Voltage-responsive vesicles based on orthogonal assembly of two homopolymers

Article abstract of DOI:10.1021/ja1027502

Two end-decorated homopolymers, poly(styrene)-β-cyclodextrin (PS-β-CD) and poly(ethylene oxide)-ferrocene (PEO-Fc), can orthogonally self-assemble into a supramoleculardiblock copolymer (PS-β-CD/PEO-Fc) in aqueous solutions based on the terminal host-guest interactions. These assemblies can further form supramolecular vesicles, and their assembly and disassembly behaviors can be Reversibly switched by voltage through the Reversible association and disassociation of the middle supramolecular connection. The vesicles possess an unprecedented property that their assembly or disassembly speed can be controlled by the applied voltage strength. Luminescence spectroscopy demonstrates that the vesicles act as nanocapsules carrying molecules within their hollow cavities and that the external voltage strength accurately regulates the drug release time.

Full text of DOI:10.1021/ja1027502

Published on Web 06/21/2010
Voltage-Responsive Vesicles Based on Orthogonal Assembly of Two
Homopolymers
Qiang Yan, Jinying Yuan,* Zhinan Cai, Yan Xin, Yan Kang, and Yingwu Yin
Key Lab of Organic Optoelectronic & Molecular Engineering of Ministry of Education, Department of Chemistry,
Tsinghua UniVersity, Beijing, 100084, China
Received April 14, 2010; E-mail: yuanjy@mail.tsinghua.edu.cn
Scheme 1. Structure of PS-ꢀ-CD and PEO-Fc and Schematic of
Abstract: Two end-decorated homopolymers, poly(styrene)-ꢀ-
cyclodextrin (PS-ꢀ-CD) and poly(ethylene oxide)-ferrocene
(PEO-Fc), can orthogonally self-assemble into a supramolecu-
lar diblock copolymer (PS-ꢀ-CD/PEO-Fc) in aqueous solutions
based on the terminal host-guest interactions. These as-
semblies can further form supramolecular vesicles, and their
assembly and disassembly behaviors can be reversibly switched
by voltage through the reversible association and disassocia-
tion of the middle supramolecular connection. The vesicles
possess an unprecedented property that their assembly or
disassembly speed can be controlled by the applied voltage
strength. Luminescence spectroscopy demonstrates that the
vesicles act as nanocapsules carrying molecules within their
hollow cavities and that the external voltage strength accurately
regulates the drug release time.
the Voltage-Responsive Controlled Assembly and Disassembly of
PS-ꢀ-CD/PEO-Fc Supramolecular Vesicles
was studied in detail. It is expected that this supramolecular
copolymer connected through terminal host-guest inclusion would
reversibly undergo an association and dissociation effect, inducing
a desirable assembly and disassembly of vesicles upon voltage, as
shown in Scheme 1.
To date, several reports have been shown for the fabrication of
block-copolymer-free vesicles, but these systems generally involved
an inactive connection and irreversible structural transition.7a,b In
this study, a new type of macromolecular adduct, denoted by PS-
ꢀ-CD/PEO-Fc, is shown to have an active connection in response
to external stimuli and possess desirable solubility in water. (For
details of the synthesis and characterization, see the Supporting
Information.)
Dripping an equal amount of PEO-Fc aqueous solution to PS-
ꢀ-CD enables self-assembly, which is suggested by the formation
of a slightly turbid colloidal mixture. The critical aggregate
concentration (CAC) of PS-ꢀ-CD/PEO-Fc was ∼0.28 mg/mL,
monitored by the surface tension measurement. The size of the
aggregates was determined by dynamic light scattering (DLS)
to be ∼102 nm in average radius (Figure S1-S3). To further
investigate their nanostructures of the PS-ꢀ-CD/PEO-Fc com-
plex, transmission electron microscopy (TEM) was used to
visualize the aggregates. The results in Figure 1a clearly show
that these supramolecular assemblies have a typical vesicular
structure, as evidenced by the distinct contrast between the dark
periphery and the lighter central part. The mean wall thickness
is ∼19 nm, which is in line with the interdigitated molecular
length of the PS-ꢀ-CD/PEO-Fc pseudocopolymer (13.1 nm by
CPK model), indicating the orthogonal assembly in the bilayer
membrane (Scheme 1). It is worth noting that these vesicles were
quite stable for 3 months without any external stimuli. Surpris-
ingly, upon +1.5 V voltage stimuli, the homopolymer of PEO-
Fc was oxidized into charged PEO-Fc+ species, which could
dissociate from PS-ꢀ-CD; thus the vesicles partially disassembled
and the membrane started to disrupt within 2 h (Figure 1b).
Furthermore, the vesicles could completely self-disaggregate into
Stimuli-responsive polymeric vesicles have recently attracted
significant attention because of their promising applications in the
fields of controllable drug transport and gene delivery.1 As a type
of intelligent assembly, they can undergo reversible physical or
chemical changes and adjust their aggregated nanostructures in
response to external stimuli such as pH,2 light,3 temperature,4
molecules,5 and redox.6 In a cell biomembrane system, a typical
stimuli-responsive life phenomenon is the triggering of lipid bilayer
activities, like membrane fusion and disassembly, by membrane
potential. Thus, developing new electrostimuli-responsive as-
semblies is conducive to elucidating and biomimicing the biological
activities of the bilayers. Moreover, artificial voltage-responsive
vesicles are well-suited to drug encapsulation and controlled release,
and electrical stimulation is easy to realize in cells and the human
body.
At present, a general approach to making responsive vesicles is
based on the fabrication of a block copolymer. Recently, a “block-
copolymer-free” strategy has been pioneered by O’Reilly and
Weck’s groups. They have synthesized pseudocopolymers based
on the orthogonal self-assembly of two or three homopolymers by
supramolecular interaction at chain ends, such as H-bonding and a
metal-ligand bond.7 Alternatively, host-guest interaction is also
an adaptive noncovalent interplay for fabrication. For example,
ꢀ-cyclodextrin (ꢀ-CD) can exactly form a 1:1 inclusion complex
with ferrocene (Fc). Normally, uncharged Fc species or its
derivatives are strongly bound in the cavity of ꢀ-CD, whereas the
charged species (Fc+) dissociate rapidly from the cavity, and this
process can be reversibly switched under external voltage.8 To
realize the polymer vesicles possessing voltage responsiveness,
poly(styrene) with ꢀ-CD end-decoration (PS-ꢀ-CD) and poly(eth-
ylene oxide) containing Fc uncharged end-capping (PEO-Fc) were
designed and synthesized, and their self-assembly behavior in water
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C O M M U N I C A T I O N S
small fragments (several nanometers) after 5 h of electrostimu-
lation, indicating the whole disassembly of the vesicular structure
(Figure 1c). The disassembly system can be reassembled by
exerting a reductive voltage of -1.5 V, and vesicles with similar
shapes and sizes can be reformed because the reductive PEO-
Fc+ loses one electron and associates with PS-ꢀ-CD again.
To further elucidate the reversibility, cyclic voltammetric (CV)
analysis was used. As expected, the redox curve demonstrates that
the vesicles underwent an electrochemically controlled assembly-
disassembly process (Figure S4a). With no external electric field,
the CV profile exhibited a +0.41 V half-wave potential, indicating
PS-ꢀ-CD/PEO-Fc complex formation. In contrast, upon oxidative
voltage, Fc changes to an Fc+ moiety, which results in a remarkable
decrease of half-wave potential to +0.30 V concomitant with a
current rise from 1.8 to 4.1 µA, indicating a dissociated process
between PS-ꢀ-CD and PEO-Fc.9 In the presence of an opposite
voltage for reducing the Fc+ moiety, the analogous CV profile
(+0.40 V) is restored. By applying an oscillating electric field to
the supramolecular vesicles, this reversible procedure could be
cycled many times (Figure S4b). The average radius of the
assemblies jumping repeatedly from 102 to 7 nm upon alternating
potential (+1.5 and -1.5 V) by DLS results confirms the voltage-
responsive self-assembly and disassembly behavior of the polymer
vesicles (Figure S4c). In addition, notably, tuning the external
voltage from +0.50 to +5.0 V can accelerate the aggregated
disruption from 680 to 12 min. It was therefore proven that the
orthogonal assembly of two simple homopolymers endows the
formed vesicle with favorable voltage responsiveness.
Figure 2. Controlled release of RB from the supramolecular vesicles upon
various voltage stimuli as a drug nanocapsule and in comparison with the
free release of RB from the vesicles without stimuli.
the RB release time could be precisely tuned through variation
of the external potential strength. Encapsulated molecules showed
a slower release (∼120 min) upon lower voltage stimuli (+2.0
V) and the slowest rate (∼450 min) at the lowest voltage (+1.0
V). Moreover, triggered by different voltages, the release
quantities of RB could all reach ∼100%, comparing favorably
with other polymer nanocapsulated systems. It should be pointed
out that, even by exerting a voltage of +0.4 V (slightly greater
than the standard electrode potential: Fc+ + e- T Fc, E° )
0.32 V), the vesicles were still able to undergo a distinct self-
disruption, indicating good sensitivity to stimuli and mild
operation conditions. In contrast, in the absence of external
potential, the capsules only showed a low-level free release that
is less than 25% within 10 h. Thus, the conclusion can be drawn
that PS-ꢀ-CD/PEO-Fc supramolecular vesicles can serve as
nanocapsules that will release functional molecules or drugs over
a tunable time and quantity through artificial voltage control.
In summary, the orthogonal self-assembly of two end-decorated
homopolymers and their voltage-responsive reversible assembly and
disassembly were investigated. The new supramolecular vesicular
system is highly sensitive to the electric response mode, and various
voltage strengths can manipulate the self-disaggregation speed of
these vesicles. Considering the active nature of the host-guest linker
existing in the PS-ꢀ-CD/PEO-Fc pseudocopolymer and the stimulus
conditions readily realized, it is anticipated that this kind of voltage-
responsive supramolecular assembly has potential to function as
drug-loaded nanocapsules, enabling a new type of electrochemical
therapeutics.
Acknowledgment. This work was supported by the National
Science Foundation of China (20974058, 20836004) and the
National Basic Research Program of China (2009CB930602).
Figure 1. TEM images of the reversible assembly and disassembly of the
voltage-responsive PS-ꢀ-CD/PEO-Fc vesicles upon electric stimuli: (a) no
external voltage, (b) +1.5 V (after 2 h), (c) +1.5 V (after 5 h), and (d)
-1.5 V (after 5 h). All vesicle solutions were at 0.30 mg/mL in water.
Supporting Information Available: Synthesis, characterization, and
other experimental details. This material is available free of charge
via the Internet at http://pubs.acs.org.
As demonstrated, this kind of voltage-responsive vesicles can
be employed to encapsulate and release small molecules. Using
fluorescent Rhodamine B (RB) as a model, RB-loaded PS-ꢀ-
CD/PEO-Fc vesicles were prepared to perform controlled release
experiments. The assemblies solution was dialyzed against the
deionized water until the water outside the dialysis tube exhibited
negligible RB fluorescence. To understand the release behavior
of the RB molecules upon various voltages, a solution of RB-
loaded vesicles was kept in a dialysis tube and then exposed to
an external potential. Thus, the release of RB was monitored by
the increasing fluorescence of the solution outside the tube. From
the curve in Figure 2, an abrupt release (∼32 min) was observed
upon application of high voltage (+4.0 V). More importantly,
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