Propagation of Enzyme-Induced Surface Events inside Polymer Nanoassemblies for a Fast and Tunable Response

Article abstract of DOI:10.1002/anie.201803029

We report a new molecular design strategy that allows for the propagation of surface enzymatic events inside a supramolecular assembly for accelerated molecular release. The approach addresses a key shortcoming encountered with many of the currently avail

Full text of DOI:10.1002/anie.201803029

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Accepted Article
Title: Propagation of Enzyme Induced Surface Events Inside Polymer
Nanoassemblies for a Fast and Tunable Response
Authors: Jiaming Zhuang, Hatice Secinti, Bo Zhao, and Sankaran
Thayumanavan
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10.1002/anie.201803029
Angewandte Chemie International Edition
COMMUNICATION
Propagation of Enzyme Induced Surface Events inside Polymer
Nanoassemblies for a Fast and Tunable Response
Jiaming Zhuang,[a] Hatice Secinti, [a] Bo Zhao, [a] and S. Thayumanavan*[a]
Abstract: We report a new molecular design strategy that allows for
propagation of surface enzymatic events inside a supramolecular
assembly for accelerating molecular release. The approach
addresses a key shortcoming in many of the current enzyme-
induced disassembly strategies, which rely on unimer-aggregate
equilibrium of amphiphilic assemblies. Programmable enzymatic
response of the host to predictably tune guest molecule release
kinetics is further achieved by controlling substrate accessibility
through electrostatic complexation with a complementary polymer.
Accelerated guest release in response to the enzyme has been
shown to be accomplished by a cooperative mechanism of enzyme-
triggered supramolecular host disassembly and host reorganization.
strategy in which the enzyme-sensitive moiety is displayed on
the surface of assembly, but the effect is transmitted to the
hydrophobic interior (Scheme 1). Our design hypothesis is that if
the molecular assembly is designed such that the enzyme-
induced interfacial event would trigger a cascade reaction to
cleave the hydrophobic interior, then the supramolecular
disassembly would occur at a substantially higher rate. This is
reasonable because the surface availability of the substrate
moiety obviates the dependence on the unimer-aggregate
equilibrium, without compromising the guest encapsulation
stability of the assembly.
Rationally designed enzyme-responsive supramolecular
assemblies that independently exhibit adaptive interfacial
behavior,
programmable
host-guest
properties
and
manipulatable morphological features have been of great
interest.[1] Since enzymes have been recognized as the primary
biological imbalance for many human pathologies,[2] assemblies
featuring these properties have been pursued for potential
applications in areas such as drug delivery, sensing, and
diagnostics.[3] In any responsive system, two of the most desired
features involve rapid and amplified response. Enzymes
inherently satisfy both these requirements, because of their
catalytic function and fast turnovers. However, enzyme
responsive nanoassemblies do not typically capture these
features, especially the fast kinetics that is characteristic of small
molecule substrates. This is mainly attributed to the limited
accessibility of deeply buried hydrophobic substrates in
amphiphilic assemblies.[1e],[1h],[4] We and others have shown that
unimer-aggregate equilibrium, between the amphiphilic
molecular constituents and its assembly, plays a critical role in
determining the reaction rates, because the enzymatic reaction
is favored to occur on unimeric state where the access to
substrate functionalities is better.[4f],[5] Though these rates can be
significantly enhanced by shifting the equilibrium towards the
unimer state, an undesired consequence is that guest
encapsulation stability of the assembly would be dramatically
Scheme 1. Propagation of a surface enzymatic event inside responsive
polymer assembly via self-immolation.
To test our design hypothesis, we chose alkaline
phosphatase (ALP) as the enzyme and amphiphilic
homopolymer, P1, as a precursor to form ALP-responsive
nanoassembly (Scheme 1).
In each repeat unit of the
homopolymer, a phosphate substrate moiety is presented as the
hydrophilic functionality, while the other components of the
repeat unit are hydrophobic. The phosphate groups are
displayed on the surface and are therefore readily accessible to
ALP. Enzymatic cleavage of the phosphate moiety would trigger
the self-immolation towards polymer backbone via 1,6-benzyl
elimination[7] degrading the hydrophobic segment. We
envisioned that this self-immolation process should convert the
amphiphilic polymer P1 to
a
hydrophilic polymer,
compromised.[4f],[5c],[6]
Thus,
simultaneously
accelerating
poly(hydroxylethylmethacrylate)
(pHEMA) and cause
supramolecular disassembly. Indeed, 1H NMR peaks
corresponding to the generation of the anticipated self-
immolation products, pHEMA and 4-hydroxyl benzyl alcohol,
were evident upon treating P1 with ALP; 31P NMR offered further
evidence for phosphate cleavage (Figure 1A). The mechanistic
pathway for degradation, involving the p-quinone-methide
intermediate, was also supported by the presence of additional
enzymatic response and maintaining stable host-guest property
of a supramolecular assembly is a significant challenge.
To address this issue, we demonstrate here a new
[a]
Dr. J. Zhuang, Dr. H. Secinti, B. Zhao, Prof. Dr. S. Thayumanavan
Department of Chemistry
1
University of Massachusetts Amherst,
Amherst, MA 01003, United States
E-mail: thai@chem.umass.edu
peaks (highlighted by arrow) in the H NMR, which correspond
to the addition of the Tris base (in the buffer) to this reactive
intermediate (Figure 1A, S1-S3). The possibility of adventitious
hydrolysis under mildly basic conditions was also ruled out
through control experiments (Figure S4).
Supporting information for this article is given via a link at the end of
the document.
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Next, since the amphiphilic P1 assembly can act as a host
for hydrophobic guests, the possibility of enzyme-responsive
guest release was investigated. P1 afforded ~8 nm assemblies
that accommodate hydrophobic fluorophores, such as perylene
(Figure S5). When this perylene-loaded assembly was subjected
to different concentrations of ALP, release of perylene from the
assembly was evident from the decreasing fluorescence; no
appreciable change in fluorescence was observed in the
absence of enzyme (Figure 1C, S6). There is a concentration-
dependent release between 2.5 nM and 12.5 nM ALP
concentration and the percent release was invariant above 12.5
nM. Interestingly, the molecular release also saturates at 45%,
which is attributed to pHEMA product’s capability to bind some
of the guest molecules.[4c],[8] This was further confirmed by
spectroscopic observation of significant encapsulation of
perylene in pHEMA homopolymer (Figure S7).
the ALP-induced supramolecular disassembly of P1 assemblies.
The presumed enzyme-induced morphological transformation,
accompanying the supramolecular disassembly of P1
assemblies, seems to be the effect of limited solubility of
pHEMA.[4c],[8] At the beginning of enzymatic reaction pHEMA
concentration was low enough to solubilize in solution (observed
as size decrease in the first 30 minutes), while it starts to form
large structures as its concentration builds up in the reaction
mixture (Figure S8).
Figure 2. A) Structure of coumarin containing phosphate polymer, P2; B) UV-
vis spectra of P2 and crosslinked P2; C) Dephosphorylation of assembly by
chromogenic assay; D) Perylene release in the presence of 3 and 18 nM ALP.
.
The results above show that the host character of P1
assembly can be compromised by ALP and that the response is
quite fast. However, this does not rule out the possibility that the
enzymatic reaction does still depend on the unimer-aggregate
equilibrium. To test this possibility, photo-crosslinkable coumarin
moieties were incorporated into the polymer P2 in such way that
the equilibrium micelle-like aggregate state can be locked by
photo-crosslinking the assembly (Figure 2A). If similar
phosphate degradation kinetics were observed for both
crosslinked and non-crosslinked P2 assemblies, then it is
reasonable to conclude that the unimer state is not required for
accessing the phosphate moieties. First, the P2 assembly was
characterized in aqueous solution and was found to form
assemblies with size of ~8 nm (similar to P1). The P2 assembly
was further subjected to photo-irradiation (λ= 360 nm) to
crosslink the assembly.[10] The degree of photo-crosslinking was
found to be ~40%, as assessed by the decrease in coumarin
absorbance (Figure 2B). The susceptibility of crosslinked
assemblies toward ALP was monitored using 31P NMR, as well
as by DLS (Figure S11,12). The degree of dephosphorylation
was further quantified by directly following production of
phosphate ions using a chromogenic assay[4c] (Figure 2C). We
were gratified to find that the dephosphorylation rates were
independent of whether the assemblies are crosslinked. This
observation supports our design hypothesis that polymer
degradation occurs at the surface of the nanoassembly.
Figure 1. A) ALP-induced self-immolation of P1 followed by 1H and 31P NMR
(blue: P1 treated with ALP for 60 min, red: P1 without ALP); B) DLS and TEM
images of P1 assembly; C) ALP concentration dependent perylene release .
In order to draw a direct correlation between ALP-triggered
host disassembly and guest release, transformation of the host
was also monitored by dynamic light scattering (DLS) (Figure
S8). A slight decrease in size was observed at the beginning of
enzymatic reaction (30 minutes), followed by a significant size
increase after 1 h.[9] This possible morphological transformation
was then characterized by TEM (Figure S9). It is clear that P1
assemblies transformed from a fairly spherical micelle-like
structure to irregular assemblies at the first 30 minutes. These
assemblies seemed to aggregate to form large secondary
nanoassemblies after 1 h, which is likely to be responsible for
the apparently incomplete guest release. To further evaluate the
nature of these large secondary nanoassemblies, these were
collected as a precipitate by ultracentrifugation and analyzed by
NMR. 1H NMR clearly shows that these large aggregates are
solely based on the pHEMA byproduct (Figure S10). The
supernatant contained the small molecule by-products and some
pHEMA as well. The supernatant was further subjected to DLS
measurement (Figure S10), which showed very small
assemblies of ~2 nm, which is likely due to single chain pHEMA.
We were gratified to observe the presence of pHEMA after the
enzymatic reaction in both phases, as it is a direct indication of
The impact of the crosslinking upon guest release was
subsequently investigated. No significant difference on release
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kinetics was observed between crosslinked and non-crosslinked
determined the overall concentration of the phosphate substrate
moieties in solution. Both NC and PC complexes exhibited
P2 assemblies when they were incubated with 18 nM ALP
(Figure 2D, S13), as observed with the dephosphorylation assay. slower kinetics, relative to P2 alone, suggesting compromised
At 3 nM ALP, the guest release was only slightly faster in the
non-crosslinked counterpart. This suggests that there is a subtle
difference in the influence of crosslinks on molecular release.
Because the difference is small, it makes no difference at higher
enzyme concentrations. Interestingly, release extents for both
crosslinked and non-crosslinked P2 nanoassemblies saturate at
~40%. This observation is consistent with the fact the product of
the enzymatic reaction of the fully converted P2 and crosslinked
P2 is the same, pHEMA. which is capable of sequestering a
smaller percentage of this guest molecule.
substrate accessibility by complexation (Figure 3D).
Dephosphorylation in NC complexes was however much faster
and more complete, compared to the PC complexes. This is
understandable, because although both complexes have
phosphate substrates that are masked by pDADMAC, the NC
complexes have a significant number of phosphate groups
available on the surface for the initial reaction. On the other
hand, in PC, since the surface is dominated by pDADMAC, the
substrate availability is small. Among NCs, kinetics and extent
substrate accessibility was also found to be size-dependent,
likely due to the more buried and efficiently covered phosphate
moieties by P3 in bigger particles and the higher surface area of
the smaller particles. Smaller particles had faster enzymatic
reaction as indicated by the dephosphorylation kinetics.
Interestingly, dephosphorylation of PC-2 (P3:P2 ratio of 1.83)
was slower than PC-1 (P3:P2 ratio of 1.22) despite the smaller
size of PC-2. This observation is attributed to the more efficient
coverage by pDADMAC at higher ration in PC-2. This
programmability can be further translated to tunability in guest
release. When tested for perylene release in the presence of
ALP, the kinetics and extent of guest release were consistent
with the dephosphorylation behavior of these complexes (Figure
3E, S15). Smaller difference in guest release than that in
desphosphorylation degree between NC1 and PC1 is attributed
to the different host-guest capabilities of the reorganized
enzymatic products of these two complexes.
Figure 3. A) Schematic illustration of electrostatic complexation; B) Size of the
complexes; C) Zeta potential of the complexes; D) dephosphorylation kinetics;
E) Perylene release profile of complexes. Note: dephosphorylation and
release kinetics in longer time scale shown in Figure S16 .
Next, we were interested in testing whether these
assemblies can be programmed to control the degree of enzyme
accessibility, as this provides an inherent tunability that is
desired in any such molecular design. The accessibility of ALP
to phosphate substrates can be tuned using an interfacial barrier
aided by electrostatic complexation (Figure 3A). Accordingly,
crosslinked P2 assembly was treated with cationic polydiallyl-
dimethylamonium chloride (P3, pDADMAC). We targeted two
types of complexes, both prepared by simply mixing P2 and P3.
These are designed to be negatively charged (NC) or positively
charged (PC) complexes based both on the relative
stoichiometry of the two polymers and their order of addition.
The weight ratio of P3/P2 in final complexes NC-1 to NC-4 was
0.088, 0.132, 0.176 and 0.264, while the ratio for PC-1 and PC-2
were 1.22 and 1.83. The DLS-based solution size of all
complexes, except PC-2, were understandably bigger (90-400
nm), relative to P2 (Figure 3B). The size of PC-2 was found to
be ~10 nm, which is taken to suggest that a single P2 assembly
is fully coated by pDADMAC at this higher ratio, thereby
Figure 4. A) Time-dependent size evolution of NC-1 triggered by ALP; B) TEM
images of ALP-treated NC-1 at corresponding time point; C) Time-dependent
size evolution of PC-1 triggered by ALP; D) Corresponding TEM images of
ALP-treated PC-1. Note: no ALP was added in 0 h and full TEM images are
included in Figure S17&18.
Supramolecular transformation of complexes following
enzymatic reaction was investigated using NC-1 and PC-1.
When investigating the PC-complexes, we observed that a
drastic size decrease and morphological transformation of PC-1
was induced by ALP dephosphorylation between 3 and 6 hours
(Figure 4C,D & S18). The uniformly spherical structures of PC-1
was compromised and transformed into irregular assemblies
with much smaller size. In absence of ALP, the PC-1 complex
was found to be stable during this time, as indicated by the
constant size and negligible morphological evolution of the
producing only
a
small size increase. Zeta potential
measurements confirmed the surface charge of these
complexes (Figure 3C).
Substrate accessibility in these complexes was
investigated by measuring the kinetics of dephosphorylation,
where the concentration of P2 was kept constant, as this
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upon the ALP-induced transformations. As shown in Figure 4A,
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were also observed in the same sample after 3 hours, which
remained stable at longer time periods also (Figure S17). The
ALP-induced morphological transformation of the complexes is
likely due to the change in the ratio between cationic polymer
and anionic particles during dephosphorylation process, where
anionic particles decrease with time without any effect on the
cationic polymer. NC-1 itself without ALP remained same size
and morphology for more than 24 hours, suggesting the complex
itself is quite stable (Figure S17).
In summary, a novel molecular design that places enzyme-
responsive moieties on the surface of supramolecular
assemblies can be used to cause enzyme-induced disassembly
to occur at substantially high rates. In this study, we have shown
that (i) the molecular design overcomes a key shortcoming in
many of the current enzyme-induced supramolecular
disassembly strategies, which rely on the unimer-aggregate
equilibrium. (ii) Self-immolation strategies can be used to
propagate a molecular event on the surface inside a molecular
assembly and compromise its host-guest properties by means of
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disassembly
and
reorganization.
(iii)
Electrostatic complexation with a complementary polymer can
be utilized to control the surface accessibility of the enzymatic
substrates, which provide programmability in the kinetics and
extent of molecular release from these nanoscopic hosts. The
molecular design strategies outlined here could form the basis
for designing next generation nanoassemblies for biosensing
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Acknowledgements
We thank the U.S. National Science Foundation (CHE-1740597)
for support and TUBITAK fellowship form Turkish Goverment
visting scientist fellowship for HS. We thank Bin Liu for providing
pHEMA homopolymer.
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Keywords: Enzyme responsive polymer • Self-immolation •
Self-assembly• Host-guest properties • Electrostatic complexes
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COMMUNICATION
COMMUNICATION
Enzyme-induced disassembly
strategies typically rely on unimer-
aggregate equilibrium of amphiphilic
assemblies, which results in slow
response. This issue has been
addressed by directly propagating a
surface enzymatic reaction to interior
of the supramolecular assembly
through self-immolation.
Jiaming Zhuang, Hatice Secinti, Bo
Zhao, S. Thayumanavan*
Page No. – Page No.
Propagation of Enzyme Induced
Surface Events inside Polymer
Nanoassemblies for a Fast and
Tunable Response
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