Multi-Stimuli-Responsive Directional Assembly of an Amphiphilic Donor–Acceptor Alternating Supramolecular Copolymer

Article abstract of DOI:10.1002/chem.201803170

The stimuli-responsive supramolecular co-assembly of two π-amphiphiles, NDI-1 and Py-1, in which an acceptor (A) (naphthalene diimide) and a donor (D) (pyrene) chromophore, respectively, serve as the hydrophobic segment, is described. In addition, both contain an amide group in a designated location so that H-bonding and D–A charge-transfer (CT) interactions can operate simultaneously. H-bonding among the amide groups not only enhanced the CT interaction promoted by the alternating D–A stacking propensity, but also fixed the lateral orientation of the two chromophores and thus compelled the anionic and nonionic hydrophilic head groups, appended with the D and A amphiphiles, respectively, to remain segregated on two opposite sides of the amphiphilic alternating supramolecular copolymer. This copolymer showed spontaneous polymersome assembly with the D-appended anionic groups displayed at the outer surface, whereas the A-appended hydrophilic wedge converged at the inner lacuna. In contrast, spherical or cylindrical micellar structures were produced by Py-1 and NDI-1, respectively. Effective functional-group display in the D–A supramolecular polymersome enabled protein-surface recognition and inhibition of the enzymatic activity of Cht. Under a reducing environment, formation of NDI^.? jeopardized the D–A interaction and thus the A chromophores were ejected out of the membrane of the polymersome causing its gradual contraction in size by >75 %. D–A supramolecular polymersomes also exhibited a lower critical solution temperature that could be tuned across a temperature window of 40 to 70 °C by varying the ratio of the A and D components in the alternating supramolecular copolymer.

Full text of DOI:10.1002/chem.201803170

A Journal of
Accepted Article
Title: Multi-stimuli Responsive Directional Assembly of Amphiphilic
Donor-Acceptor Alternating Supramolecular Copolymer
Authors: Suhrit Ghosh, Saptarshi Chakraborty, Debes Ray, and Vinod
K Aswal
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201803170
Link to VoR: http://dx.doi.org/10.1002/chem.201803170
Supported by

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Multi-stimuli Responsive Directional Assembly of Amphiphilic
Donor-Acceptor Alternating Supramolecular Copolymer
[a]
[b]
[b]
[a]
Saptarshi Chakraborty, Debes Ray, Vinod K. Aswal, and Suhrit Ghosh*
Abstract:
This
manuscript
describes
stimuli-responsive
functional groups, but at the same time brings new opportunities
[
2a]
supramolecular co-assembly of two π-amphiphiles NDI-1 and Py-1 in
as they exhibit responsive nanostructures
with rich
Two-component amphiphilic
systems including donor (D)-acceptor (A) type π-chromophores
[
3b, 3l]
which an acceptor (A) (naphthalene diimide) and a donor (D)
photophysical properties.
(pyrene) chromophore, respectively, serve as the hydrophobic
[
4]
segment. In addition both contain an amide group in designated
location so that H-bonding and D-A charge-transfer (CT)-interaction
can operate simultaneously. H-bonding among the amide groups not
only enhanced the CT-interaction promoted alternating D-A stacking
propensity, but also fixed the lateral orientation of the two
chromophores and thus compelled the anionic and non-ionic
hydrophilic head groups, appended with the D and A amphiphiles,
respectively, to remain segregated in two opposite sides of the
amphiphilic alternating supramolecular copolymer. It showed
spontaneous polymersome assembly with the D-appended anionic
groups displayed at the outer surface while the A-appended
hydrophilic wedge converged at the inner lacuna. In contrast,
spherical or cylindrical micellar structures were produced by Py-1
and NDI-1, respectively. Effective functional group display in the D-A
supramolecular polymersome enabled protein surface recognition
and inhibition of the enzymatic activity of Cht. Under reducing
have also been studied. We have recently demonstrated
vesicular assembly of NDI-derived unsymmetric bola-shape π-
amphiphiles with H-bonding regulated distinct functional group
[5]
display at the inner and outer surface of the vesicle. We
envisaged extending such supramolecular designs from single
to two/ multi-component amphiphilic systems would further
enhance the complexity and functional value of these emerging
nanostructures. In fact two component D-A systems have been
extensively used as complementary supramolecular building
[
6]
blocks as they form charge-transfer (CT) complex
through
alternating stack. However, weak binding constant of majority of
[
7]
the D-A complexes has been the major limitation. To
circumvent this issue, we have designed amide group appended
D and A chromophores (Py-1 and NDI-1 in Scheme 1) with pre-
[
8]
estimated matching spacer lengths between the chromophores
and the amide group so that they could exhibit H-bonding
assisted alternating D-A supramolecular copolymerization in
water with long range order. NDI-1 contains the electron
deficient naphthalene diimide (NDI) chromophore, to which a
benzamide group and a hydrophilic wedge are attached in its
two opposite arms. On the other hand, in Py-1, the donor
chromophore though is similarly attached with a benzamide
group, the hydrophilic part consists of the carboxylic acid groups
which are expected to be de-protonated under basic condition.
•
–
environment, formation of NDI jeopardized the D-A interaction and
thus the A chromophores were ejected out of the membrane of the
polymersome causing its gradual contraction in size by >75 %. D-A
supramolecular polymersome also exhibited lower critical solution
temperature which could be tuned across a temperature window of
40 °C to 70 °C by varying the ratio of the A and D components in the
alternating supramolecular copolymer.
Introduction
Stimuli-responsive aggregation of amphiphilic polymers have
been studied extensively as they offer multiple advantages over
[
1]
small molecule surfactants in context of biological applications.
More recently, amphiphiles containing π-systems have emerged
[
2-3]
as a distinct class which holds the properties of polymeric
amphiphiles such as low critical aggregation concentration,
particle size in the range of 100 nm and multivalent display of
[
[
a]
b]
Mr. Saptarshi Chakraborty and Prof. Dr. Suhrit Ghosh
Polymer Science Unit
Indian Association for the Cultivation of Science
Scheme 1. Structure of the amide-appended donor and acceptor type π-
amphiphiles and control molecule NDI-2
2A and 2B Raja S. C. Mullick Road, Kolkata, India-700032
E-mail: psusg2@iacs.res.in
Dr. Debes Ray and Dr. V. K. Aswal
Solid State Physics Division,
Bhaba Atomic Research Centre
Trombay, Mumbai, India-400085
Due to the involvement of the amide groups, it was anticipated
that in the H-bond assisted alternating stack, the lateral
orientation of the NDI and the pyrene chromophores would be
fixed, resulting in segregation of the appended functional groups
in two opposite sides of the wall. In this article we reveal multi-
Supporting information for this article is given via a link at the end of
the document.
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Chemistry - A European Journal
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[
9]
stimuli (temperature and redox) responsive polymersome
with the size obtained from TEM for the spherical assemblies of
Py-1 or NDI-1 + Py-1, but in case of the anisotropic structure of
NDI-1, no attempt was made to correlated the size obtained
from DLS and TEM as the DLS data was obtained by collecting
the scattering at a single angle.
assembly of this alternating supramolecular D-A copolymer with
precise internal order and impact on functional group display
and enzyme activity inhibition.
Small-angle neutron scattering (SANS) studies: To further
analyze the nanostructure in detail, SANS studied were
Results and Discussion
[
11]
performed.
The SANS data have been shown in Figure 2 and
the fitted parameters in Table 1. Py-1 aggregated sample was
found to consist of spherical micelles whereas NDI-1 formed
cylindrical micelles. On the other hand, the data for the mixed
system of NDI-1 + Py-1 (1:1) was well-fitted and analyzed using
a model of a spherical shell for unilamellar vesicles. The
scattering intensity in the low-Q region of the data for NDI-1 and
NDI-1 + Py-1 (1:1) decreased in almost a straight line with a
D-A Composition dependent nanostructure: Aqueous
solution (pH 9.0) of NDI-1 + Py-1 (1:1) revealed a deep red color
(
inset, Figure 1a) indicating formation of the CT-complex with a
critical aggregation concentration of 0.08 mM.
2
slope of (−1) [as 1/Q] and (−2) [as 1/Q ], thus indicated the
formation of cylindrical micelles and vesicles, respectively. The
absence of lower cut-offs in the data indicated that the length of
the cylinder and size of the vesicle are larger than what can be
determined from the accessible Qmin of the instrument and
therefore these two parameters have been kept fixed higher
than to a value 2π/Qmin, i.e., ≈ 350 Å. The cylindrical micelle was
characterized by the cross-sectional radius whereas the vesicle
by the membrane thickness (Table 1).
Figure 1. TEM images of a) NDI-1+Py-1 (1:1) b) NDI-1 and c) Py-1. Insets
show the picture of the vial in each case. In all cases aqueous solution (pH 9)
of the compound (s) (C = 0.5 mM) was drop-casted on a carbon-coated Cu-
grid and was stained with 2 % uranyl acetate solution and dried before
imaging. d) DLS profile of the individual components and their 1: 1 mixture (C
=
0.2 mM) in water (pH = 9.0).
Figure 2. Plot of scattering intensity as a function of scattering vector Q for Py-
1, NDI-1 and NDI-1 + Py-1 (1:1).
Transmission electron microscopy (TEM) images (Figure 1a, S1)
showed spherical objects with diameter in the range of 80-110
nm, typically observed for polymersome. Interestingly the
morphology of the individual components was found to be
distinctly different than that of the mixed D-A assembly. NDI-1
showed (Figure 1b, S1) 1D entangled fibrillar structure with
diameter of the individual fibers ranging between 50-100 nm and
produced a hydrogel (inset, Figure 1b) as reported by us
Table 1. SANS data of the different self-assembled structures
System
Py-1
Structural parameters
Radius = 10.2 Å
Morphology
Spherical micelles
Cross-sectional radius = 32.5 Å
Length of the cylinder > 350 Å
Vesicle thickness= 18.8 Å
Size of Vesicle > 350 Å
NDI-1
Cylindrical micelles
Py-1 + NDI-1
Unilamellar
vesicles
[
10]
before. In contrast aggregation of Py-1 generated (Figure 1c,
S1) relatively smaller particles with diameter in the range of 20-
(1:1)
4
0 nm and remained as a colorless sol (inset, Figure 1c).
Dynamic light scattering studies (Figure 1d) showed a sharp
single peak for the 1:1 mixture with average D = 120 nm which
was distinctly different from the peaks for the individual
components corresponding to D = 530 nm and 50 nm,
respectively, for NDI-1 and Py-1. The DLS results corroborated
Spectroscopy studies: UV/Vis absorption spectra of NDI-1 +
Py-1 (1:1) in water showed (Figure 3a) a broad absorption band
h
(λmax = 550 nm) which confirmed formation of the CT-complex
h
[
6]
between NDI and Py.
However in THF, no such band
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appeared indicating the CT-complex formation was driven by
hydrophobic association of the chromophores in water. The
band intensity at λmax was monitored as a function of the D/A
ratio (Figure S2) which revealed (Figure 3b) maximum intensity
at 1:1 mixture indicating perfect alternating assembly of the NDI
and Py chromophores. Association constant of the CT-complex
To directly probe H-bonding, FT-IR spectra of NDI-1+Py-1 (1:1)
in water was compared with those of the individual components
in monomeric state in THF (Figure 5a). For the CT-complex in
-1
water, several peaks appeared in the region of 1650-1800 cm
which could be assigned to carboxylic acid C=O, ester C=O, and
asymmetric imide C=O. However for NDI-1 in THF, there is an
4
-1
-1
was estimated to be 0.9 x 10
M
at 298 K from the
intense peak at 1672 cm which was assigned to the symmetric
concentration dependent UV/Vis spectra (Figure S3) using
literature reported procedure.
imide C=O together with the amide C=O. In the CT-complex,
the band appeared as a broad one and the maximum peak
[
12]
-1
intensity shifted to 1640 cm indicating the amide groups were
engaged in H-bonding in the alternating stack of NDI and Py
chromophores. It was further evident by urea-mediated
disassembly experiment which showed gradual decrease of the
CT-absorption band intensity to > 80 % in presence of urea
(
Figure 5b). Urea is common protein denaturing agent and
[14]
known to jeopardize the secondary structure of proteins
due
to its ability to interfere with the H-bonding network. Therefore
urea-mediated disassembly can be considered as an indirect
additional evidence for the decisive role of H-bonding on the
vesicular assembly of the present D-A pair.
Figure 3. a) Solvent dependent UV/Vis absorption spectra (selected region) of
NDI-1 + Py-1 (1:1) (C = 5.0 mM) showing the appearance of the CT-band in
water. b) Job’s plot constructed by variation of the band intensity at 550 nm as
a function of D/A stoichiometry showing maximum at 1:1 ratio.
To further probe the CT-complex, isothermal titration calorimetry
(
ITC) experiment (Figure 4) was performed where a solution of
Py-1 was gradually injected to a solution of NDI-1. At each
successive addition of the donor to the acceptor, the heat
change (∆H) indicated formation of the CT-complex which was
saturated at approximately 1:1 D/A ratio. The data could be well
[
13]
fitted with a 1:1 binding model
which revealed the K
and thus corroborated satisfactorily with the value
obtained from the UV/Vis experiment. From the ITC experiment
H and ∆S were estimated to be -1.13 Kcal/ mol and -19.2
a
= 1.3 x
Figure 5. a) FT-IR spectra (selected region) of NDI-1 and Py-1 in THF and
4
-1
10
M
their mixture in NaOD in D O (C = 5 mM). b) Gradual decrease of the CT-band
2
intensity of NDI-1 + Py-1 (1:1) (C = 1.0 mM) in water in presence of urea (200
mg). A minor negative absorption at ~ 470 nm in the black spectrum could be
related to the change in the baseline intensity during the experiment.
∆
cal/mol/deg, respectively, indicating an enthalpy driven
spontaneous assembly.
Figure 4. a) ITC binding experiment for titration of NDI-1 (c=0.25 mM) into
solution of Py-1 (2.5 mM) with 2µl x 20 aliquots at T = 25 °C in pH 9 buffer
solution, b) Fitting the data set with 1:1 binding model. In addition to the major
peaks, there is a small heat release associated with each injection. A titration
of the acceptor alone revealed (Figure S4) no significant heat release in the
same concentration window and therefore confirms this small heat change is
not associated with the disassembly of the NDI-1 prior to its binding with Py-1.
However the reason for this heat change could not be understood at the
moment.
1
Figure 6. Solvent dependent H-NMR spectra (selected region) of NDI-1 + Py-
1
(1:1) (C= 5.0 mM).
The π-stacking was evident from solvent dependent NMR
spectroscopy (Figure 6) studies. In a good solvent DMSO-d6,
sharp peaks were noticed in the region of : 7-11 ppm due to the
presence of aromatic protons of the NDI and pyrene
4
-1
chromophores in monomeric state. In NaOD-D O, several of
these peaks merged and appeared as broad peaks in
2
It is noteworthy that the observed K
is remarkably high in context of D-A CT-complex
a
value in the order of 10 M
[
6]
which is
believed to be the consequence of H-bonding assisted assembly.
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significantly up-field region which can be attributed to the
shielding effect in the alternating D-A stack.
To examine the importance of H-bonding, we also examined
(Figure S5) co-assembly of Py-1 with a control molecule NDI-2
(
Scheme 1) that contains an ester group instead of amide. In
this case, extended H-bonding is not possible in the alternate D-
stacking and thus self-assembly features should differ
significantly if H-bonding is indeed important as depicted in
Scheme 2It was noticed that the aggregate size (average D
Based on the results obtained from the TEM, DLS, SANS,
UV/Vis, FT-IR and NMR studies, a possible model for the
supramolecular assembly of the NDI-1, Py-1 and their mixture is
depicted in Scheme 2. The non-ionic NDI-1, undergoes a
supramolecular polymerization by H-bonding to produce
cylindrical micelle and their entanglement at higher
concentration leads to the formation of hydrogel. On the other
hand, for Py-1, due to the presence of the anionic head groups,
charge repulsion inhibits elongation; rather in this case a
spherical micelle is formed in which the hydrophobic pyrene
chromophores stack with a rotational displacement to produce
the core of the micelle. For 1: 1 mixture of NDI-1 +Py-1,
alternating stack (as evident from the intense CT band) involving
the H-bonding can only occur through a particular lateral
orientation of the two components that segregates the non-ionic
wedge and the anionic head groups in two different arms of the
A
h
)
reduced to 70 nm in contrast to 120 nm for Py-1 + NDI-1. The
CT-band intensity also reduced by ~ 50 % and more importantly
the zeta potential was found to be only -10 mV (instead of -35
mV for Py-1 + NDI-1) suggesting lack of efficient display of the
anionic groups. Therefore it is evident that H-bonding plays a
decisive role in self-assembly and controlling the lateral
orientation of the two chromophores resulting in efficient display
of functional groups.
Enzyme activity inhibition: We sought to examine the ability of
the anionic vesicle for electrostatic interaction based
reorganization of α-chymotrypsin (Cht) having cationic surface
[
15]
alternating D-A stack. Now from TEM and SANS experiments
it is clear that this alternating copolymer (resembling with
polymerized unsymmetric bola-amphiphile) forms a vesicular
structure. In principle, it can form two types of vesicles (Scheme
h
charge. DLS profile (Figure S6) of Cht showed a peak with D <
10 nm while that for the polymersome appeared at ~ 120 nm.
Both of these peaks disappeared in their mixture and in lieu, a
new peak appeared at ~ 170 nm indicating effective binding of
the protein to the polymersome surface. To test its impact,
activity assay was performed with N- Succinyl-L-Phenylalanine-
p-nitroanilide (SPNA) (Figure 7) as a chromogenic substance
which produces p-nitro aniline (λmax = 405 nm) by enzymatic
2) depending on the direction of curvature. For type-1, the non-
ionic wedge should be displayed at the outer surface while for
type-2, the anionic groups should be at the outer surface while
the wedge should be at the core. However, the zeta potential (ξ)
measurement revealed highly anionic surfaced with = -35 mV,
clearly suggesting the anionic groups are displayed at the outer
surface and thus confirmed formation of type-2 vesicle. This is
also intuitively conceivable as in this case the charge-charge
repulsion is expected to be relatively less severe compared to
type-1 where the charge repulsion would have been maximum
due to close proximity of the carboxylate groups in the core of
the vesicle. The thickness of the membrane estimated by SANS
studies (Table 1) matches with the length of the hydrophobic
domain of the alternately stacked D-A chromophores and thus
supports the model depicted in Scheme 2.
[
16]
hydrolysis of Cht. Therefore, to probe the enzymatic activity,
the change in the absorption intensity at 405 nm was monitored
(Figure 7a) as a function of time after addition of a solution of
SPNA to a solution of Cht, pre-incubated with NDI-1 + Py-1 (1:1)
in buffer (pH 9). Similar experiment in the absence of CT-
complex was performed which served as the control and the
activity in this case was considered as 100 %. It was found that
in presence of the D-A vesicle, the activity of Cht was drastically
reduced by >85 %. In fact the ability of the vesicular assembly to
inhibit the enzyme activity was found to be significantly superior
than that of the micellar aggregate of Py-1 which also had a
negatively charged surface but with a significantly lesser zeta
potential value (-15 mV) than that of the vesicle (-35 mV).
Figure 7. a) Concentration versus time plot of p-nitroaniline produced during
enzymatic hydrolysis of SPNA in the presence of Cht (8 µm) after incubation
with NDI-1 or Py-1 or NDI-1+Py-1 (1 mM) or without any chromophore at pH 9
buffer. b) Activity of α-chymotrypsin
Scheme 2. a) Schematic showing different nanostructure formation by NDI-1,
Py-1 and NDI-1 + Py-1 (1:1)
On the other hand, for the non-ionic hydrogel of NDI-1, the
enzymatic activity mostly retained as anticipated due to lack of
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any negatively charged surface in this case. CD spectra (Figure
S7) of vesicle treated Cht showed no sign of denaturation and
therefore confirmed that the observed activity inhibition was not
a consequence of denaturation of the protein during the course
of the experiment. It is noteworthy that Cht activity inhibition to
an extent of >85% ranks among the most efficient systems
with addition of the Na
2
S
2
O
4
while a gradual decrease of the
particle size was noticed (Figure 8c) with increasing amount of
the reductant. Initially the particle size was > 250 nm for the
polymersome which reduced to ~ 100 nm in presence of 1.0
equivalent of Na S O and subsequently it started decreasing
2 2 4
further and eventually saturated at around 30-40 nm at the end
[16]
• –
reported in the past
including amphiphilic polymer aggregates, of the titration when the formation of NDI also showed some
organic nanotubes, cyclic peptide assemblies, dendrimer
assemblies, nanoparticles or graphene oxide nanosheet. It is
postulated that in addition to the effective surface functional
group display, close vicinity of the -surface (array of substituted
phenyl rings) to the negative charges further facilitates effective
interaction of the D-A vesicles with the protein surface by
electrostatic and hydrophobic interaction as the protein surface
also contains hydrophobic patches around its active site.
kind of saturation as per the spectral changes observed in the
UV/Vis titration. It possibly indicates, by chemical reduction
•
–
when the NDI chromophore is converted to NDI , repulsion from
the adjascent pyrene donor ejects the radical anion out of the
membrane resulting in change in its composition (D/A ratio).
•–
With more and more production of the NDI , the membrane
becomes richer with the pyrene chromophore, appended with
anionic head groups, and thus the enhanced electrostatic
repulsion might have reduced the radius of curvature causing
shirnkage of the vesicle as observed by DLS measurement.
Multi-stimuli responsive assembly: Multi-stimuli responsive
[
1, 17]
assemblies
of amphiphiles have been studied with great
interest owing to their relevance in biological applications in
context of triggered release. We examined the fate of the
present D-A supramolecular polymersome with response to
[
18]
biologically relevant redox stimuli
considering the
susceptibility of the CT-complexes against redox-state of the
[
7, 19]
D/A chromophore.
NDI chromophore, being electron
[
20]
deficient in nature, can be easily reduced to its mono-anion.
It
was anticipated that unlike the parent chromophore, the reduced
derivative would not be able to act as an acceptor anymore and
therefore the membrane constructed by alternating D-A
assembly could be ruptured. To test these possibilities, the D-A
supramolecular polymersome was treated with a reducing agent
2 2 4 2 2 4
Sodium dithionate (Na S O ). With addition of Na S O , the color
of the solution immediately changed to deep red indicating the
redox-responsiveness of the chromophoric assembly. With
subsequent addition of an oxidizing agent Ceric ammonium
nitrate (CAN), the original light orange color of the solution
reappeared suggesting reversible redox-responsiveness (Figure
8
a). To further elucidate this phenomenon, UV/Vis spectra of
NDI-1 + Py-1 (1:1) were examined with gradual addition of
Na (Figure 8b). The spectrum of the solution before
2
2 4
S O
addition of the reducing agent showed intense absorption bands
in the UV region (300-400 nm) due to the presence of the NDI
and pyrene chromophores and a less intense characteristic
broad CT-band in the visible region (λmax = 550 nm). With
increasing amount of added Na S O , several new peaks
2 2 4
appeared in the visible-NIR region having λmax at 452, 490, 531,
and 576 nm with concomitant reduction of the peak intensity in
Figure 8. a) Colorimetric change of NDI-1 + Py-1 (1:1) (C = 1.0 mM) from light
brown to dark brown by addition of 2.0 equivalent of Na S O and
2 2 4
reappearance of light brown color in presence of 2.0 equivalent of CAN. b)
Variation of the UV-Vis spectra NDI-1 + Py-1 (1:1) (C = 1.0 mM) by gradual
3
00-400 nm region which indicated generation of NDI radical
[
20-21]
anion.
Electron Paramagnetic Resonance (EPR) studies
(
inset, Figure 8b) of the solution produced at the end of the
addition of Na
reduced solution at the end of the titration; c) Variation of the DLS profile of
NDI-1 + Py-1 (1:1) (C = 1.0 mM) by gradual addition of Na ; Inset-
2 2 4
S O ; Inset- EPR spectra at 195 K of the sample taken from the
titration showed a typical signal that confirmed presence of
•
–
paramagnetic NDI . To check reversibility, CAN was added to
the solution at the end of the titration while the spectrum
changed immediately and appeared similar to the original one
2 2 4
S O
Particle size variation with increasing amount of the reducing agent. pH= 9 for
all studies. Larger size of initially formed vesicle in this case (compared to DLS
shown in Figure 1d) is attributed to higher concentration.
(
Figure S8) confirming the reversibilty of the process
corroborating with the visual color change (Figure 8a). To
examine the impact of reduction of the NDI acceptor on the D-A
polymersome structure, DLS measurmenets were carried out
As appeared from the data shown in inset-Figure 8c, with
addition of > 1.0 equiv of the reductant the size reducation
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became more prominent and eventually produced particle with Conclusions
size comparable to micellar structure of Py-1. In fact TEM
images (Figure S9) of the sample prepared from the Na
treated NDI-1 + Py-1 (1:1) solution at two different stages of the
titration revealed significant change of the initial vesicular
assembly. With 1.0 equivalent Na S O (incomplete reduction),
2 2 4
the vesicle size reduced to ~ 50 nm whereas at the end of the
titration irregular spherical particles with much smaller diameter
2
S
2
O
4
Overall, in this manuscript we have shown multi-stimuli
responsive polymersome assembly of alternating amphiphilic D-
A copolymer while the D and A components individually formed
spherical and cylindrical micelle, respectively. D-A CT-
interaction has been utilized in the past to construct various
[
24]
elegant supramolecular systems including foldamers,
supra-
[
25]
[23d, 26]
[6]
(
20-40 nm) were noticed which corroborates with the DLS
amphiphiles,
gels,
and others. Nevertheless the
results confirming redox responsiveness of D-A polymersome
assembly.
present system brings important new features to this age old
supramolecular assembly motif. First of all, due to the presence
of the single amide functionality in the D and A chromophores,
H-bonding comes to the fore which not only enhances the
binding constant but more importantly controls the directionality
in lateral orientation of the two chromophores. Consequently, the
functional groups attached to the D and A chromophores remain
projected in opposite directions to each other. This made an
unsymmetric polymersome with the D-appended anionic groups
diverged at the outer surface to minimize electro-static repulsion.
Such directional assembly helped in efficient functional group
display and protein surface recognition enabling very effective
enzymatic activity inhibition of Cht to > 85 %. In presence of a
Figure 9. a) Temperature depending variation in absorbance at 750 nm of
dispersion of NDI-1 + Py-1 at various ratios as indicated. Total concentration
remains same as 1.0 mM in all cases and pH = 9. b) Tunable cloud point
depending on D/A ratio in the supramolecular copolymer.
•–
reducing agent, formation of NDI destroyed the D-A CT-
interaction and resulted in expulsion of the NDI chromophore (in
reduced form) from the membrane causing its gradual shrinkage
and eventually conversion to small micellar particle consisting of
only/ largely the donor chromophore. It also showed thermo-
Covalent polymers with pendant oligo-oxyethylene chains are
well known for exhibiting a lower critical solution temperature
responsiveness with tunable LCST over
a rather wide
temperature window (40 °C to 72 °C) depending on the ratio of
the D and A components in the supramolecular copolymer.
Considering the directionality, distinct functional groups display
at the inner and outer membrane and reversible multi-stimuli-
responsive changes in the structure, the present D-A
nanostructure assembly should be of interest to in context of
multi-valent effect, targeting and delivery of therapeutics which
are underway in our laboratory.
[
22]
(
LCST)
which has also been demonstrated in limited recent
[2b, 17, 23]
examples of supramolecular polymers.
To test any such
thermo-responsive property of the D-A supramolecular
polymersome, aqueous dispersion of NDI-1 + Py-1 (1:1) was
gradually heated from 25 °C to 95 °C and the intensity at 750 nm
was monitored as a function of temperature (Figure 9a). At
about 70 °C, the absorption at 750 nm started increasing
abruptly indicating this to be the LCST. The enhanced intensity
of the absorption at 750 nm (chromophores do not have any
absorption in this wavelength) is attributed to scattering due to
the increasing turbidity of the medium beyond LCST. TEM
image (Figure S10) of the sample prepared from drop-casting a
hot solution (T > LCST) showed absence of any nano-vesicles,
instead significantly larger particles were seen indicating
collapse of the vesicular structure and their coagulation above
LCST. NDI-1 also showed LCST but at much lower temperature
Experimental Section
Materials and Methods: All the reagents were received from Sigma
Aldrich Chemical Co. and used without further purification. Solvents were
[27]
purchased from commercial sources and purified by reported protocol.
1
Spectroscopy grade solvents were used for physical studies. H NMR
and C NMR experiments were done on a Bruker DPX-400 MHz and
00 MHz NMR machine and all the data were calibrated against TMS.
13
5
(
40 °C) while Py-1 did not show any such temperature
UV/ Vis absorption experiments were performed in a Perkin-Elmer
Lambda 25 spectrometer. Mass spectrometric data were acquired by an
electron spray ionization (ESI) technique on a Q-tof-micro quadruple
mass spectrometer (Micro mass). FT-IR spectra were recorded in a
Perkin Elmer Spectrum 100FT-IR spectrometer. Transmission electron
microscopy (TEM) images were captured in a JEOL-2010EX machine
operating at an accelerating voltage of 200 kV. Isotherthrmal titration
calorimetry was done in Microcal-200-ITC ultra-sensitive isothermal
titration microcalorimeter. EPR experiment was performed in Jeol (JES
FA 200) spectrophotometer.
responsive behaviour. From these observations we envisaged
that there could be a possibility of tuning the LCST in these D-A
supramolecular copolymers by varying the composition of the
two components. To test this, variable temperature UV/Vis
experiments were performed with different solutions of NDI-1 +
Py-1 with varying D/A ratio. It was found that with increase in the
mole fraction of the Py-1 in the mixture, the LCST increased
linearly (Figure 9b) and could be tuned within a large window of
40 °C to 72°C. Although tunable LCST has been reported for
covalent copolymers containing pendant oligo-oxyethylene
Sample preparation: Stock solutions of Py-1 and NDI-1/ NDI-2 were
prepared in THF (C = 5.0 mM). Measured amount (200 l) of each stock
solution was transferred to a screw capped vial, mixed together and
[
22]
chains and variable composition,
to our knowledge it has not
been reported before for supramolecular copolymers.
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Chemistry - A European Journal
10.1002/chem.201803170
FULL PAPER
solvent was evaporated by blowing air which produced a red film. To this
Chymotrypsin activity assays: All the experiments were performed in
20.0 mM potassium borate buffer at pH 9.0 with [Cht] = 8 μM at T= 25 C
o
200 l of water (pH 9.0) was added and the sample was subjected to a
few cycles of sonication and gentle heating which produced a clear red
solution in which concentration of each component was 5.0 mM. This
solution was equilibrated for 1h before physical studies were carried out.
and [chromophore] = 100 μM (above critical aggregation concentration).
A SPNA stock solution (10 μL) was added into a pre-incubated (for 2 h at
25 °C) Cht-Chromophore mixture (190 μL) to reach a final SPNA
concentration of 2.0 mM. Hydrolysis of SPNA was monitored by
increasing intensity of the absorption at 405 nm for 2 h. Likewise
hydrolysis of SPNA by Cht without any chromophore was monitored
under same condition. Form rising absorbance at 405 nm after each time
interval, the concentration of produced p-nitro aniline was estimated
TEM and DLS studies: Freshly prepared sample of Py-1+NDI-1 (1:1) or
Py-1 + NDI-2 (1:1) was diluted with water (pH 9.0) to make c = 0.5 mM
for each component and was drop casted onto a freshly cleaned (by glow
discharge) carbon-coated Cu grid (400 mesh). Soon after that the grid
was negatively stained with 5 µl of uranyl acetate (2% in water) and
finally the water was removed by a filter paper and the grid was dried for
-
1
-1
using its reported extinction coefficient (9800 M cm ) and plotted against
time. From this plot the slope of each different straight line was estimated
4
0
8 h before capturing images. For DLS studies, samples were diluted to
.2 mM and measurements were done with a scattering angle of 173 °.
that gave the rate of formation (K
inhibitor and presence of inhibitor (K). For each inhibitor, the ratio of rate
constant (K/K ) was considered the remained activity of Cht.
0
) of p-nitro aniline in the absence of
0
SANS measurements: Small-angle neutron scattering experiments were
performed at the SANS diffractometer at Guide Tube Laboratory, Dhruva
Redox responsive studies: Charge transfer solution (C = 1 mM) of NDI-
1+Py-1, was treated with gradual addition of buffer solution of 2 eqv
[
28]
Reactor, Bhabha Atomic Research Centre, Mumbai.
In SANS, the
coherent differential scattering cross-section (dΣ/ dΩ) per unit volume is
measured as a function of wave vector transfer Q (= 4π sin θ/λ, where 2θ
is the scattering angle and λ is the wavelength of the incident neutrons).
It provides the information about the shape and size of the scattering
particles on the length scale of 10−1000 Å. The mean wavelength of the
monochromatized beam from the neutron velocity selector is 5.2 Å with a
spread of Δλ/λ ≈ 15%. The angular distribution of neutrons scattered by
2 4
NaS O and UV spectra (extended upto near NIR region) as well as DLS
was recorded at T = 298 K.
EPR spectroscopy: For EPR studies, equimolar solution of NDI-1+Py-1
(c = 1 mM) was treated with 2.0 eqv. NaS O and the solution was
2
4
quickly transferred to a EPR tube and frozen at -78 °C. EPR spectra
were performed in Jeol (JES FA 200) spectrophotometer, microwave
frequency 9.101 GHz; microwave power 0.995 mw; and modulation
amplitude 5 Gauss (G)and Mod. Width = 1 mT at 195 K. The observed
peak is isotropic in nature with g = 1.9898. Modulation amplitude and
microwave power were optimized for high signal-to-noise ratio and
narrow peaks.
3
the sample is recorded using a 1 m-long one-dimensional He position-
−
1
sensitive detector, over a Q range of 0.017−0.35 Å . For SANS data
analysis, see the Supporting Information.
Determination of association constant and critical aggregation
concentration for D-A complex: Mixed D-A solution (10.0 mM) was
prepared in water (pH 9.0) following the procedure described above. It
was gradually diluted with a known volume of water (pH 9) and intensity
of the CT-band (λmax = 550 nm) was monitored after each dilution. After
Thermo-responsive studies: Freshly prepared sample of Py-1+NDI-1
(1:0/ 1:1 /2:3 /1:4 /0:1) (C = 1.0 mM, pH 9.0) was taken in a quartz
cuvette of 1.0 cm path length and heated from 25 °C to 90 °C with
temperature intervals 1 °C. At each temperature, the solution was settled
for 1.0 min before measurement (absorption at 750 nm). The absorbance
of 750 nm was plotted against temperature and LCST for different D:A
ratio were obtained from the inflection point of such a plot.
a
each dilution stirring was done for 5 min to ensure proper mixing. K was
[
29]
estimated by fitting the experimental data to the following equation.
C
A
1
1
1



Kl
A
l
Where c, A, l and Ԑ indicates concentration, absorbance, optical path
length and extinction coefficient, respectively.
Critical aggregation concentration was estimated by concentration
dependent UV/Vis studies (Figure S12) and monitoring the variation of
the CT band intensity as a function of concentration.
Acknowledgements
SC thanks CSIR, India for a research fellowship. SG thanks DST,
India, for funding through the SwarnaJayanti Fellowship Project
(DST/SJF/CSA-01/2-14-15).
Isothermal Titration Calorimetric (ITC) Analysis: ITC studies were
performed on
a Microcal-200-ITC ultra-sensitive isothermal titration
microcalorimeter. The reference cell was filled with pH 9 buffer solution.
All titrations were run at 25 °C. Sample was degassed at 25 °C for 10 min
using the Thermovac (a vaccum thermostating system) before doing any
experiment. Each of 20 injections of 2 µL of the donor solution (Py-1, 2.5
mM) was added into a solution of NDI-1 (0.25 mM) over 12s by a syringe
spinning at 400 rpm, with a 180 s equilibration time between two
injections. Data from control experiments in which blank solvent was
titrated with the solution of Py-1, were subtracted from the data obtained
from donor-acceptor titration experiment to eliminate the effect of the
heat of dilution from the final thermodynamic parameters. The interaction
stoichiometry, N was determined experimentally from the fit procedure
using MicroCal Origin Software package (version 7.0). The one set of
binding model (N = 1), provided in the software, perfectly fitted to the
Keywords: Supramolecular Assembly • Amphiphiles • Donor-
Acceptor Charge Transfer Interaction • H-bonding • Stimuli
Responsive Polymersome • Enzyme Inhibition
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Entry for the Table of Contents
FULL PAPER
Saptarshi Chakraborty, Debes Ray,
Vinod K. Aswal, and Suhrit Ghosh*
Page No. – Page No.
Multi-stimuli Responsive Directional
Assembly of Amphiphilic Donor-
Acceptor Alternating Supramolecular
Copolymer
H-bonding promoted directional alternating donor-acceptor stacking leads to
formation of multi-stimuli responsive supramolecular polymersome with desired
functional group display. In contrast the individual components form micelle and
hydrogel respectively.
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