Tuneable Transient Thermogels Mediated by a pH- and Redox-Regulated Supramolecular Polymerization

Article abstract of DOI:10.1002/anie.201708857

A multistimuli-responsive transient supramolecular polymerization of β-sheet-encoded dendritic peptide monomers in water is presented. The amphiphiles, which contain glutamic acid and methionine, undergo a glucose oxidase catalyzed, glucose-fueled transient hydrogelation in response to an interplay of pH and oxidation stimuli, promoted by the production of reactive oxygen species (ROS). Adjusting the enzyme and glucose concentration allows tuning of the assembly and the disassembly rates of the supramolecular polymers, which dictate the stiffness and transient stability of the hydrogels. The incorporation of triethylene glycol chains introduces thermoresponsive properties to the materials. We further show that repair enzymes are able to reverse the oxidative damage in the methionine-based thioether side chains. Since ROS play an important role in signal transduction cascades, our strategy offers great potential for applications of these dynamic biomaterials in redox microenvironments.

Full text of DOI:10.1002/anie.201708857

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Tuneable Transient Thermogels Mediated by a pH- and Redox-
Regulated Supramolecular Polymerization
Authors: Daniel Spitzer, Leona Lucas Rodrigues, David Straßburger,
Markus Mezger, and Pol Besenius
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201708857
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Tuneable Transient Thermogels Mediated by a pH- and Redox-
Regulated Supramolecular Polymerization
Daniel Spitzer,[a] Leona Lucas Rodrigues,[a] David Straßburger,[a] Markus Mezger,[b] Pol Besenius*[a]
Abstract: We present
a
multi-stimuli responsive transient
Miravet[7] have reported enzyme catalyzed transient hydrogel
assemblies with a tuneable time domain. The connection of the
molecular stimuli to a kinetically controlled reaction thus leads to
programmable and autonomous transitions in adaptive soft
materials. The glucose oxidase (GOx) catalyzed oxidation of β-D-
glucose to gluconolactone and concomitant reduction of
molecular oxygen to hydrogen peroxide is a powerful tool to
address responsive materials that operate in both a pH and redox
microenvironment.[8] The hydrolysis of lactone derivatives on their
own has been used to trigger pH-responsive multi-component
assemblies.[9] In redox-responsive molecular and polymeric
materials the incorporation of thioether functional groups has
been a promising approach, since the oxidation to the sulfoxide
species generates a large increase in hydrophilicity.[10] This shift
induces water solubility and a triggered disassembly of the
supramolecular structures. Here, we propose to use the GOx
catalyzed and glucose fueled release of protons coupled with the
production of H2O2, in order to simultaneously generate two
different chemical stimuli. In the ß–sheet encoded glutamic acid
and methionine containing amphiphiles (Figure 1), these trigger
molecular changes on two different time scales and the resulting
kinetic differentiation induces transient states with tuneable
lifetimes in an autonomous supramolecular polymerization set-up,
where we also investigate the impact on the formation of a stimuli-
responsive gel.[11]
supramolecular polymerization of ß-sheet encoded dendritic
peptide monomers in water. The glutamic acid and methionine
containing amphiphiles undergo a glucose oxidase-catalyzed,
glucose-fueled transient hydrogelation in response to an interplay
of pH- and oxidation-stimuli, promoted by the production of
reactive oxygen species (ROS). By adjusting the enzyme and
glucose concentration we tune the assembly and the disassembly
rates of the supramolecular polymers, which dictate the stiffness
and transient stability of the hydrogels. The incorporation of
triethylene glycol chains introduces thermoresponsive properties
to the materials. We further show that repair enzymes are able to
reverse the oxidative damage in the methionine-based thioether
side chains. Since ROS play an important role in signal
transduction cascades, our strategy offers great potential for
applications of these dynamic biomaterials in redox microen-
vironments.
A key feature of living systems is their ability to adapt transient
non-equilibrium states and thereby regulate structural and
functional states with exceptional spatio-temporal control. The
materials, polymer science and systems chemistry communities
have pursued a variety of avenues to mimic such complex higher-
order assemblies using synthetic man-made building blocks.[1]
The successful integration of feedback-driven or multiple coupled
equilibria into supramolecular self-assembly processes has led to
non-equilibrium kinetically controlled processes and dissipative
self-assembled materials.[2] The large majority of these systems
relies on a catalyzed reaction that induces a change in the
hydrophobic/hydrophilic balance of the supramolecular building
blocks. For example, George and co-workers have shown that an
enzyme-catalyzed and nucleoside triphosphate-fueled system is
able to show a transient change in the helicity of supramolecular
polymers.[3] The Hermans laboratory has disclosed a strategy to
keep a fueled supramolecular polymerization in a non-equilibrium
state, when operated in a reactor that continuously removes
waste products of the enzyme catalyzed process.[4] Using short
hydrophobic oligopeptide hydrogelators, Ulijn,[5] Walther,[6] and
We have previously reported a range of dendritic C3-
symmetric peptide amphiphiles that respond to pH and ionic
strength and self-assemble into one dimensional (1D) nanorod-
like supramolecular polymers in water.[12] We have focused on the
use of alternating sequences of hydrophobic and hydrophilic
[a]
D. Spitzer, L. L. Rodrigues, D. Straßburger, Prof. Dr. P. Besenius
Institute of Organic Chemistry
Johannes Gutenberg-University Mainz
Duesbergweg 10-14, 55128 Mainz (Germany)
E-mail: besenius@uni-mainz.de
[b]
Jun.-Prof. Dr. M. Mezger
Institute of Physics
Johannes Gutenberg-University Mainz,
Max Planck Institute for Polymer Research
Ackermannweg 10, 55128 Mainz (Germany)
Figure 1. A) Molecular structures of the ß–sheet encoded dendritic peptide
amphiphile I and its oxidized form II; B) Schematic representation of the pH-
driven supramolecular polymerization and the oxidation-triggered disassembly.
Supporting information for this article is given via a link at the end of the
document.
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Figure 2. A) pH dependent CD spectra for I (60 µM in 10 mM phosphate buffer); B) Normalized CD data for 60 µM solutions of I and II in 10 mM phosphate buffer
at λ = 220 nm. Dimensionless degree of aggregation is set to 1 for the fully polymerized state and to 0 for the monomeric state; C) Probing the oxidation of I to II
(60 µM, 40 °C) over time in the presence of varying amounts of H2O2, by monitoring the intensity of the CD-band at λ = 265 nm; D) Cryo-TEM of I (2.5 mg·mL‑1 at
pH 3.0, 10 mM TRIS); E) Rheological temperature dependent time sweeps of I (7 mg·mL‑1 in H2O pH 3.00, containing 50 mM glucose, with a constant frequency of
1 Hz). F) Analytical RP-HPLC chromatograms showing the enzymatic reduction of II to I, accompanied with a hydrophobic shift in retention time followed at
1
λ = 210 nm over time. Reduction conditions: 60 µM II, 15 mM DTT, 8 µg·mL‑ MSRA, 8 µg·mL‑1 MSRB2, 20 mM TRIS-buffer, pH 7.4, 40°C.
amino acids and shown that they are strong ß-sheet directing
supramolecular units.[12] Here, we report the use of
130 nm, was shown by cryoTEM and TEM images in acidic pH
(Figure 2D and Figure S4). To determine the intermolecular
dimensions of the aggregates, we performed X-ray scattering. A
strong scattering peak was observed at 13.3 nm−1, corresponding
to a real space distance of d = 0.47 nm (Figure S13). This peak
was assigned to the intermonomer distance and is in agreement
with our previously published molecular dynamics simulations,
which suggested values of 0.45 nm.[12a]
a
pentapeptide sequence FEMEM where the pH-switchable
glutamic acid (E) and the redox-responsive methionine (M) amino
acids result in multi-stimuli responsive properties. Using a
convergent synthetic approach, we coupled an azido glycine
terminal pentapeptide, bearing a hexyl spacer and triethylene
glycol functionalized Newkome-type dendron,[13] to 1,3,5-
triethynylbenzene
using
Cu(I)-catalyzed
azide-alkyne
Importantly, when selectively oxidizing the methionine
residue of building block I into the sulfoxide species II using H2O2,
we did not observe any formation of supramolecular polymers by
CD or TEM, even at low pH (Figures 2B, 2C, S2 and S5). The
increased hydrophilicity of the sulfoxide functional group
compared to the thioether precursor is accompanied by a strong
increase of the dipole moment and a downfield shift of the NMR
signal of the methyl protons next to the sulfur atom from 2.1 ppm
to 2.5 ppm (Figure S6).[10e, 10h] In addition, signal broadening is
observed due to the formation of a mixture of six racemic sulfoxide
stereocenters. It is important to note that the switch in
hydrophilicity is a well-known phenomenon used for oxidation-
responsive thioether containing amphiphilic systems.[10]
A straightforward way to follow the reduction of the sulfoxide
(i.e. the repair process) is given by analytical reversed-phase
HPLC tracing, which shows a strong shift towards higher elution
times, due to the increase in hydrophobicity after reduction of the
sulfoxide bearing amphiphile II to the thioether functional I (Figure
2F).[16] We used dithiothreitol (DTT) as stoichiometric reducing
agent and a mixture of the enzymes methionine sulfoxide
reductase A (MSRA) and B2 (MSRB2), specific for the S- and R-
methionine sulfoxide diastereomers, respectively. We followed
the conversion of II into I, at 40 °C over time. Between 30 min and
4.5 h the HPLC chromatogram shows the appearance of
cycloaddition chemistry.[14] After acid deprotection, the C3-
symmetric amphiphilic monomer I (Figure 1) was obtained in four
synthetic steps. The detailed synthetic procedures and material
characterization are provided in the supplementary information.
We first investigated the pH-dependent self-assembly
process of I in 10 mM aqueous phosphate buffer by circular
dichroism (CD) spectroscopy (Figure 2A). At neutral pH = 7.2,
only weak CD bands at λ = 202 nm and λ = 218 nm are observed,
suggesting the presence of molecularly dissolved species, which
is further supported by negative stain transmission electron
microscopy (TEM) images (Figure S4). Repulsive Coulomb
interactions of the deprotonated glutamic acid side chains in the
pentapeptide sequence hamper the ß–sheet directed formation of
supramolecular nanorods. Upon decreasing the pH, positive CD
bands appear at λ = 200 nm, 248 nm, 273 nm and one negative
band at λ = 225 nm. When monitoring the intensity of the strong
negative CD band, a sharp transition at pH 5.4 is observed, which
is indicative of the formation of ordered supramolecular polymers.
In agreement with our previously reported investigations, the
strong thermodynamic driving force for self-assembly leads to a
pronounced shift of the apparent pKa values of the glutamic acid
side chains.[15] The formation of ordered 1D supramolecular
polymers, with a thickness of 5.7 nm and average length of
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10.1002/anie.201708857
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numerous hydrophobic species, which we assign as partially
reduced derivatives of II. After 6 h the chromatogram shows one
reduced species, with the same retention time as the thioether
derivative I. In addition, the consumption of DTT (tR = 4.8 min) into
its oxidized disulfide form (tR = 5.2 min) is also shown by HPLC. It
should be noted that under the standard MSRA/MSRB2 reaction
conditions at pH 7.4, amphiphile I does not self-assemble, but
instead remains in its molecularly dissolved state. Since the
conditions for the pH-dependent polymerization are incompatible
with MSRA/MSRB2, we employed a derivative IV (Figure S3 and
S19), where the glutamic acids were swapped for phenylalanine
groups. Its reduced form III, with the ß-sheet encoded amino acid
sequence FMFM, does not show pH-dependent supramolecular
polymerization. Remarkably the reduction of IV to III, under
conditions where III self-assembles, proceeds on a similar time
scale as for the amphiphile I and is complete after 6 h (Figure S9).
This highlights the high robustness of the oxidation damage repair
and substrate promiscuity of this class of reductases.[17]
In many of our previous investigations, we relied on dendritic
tetraethylene glycol chains to enhance the water solubility of the
supramolecular polymers.[12, 18] We further relied on their steric
demand and high chain flexibility in order to introduce repulsive
forces in the supramolecular polymerization process, which
avoids the formation of infinitely long polymers, a process we
usually refer to as frustrated growth. Inspired by the large body of
work on thermoresponsive materials, with characteristic lower
critical solution temperature (LCST) properties,[19] we introduced
shorter triethylene glycol chains. These give rise to a thermally
induced dehydration in a biologically relevant temperature range
from 30 - 40 °C. Hence, we performed temperature-dependent
rheological studies of our supramolecular polymers at acidic pH.
Using tube inversion tests, we estimated the critical gelation
concentration of I to be slightly below 0.7 wt %. We first conducted
oscillatory shear rheology experiments with an angular frequency
range from 0.01 - 10 rad·s-1 at 20 °C and 40 °C, to show the
frequency independence of the storage (G’) and loss moduli (G’’)
(Figures S10-S11). We then used a constant frequency of 1 Hz to
perform time sweeps at 20 °C at a concentration of 0.7 wt % of I
at pH 3.0. The solution remained completely liquid and any
indication of hydrogelation was absent at this temperature.
However, upon slow heating to 40 °C the solution became
viscous and the storage modulus (G’) shows a sharp increase
while the loss modulus (G’’) remains constant, indicating the
formation of thermoresponsive hydrogels (Figure 2E).
Figure 3. Transient hydrogelation of a solution of I (7 mg·mL-1) in H2O with
300 mM glucose and 650 µg·mL-1 GOx at 40°C: A) 30 min B) 3 h C) 8 h; D)
Time sweeps at 1 Hz, 40 °C of I (7 mg·mL-1) in H2O containing 300 mM glucose,
100 mM NaCl and various amounts of GOx starting at pH 5.7; E) Time sweeps
at 1 Hz, 40 °C of I (7 mg·mL-1) in H2O containing 650 µg·mL-1 GOx, 100 mM
NaCl and various amounts of glucose starting at pH 5.7.
hydrogen peroxide. Compared to the pH decrease, H2O2 acts on
a considerably slower time scale by oxidizing methionine to the
more hydrophilic methionine sulfoxide and thereby leading to a
delayed disassembly of the non-equilibrium supramolecular
polymer state. Thus, by adjusting the concentration of GOx and
its fuel glucose at 40 °C, we aimed to tune the time-window for
the transiently stable hydrogels (Figure 3), as also shown in
elegant work on pH-responsive gels by the Walther group.[20] First,
we investigated the influence of the GOx concentration on the
transient hydrogelation while keeping
a constant glucose
concentration of 300 mM (Figure 3D). Starting from 260 µg·mL-1,
we observed an increase of the storage modulus within
approximately 50 min to 0.3 Pa, which decreases again to the
initial values after 90 min. By increasing the enzyme
concentration to 650 µg·mL‑1 time sweep measurements showed
a much stronger increase of the storage modulus within the first
45 min to reach a maximum value of 2.1 Pa at around 70 min,
which slowly decreases over the period of 180 min. This confirms
the successful formation of a transient weak hydrogel which is
stable for several hours at 40 °C, as also demonstrated by tube
inversion tests (Figure 3A-C). From these data we conclude that
by increasing the enzyme concentration, glucose is consumed
faster leading to a faster drop in pH (Figure S14), which increases
the rate of hydrogelation and leads to the formation of a stronger
hydrogel. Eelkema and van Esch have reported similar findings,
whereby the overall rate of gelation can be enhanced using acid
and nucleophilic catalysts. This leads to an increased formation
of defects in the gel forming fibres, resulting in branching fibrillary
structures and a strengthening of the gels.[2d,21] At the highest
GOx concentration, destabilization of the hydrogel is observed
after 110 min, due to H2O2 promoted oxidative damage of the
monomer building blocks inducing the depolymerization of the
supramolecular nanofibres, which subsequently results in a
Using the described multi-stimuli responsive properties, we
were eager to investigate the potential of transiently stable
thermally induced hydrogels, with a tuneable lifetime mediated by
the pH-triggered assembly and oxidative stress promoted
disassembly of the supramolecular polymers. To this end, we
used the enzyme glucose oxidase since it provides all the
requirements to perform kinetic investigations of
a fully
autonomous supramolecular system: (1) it catalyzes the oxidation
of β-D-glucose to gluconolacton which slowly hydrolyzes to
gluconic acid reaching a buffering point determined by its
pKa = 3.86. This pH drop in turn triggers the supramolecular
polymerization of I by deactivating the repulsive electrostatic
forces of the glutamic acid based carboxylic acid moieties,
accompanied by hydrogelation at temperatures T > 30 °C. (2)
While oxidizing β-D-glucose, molecular oxygen is reduced to
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1
650 µg·mL‑ , we varied the glucose concentration from 100 mM
to 300 mM (Figure 3E). In agreement with the previous
experiments, increasing the glucose concentration leads to an
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In summary, we present glutamic acid and methionine
containing dendritic peptide monomers, that are able to undergo
multi-stimuli responsive ß–sheet self-assembly in water. Using a
glucose oxidase catalyzed, glucose fueled interplay of pH- and
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obtained. Thermoresponsive side chains are able to induce the
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glucose concentration we tune the kinetics and lifetime of the
supramolecular polymers, which dictate the stiffness and time-
domain of the transient hydrogels. Furthermore, we show that
methionine sulfoxide reductase repair enzymes are able to
reverse the oxidative damage in the thioether side chains of the
monomers. Since reactive oxygen species play an important role
in signal transduction cascades, our strategy offers great potential
for applications of these dynamic responsive biomaterials in redox
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Keywords: supramolecular chemistry in water • transient self-
assembly • redox regulation • dynamic materials • kinetic control
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10.1002/anie.201708857
Angewandte Chemie International Edition
COMMUNICATION
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COMMUNICATION
ß–sheet encoded dendritic peptide
monomers containing glutamic acids
and methionines undergo a transient
supramolecular polymerization, in
response to an interplay of pH- and
oxidation-stimuli, promoted by the
production of reactive oxygen species.
By adjusting the glucose oxidase
enzyme und glucose fuel
concentrations, the assembly rates
and lifetime of the supramolecular
polymers are tuned, which dictate the
stiffness and transient stability of the
thermoresponsive hydrogels.
Daniel Spitzer, Leona Lucas Rodrigues
David Straßburger, Markus Mezger, Pol
Besenius*
Page No. – Page No.
Tuneable Transient Thermogels
Mediated by a pH- and Redox-
Regulated Supramolecular
Polymerization
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