), MeOH without stimuli
3
(orange). Dashed lines to guide the eye.
Figure 2c displays kinetic traces of the degradation processes
of pDTT-Cat100 and pDTT-Cat20, respectively. Depolymerization
was taken as the percentage conversion to cyclic monomer
1
species against time, determined by H NMR analysis (Figures
S16 and S17). As seen, both polymers exhibit complete
Figure 4 shows the absorbance in UV-vis caused by release
of Rhodamine 6 G from the gels as function of time using the two
stimuli (see Figures S22 – S24 for raw UV spectra). The important
revelation of this experiment is that the macroscopic response
degradation in DMSO-d
Et N. In fact, degradation of pDTT-Cat20 occurs essentially within
the 30 needed to record the first NMR spectrum.
Depolymerization of pDTT-Cat100 is slower than that of DTT-Cat20
6
within a few minutes of adding DTT and
3
s
,
(
increase in absorbance from the released dye) to a molecular
which we ascribe to the higher content of bulky catechol
substituents, slowing the ring-closing reaction. In addition to steric
effects, the relatively low pKa of the catechol hydroxyls may
reduce the efficiency of the base catalysis.[38] Nevertheless, the
signal is significant, no matter which of the stimuli-responsive
moieties is addressed. Thus, the pDTT-Cat20 gel can, potentially,
work as drug carrier with the self-immolative backbone or the
metal-catecholato cross-links as release functions. Note that the
release is, by and large, completed within ~60 min, independent
of the selected stimuli-responsive moiety. This similarity of the
results is not particularly surprising, as the release of a given
molecule from a hydrogel breaking up consists of additional steps
than the responsiveness actions themselves, e.g. diffusion of
small molecules and changes in polymer chain conformation.
Thus, different regimes of mass transport and diffusion would
need to be considered, if a thorough evaluation of the kinetics was
the goal. In addition, the experimental conditions were not exactly
the same in the experiments presented in Figures 3 and 4. While
the gels depicted in Figure 3 were left unperturbed for gel
degradation until pictures were captured, the corresponding
solutions above the gels for the small molecule release
measurements (Figure 4) were homogenized immediately prior to
withdrawing each sample (see Supporting Information).
Nonetheless, the experiments work nicely as proof-of-concept
illustrations of the dual-responsiveness of the gels.
response of pDTT-Cat100 to chemical stimuli (i.e. DTT/Et
rapid, with full depolymerization accomplished within 3 min.
Evident from Figure 2c, adding Et N alone does not induce
3
N) is
3
depolymerization or end-cap removal on the timescale of these
degradation experiments.
x
The facile depolymerization of pDTT-Cat is crucial for the
intended degradation of gels cross-linked by catecholato-metal
ion complexes, as steric constraints imposed by the cross-links is
expected to slow down the disulfide cyclization reaction further,
thus reducing depolymerization rate. In this study, we did not
attempt to isolate and recycle the monomeric species from the
depolymerization, but we have previously reported the recovery
and repolymerization of cDTT obtained from depolymerization of
pristine pDTT.[
21]
Hydrogel formation
Figure 3 establishes a key feature of polymers decorated with
catechol pendant groups, which is the ability to form gel networks
through formation of catecholato-metal cross-links. In this study,
hydrogels were formed and loaded with dye (for visualization) by
first dissolving pDTT-Cat20 in a solution of Rhodamine 6 G in
Finally, regeneration of gels from the acidic solution resulting
from cleaving catecholato-Al3+ cross-links was attempted by
raising pH once again. However, addition of aqueous NaOH
resulted in formation of smaller, individual gel particles rather than
a single, large gel. We ascribe this to the significant dilution of the
polymer chains when attempting direct gel reforming (starting
3
+
MeOH, and adding a solution of Al ions to produce the mono-
3
+
catecholato-Al species (Figure 3a). To induce cross-linking, pH
was raised by addition of aqueous NaOH, resulting in immediate
hydrogelation with the dye trapped in the gel (Figure 3b).
Formation of catecholato-Al3+ species is pH dependent, forming
-1
concentration of ~110 mg mL compared to a final concentration
-1
of ~25 mg mL ). Formation of smaller gel particles may find use
in e.g. drug formulation within the gels.
5
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RESEARCH ARTICLE
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Conclusion
[
We have presented a responsive polymer consisting of a
self-immolative backbone decorated with catechol units. Through
catecholato-Al3+ cross-links, the polymers form dual-responsive
hydrogels in a pH-responsive fashion. Gel degradation and
concomitant release of trapped cargo are triggered either by
lowering pH and cleaving the cross-links, or by translation of a
molecular signal, dithiothreitol, to a macroscopic response by
virtue of depolymerization of the self-immolative backbone. As
such, the two functionalities represent two orthogonal pathways
to hydrogel degradation, working in different time regimes. Both
processes result in vanishing gels and release of small molecule
cargo. Thus, molecular signals are amplified to a macroscopic
1
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This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.202108698
RESEARCH ARTICLE
Entry for the Table of Contents
Catechol functionalized self-immolative poly(disulfides) are synthesized and fashioned into dual-responsive gels through
3
+
formation of catecholato-Al cross-links. Two distinct pathways to cargo release are engineered, namely the depolymerization in a
3
+
self-immolative fashion, or breaking catecholato-Al cross-links at low pH. Both gel degradation pathways lead to release of bound
dye molecules on demand.
Institute and/or researcher Twitter usernames: @Chemistry_AU, @iNANO_AarhusUni
8
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