Supramolecular Vesicles Coassembled from Disulfide-Linked Benzimidazolium Amphiphiles and Carboxylate-Substituted Pillar[6]arenes that Are Responsive to Five Stimuli

Article abstract of DOI:10.1002/anie.201611973

Novel supramolecular vesicles based on host–guest systems were coassembled from carboxylate-substituted pillar[6]arene (CPA[6]) and disulfide-linked benzimidazolium amphiphiles, and the microstructures of the CPA-based supramolecular vesicles were clearly elaborated. The supramolecular vesicles showed controlled drug release in response to five stimuli, with glutathione, pH, CO₂, Zn²⁺ions, and hexanediamine, leading to cleavage of the disulfide bonds, protonation of the carboxylate groups, metal chelation, and competitive binding. This is the first case of a smart pillararene-based supramolecular vesicle being integrated with five stimuli-responsive functions to meet the diverse requirements of controlled drug release. Importantly, each of the five stimuli is closely related to microenvironments of tumors and diseases of the human body. The smart stimuli-responsive supramolecular vesicles have promising applications in drug therapy of tumors and relevant diseases.

Full text of DOI:10.1002/anie.201611973

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201611973
German Edition: DOI: 10.1002/ange.201611973
Supramolecular Vesicles
Supramolecular Vesicles Coassembled from Disulfide-Linked
Benzimidazolium Amphiphiles and Carboxylate-Substituted Pillar-
[6]arenes that Are Responsive to Five Stimuli
Long Jiang, Xuan Huang, Dong Chen, Hua Yan, Xueyuan Li, and Xuezhong Du*
Abstract: Novel supramolecular vesicles based on host–guest
systems were coassembled from carboxylate-substituted pillar-
[6]arene (CPA[6]) and disulfide-linked benzimidazolium
amphiphiles, and the microstructures of the CPA-based
supramolecular vesicles were clearly elaborated. The supra-
molecular vesicles showed controlled drug release in response
to five stimuli, with glutathione, pH, CO2, Zn2+ ions, and
hexanediamine, leading to cleavage of the disulfide bonds,
protonation of the carboxylate groups, metal chelation, and
competitive binding. This is the first case of a smart pillararene-
based supramolecular vesicle being integrated with five stimuli-
responsive functions to meet the diverse requirements of
controlled drug release. Importantly, each of the five stimuli
is closely related to microenvironments of tumors and diseases
of the human body. The smart stimuli-responsive supramolec-
ular vesicles have promising applications in drug therapy of
tumors and relevant diseases.
of the supramolecular vesicles have not been clearly elabo-
rated so far.
Pillararenes (PAs) are cylindrical macrocyclic hosts with
highly symmetrical structures composed of 1,4-dialkoxy-
phenyl rings linked by methylene bridges at the 2- and 5-
positions.[3] PAs are easily functionalized with a variety of
groups, and water-soluble carboxylate-substituted pillar-
[6]arenes (CPA[6]) have been used to construct supramolec-
ular vesicles with bipyridium- and ferrocene-derived amphi-
philes for pH-responsive controlled release.[4] Recently, a new
benzimidazolium guest with a high binding affinity for CPA[6]
was used to construct supramolecular nanovalves based on
mesoporous silica for controlled release in response to three
stimuli (pH, divalent metal ions, and competitors).[5] Benz-
imidazole compounds are the basic structural fragments of
many clinical drugs. Herein, dynamic covalent disulfide-
linked benzimidazolium amphiphiles with alkyl chains of
different lengths (G1 and G2) were synthesized; these could
not form vesicles on their own in aqueous solution. Supra-
molecular vesicles responsive to five stimuli were coassem-
bled from CPA[6] and G1 for the controlled release of
encapsulated drugs (Scheme 1). Glutathione (GSH) is over-
expressed in the intracellular matrices of tumor cells at levels
(1–10 mm) two to three orders of magnitude higher than those
in extracellular environments (2–20 mm).[6] GSH could cleave
the disulfide linkages of the benzimidazolium amphiphiles,
thereby resulting in disruption of the supramolecular vesicles
and the controlled release of encapsulated drugs. It is known
that tumor cells have more acidic environments than blood
and normal tissues, with early endosomes and late endo-
somes/lysosomes in the intracellular environments of tumor
cells being around pH 6.0 and pH 5.0, respectively.[7] At acidic
pH values, CPA[6] was protonated and the benzimidazolium
moieties of the amphiphiles were dethreaded from the
protonated CPA[6] as a result of a weakening of the
electrostatic interactions, thus the supramolecular vesicles
were disassembled and the encapsulated drugs were released.
CO2 is one of the most important metabolic products of the
human body, and high levels of CO2 can cause metabolic
acidosis. Similar to a pH trigger, the CO2-mediated controlled
release of drugs from the supramolecular vesicles could be
realized. This is the first example of the release of a drug from
supramolecular vesicles in response to CO2, which is com-
pletely different from the CO2-driven formation of supra-
molecular vesicles from sulfonate amphiphiles and PA[6]
substituted with tertiary amines.[8] Zinc is an essential trace
elements in the human body but has been shown to over-
express in some pathological processes, such as iron-defi-
ciency anemia, coronary diseases, hypertension, and tumors.[9]
L
iposomal formulations of some antitumor drugs have been
approved by the U.S. Food and Drug Administration (FDA)
for clinical tumor therapy. Liposomes and vesicles possess
structures with closed bilayer membranes and interior
aqueous compartments, similar to the structures of cellular
membranes. They are formed in aqueous solutions from
phospholipids and amphiphiles, and can be used for drug
delivery. The sustained release of encapsulated drugs from
liposomes and vesicles is realized by slow diffusion of drugs
and/or degradation of carriers.[1] Supramolecular vesicles are
self-assembled from supramolecular amphiphiles (building
blocks) and consist of two scaffolds connected through
electrostatic interactions, hydrogen bonding, host–guest rec-
ognition, and other noncovalent interactions.[2] This allows
the stimuli-responsive controlled release of drugs from
supramolecular vesicles for improved therapeutic efficacy
and minimized adverse effect of drugs, in contrast to tradi-
tional vesicles and liposomes. As a consequence of the
complexity of supramolecular vesicles based on host–guest
systems compared to traditional vesicles, the microstructures
[*] L. Jiang, X. Huang, D. Chen, H. Yan, X. Li, Prof. X. Du
Key Laboratory of Mesoscopic Chemistry (Ministry of Education)
State Key Laboratory of Coordination Chemistry
Collaborative Innovation Center of Chemistry for Life Sciences
School of Chemistry and Chemical Engineering
Nanjing University, Nanjing 210023 (China)
E-mail: xzdu@nju.edu.cn
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201611973.
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shielding effect of the electron-
rich CPA[6] cavity. The proton
resonances of CPA[6] also all
displayed slight changes in their
chemical shifts as well as signifi-
cant signal broadening because of
complexation
dynamics[11]
between CPA[6] and G3 (Fig-
ure S12). The changes in the
1H NMR spectra demonstrate
that G3 was completely encapsu-
lated within the CPA[6] cavity,
and the association constant was
determined to be (2.82 Æ 1.83) ꢀ
105 mÀ1 [5]
The NOESY spectrum
.
showed strong H-H correlation
signals between protons H1 and
H2 of CPA[6] and proton Hc of
G3 (Figure S13). These results
demonstrate that the benzimida-
zolium moiety was included
within the CPA[6] cavity with
a high binding affinity.
To determine whether CPA-
[6] could form a stable complex
with the amphiphiles, the host–
guest interactions of G2 (which
has a higher water solubility than
G1) were investigated by UV/Vis
spectroscopy. CPA[6] showed an
Scheme 1. Chemical structures of CPA[6], disulfide-linked benzimidazolium amphiphiles (G1 and G2),
and benzimidazolium guest (G3), as well as illustrations of their inclusion complexes, supramolecular
vesicles, and the controlled drug release in response to the five stimuli.
The carboxylate groups of CPA[6] could be chelated by Zn2+
ions at neutral pH values, so that the electrostatic interactions
between CPA[6] and the benzimidazolium moieties of the
amphiphiles were weakened, and the supramolecular vesicles
disassembled for controlled drug release. Biogenic amines are
naturally occurring organic cations in all organisms, and some
of them are derived from the enzymatic decarboxylation of
amino acids, such as cadaverine and histamine. An increase in
polyamine levels is known to be closely related to cell growth
and tumors.[10] Hexanediamine (HDA), an analogue of
biogenic amines, could competitively insert into CPA[6] and
resulted in the disassembly of the supramolecular vesicles and
the controlled release of drugs. To the best of our knowledge,
this is the first example where one smart PA-based supra-
molecular vesicle was integrated with five stimuli-responsive
performances to meet diverse requirements of controlled
drug release. Importantly, each of the five stimuli is closely
related to microenvironments of tumors and diseases of the
human body. It is clear that the smart stimuli-responsive
supramolecular vesicles have promising applications in drug
therapy of tumors and relevant diseases.
absorption maximum at l = 290 nm, and G2 displayed two
absorption maxima at l = 280 and 272 nm (Figure 1a). The
addition of 1 equiv of G2 to an aqueous solution of CPA[6]
resulted in the UV/Vis spectrum of their 1:1 mixture under-
going changes in the band intensities and a red-shift of the
long-wavelength band compared to the sum of the UV/Vis
spectra of the individual components. This finding means that
there were strong host–guest interactions between CPA[6]
and G2, most likely with the formation of a charge-transfer
complex. Furthermore, the 1:1 binding stoichiometry between
CPA[6] and G2 was confirmed by the Job method (Fig-
ure S14).
Considering the limited water solubility of G1, an ethanol
injection method was selected to prepare aqueous dispersions.
This was achieved by rapid injection of a solution of G1 in
ethanol into aqueous solutions to achieve a final ethanol
content of 1.5% (volume fraction) in the absence and
presence of CPA[6]. The critical aggregation concentration
(CAC) of G1 in water in the absence of CPA[6] was
determined to be 3.18 ꢀ 10À5 m by using fluorescence spec-
troscopy, with pyrene as a probe (Figure S15), and the CAC of
G1 in the presence of CPA[6] was 5.86 ꢀ 10À5 m (Figure S16).
The transmission electron microscopy (TEM) image of the
freeze-dried aqueous G1 dispersion showed solid aggregates
with diameters of about 35 nm (Figure 1b), while the TEM
image of the freeze-dried aqueous dispersion of CPA[6] and
G1 displayed vesicle-structured aggregates of about 165 nm in
size (Figure 1c,d). The vesicular aggregates of CPA[6] and G1
were further visualized in the scanning electron microscopy
CPA[6],[5] G1, G2, and the benzimidazolium guest (G3)
were synthesized (see Chart S1 and Figures S1–S11 in the
Supporting Information). 1H NMR spectroscopy studies with
water-soluble G3 were first used to give a deep insight into the
host–guest interactions. The addition of 1 equiv of CPA[6] to
a solution of G3 in D2O (1.0 ꢀ 10À2 m) resulted in the
resonances of protons Ha–Hd of G3 being shifted upfield by
0.27, 0.85, 1.72, and 1.08 ppm, respectively, as a result of the
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Figure 2. a) Small-angle XRD patterns of freeze-dried supramolecular
vesicles of CPA[6] (7.5ꢀ10À5 m) and G1 (1.5ꢀ10À4 m) and an aqueous
dispersion of G1. b) Microstructures of the supramolecular vesicles of
CPA[6] and G1.
(1.1 nm)[12] (Figure S18), an interdigitated bilayer structure
could be inferred from the interlayer spacing of 3.9 nm, with
partially disordered conformers of the alkyl chains, twisted
rims of CPA[6], and partial insertion of the benzimidazolium
moieties (Figure 2b). The geometric structures of aggregates
of traditional amphiphiles can be predicted on the basis of the
critical packing parameter (CPP).[13] G1 and G2 contain large
head groups, probably with CPP < 1/3, and could not form
vesicles in aqueous solution. The external diameter of PA[6]
was estimated to be 1.52 nm,[14] which corresponds to a cross-
sectional area of 1.81 nm2, while the cross-sectional area of
the saturated alkyl chains was only 0.20 nm2. The host–guest
interactions of CPA[6] and the benzimidazolium moieties of
G1 with a 1:1 binding stoichiometry resulted in a further
increase in the size of the head groups of the inclusion
complexes and a dramatic decrease in the CPP value.
However, the formed inclusion complexes could interact
with the benzimidazolium moieties of other amphiphiles
through the carboxylate groups of CPA[6] along the orienta-
tion of the alkyl chain of included G1. These supramolecular
amphiphiles, at a suitable mole ratio of host to guest,
functioned as pseudoamphiphilic PA[6] (building blocks)
with an apparent CPP value of 1/2–1 for the development of
supramolecular vesicles with mostly interdigitated alkyl
chains in bilayer membranes. The microstructures of the
supramolecular vesicles based on the host–guest systems were
clearly elaborated for the first time, which are helpful for the
understanding and design of a variety of supramolecular
vesicles.
The water-soluble dye Ru(bipy)3Cl2 was first used as
a model drug. To prepare cargo-loaded supramolecular
vesicles, a certain amount of aqueous Ru(bipy)3Cl2 solution
was added to an aqueous solution of CPA[6] followed by the
rapid injection of a solution of G1 in ethanol. The encapsu-
lation efficiency and loading efficiency of Ru(bipy)3Cl2 in the
supramolecular vesicles with a 1:2 mole ratio of CPA[6] to G1
were estimated to be 23.5% and 42.5%, respectively, higher
than those with other mole ratios. In contrast, no dye could be
encapsulated in the case of just G1 aggregates. Prior to
application of the trigger, the supramolecular vesicles showed
a slight premature release of encapsulated cargo of about
12% at pH 7.4 after 8 h (Figure 3a). In the presence of GSH,
the majority of the cargo was released as a result of cleavage
of the disulfide linkages and the subsequent disruption of the
supramolecular vesicles (Figures S19a and S20a). The cumu-
lative release efficiency was 63% at 1 mm GSH and increased
Figure 1. a) UV/Vis spectra of CPA[6] (2.0ꢀ10À4 m), G2 (2.0ꢀ10À4 m),
and their 1:1 mixture in comparison to the sum of the spectra of the
individual components. b) TEM image of the freeze-dried G1 aggre-
gates (1.5ꢀ10À4 m). c) TEM image of the freeze-dried supramolecular
vesicles of CPA[6] (3.75ꢀ10À5 m) and G1 (1.5ꢀ10À4 m). The inset
shows the photographs of aqueous dispersions of (left) CPA[6] and G1
and (right) G1. d) Enlarged TEM image of a supramolecular vesicle.
e) Hydrodynamic diameter distribution of the supramolecular vesicles
of CPA[6] (3.75ꢀ10À5 m) and G1 (1.5ꢀ10À4 m). f) Zeta potentials of
aqueous dispersions of G1 (1.5ꢀ10À4 m) in the absence and presence
of CPA[6] (3.75ꢀ10À5 m).
(SEM) image (Figure S17). The opalescence phenomenon of
the vesicular dispersion of CPA[6] and G1 was more apparent
than in the micellar solution of G1 (inset of Figure 1c). The
dynamic light scattering (DLS) result showed the aggregates
of CPA[6] and G1 in aqueous solution had an average
hydrodynamic diameter of 216 nm (Figure 1e), which also
supports the formation of supramolecular vesicles. The zeta
potential of the G1 aggregates in water was as high as 113 mV,
while the zeta potential was drastically decreased to À52 mV
upon addition of 0.25 equiv CPA[6] (Figure 1 f). This finding
demonstrates that the supramolecular vesicles of CPA[6] and
G1 were formed by host–guest interactions and were well
dispersed in aqueous solution.
The small-angle XRD patterns of the freeze-dried supra-
molecular vesicles showed a diffraction peak at 2q = 2.288,
with another peak at 2q = 3.708 resulting from the G1
aggregates (Figure 2a). The interlayer spacing of the supra-
molecular vesicles was calculated from the Bragg equation to
be 3.9 nm. Taking into account the extended molecular length
of G1 (disulfide-linked alkyl chain of 2.0 nm and benzimida-
zolium moiety of 0.55 nm) and the extended height of CPA[6]
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vesicles and cargo release (Figures S19d, S20d, and S23). The
release efficiency of the cargo was increased from 50% to
74% when the Zn2+ concentration was increased from 0.1 to
0.5 mm (Figure 3c). It is clear that the supramolecular vesicles
have promising applications in Zn2+-triggered pathological
diseases.
HDA was used as an analogue of biogenic amines. In the
presence of HDA, the cargo was released from the supra-
molecular vesicles with an increase in the release efficiency
from 42% to 78% when the HDA concentration was
increased from 0.1 to 1 mm (Figure 3d). HDA could be
protonated at a neutral pH value and inserted into CPA[6]
[16]
(association constant: 1.29 ꢀ 106 mÀ1
)
by competitive bind-
ing, which led to the disassembly of the supramolecular
vesicles and the release of the cargo (Figures S19e, S20e, and
S24). This is the first report of controlled drug release from
PA-based supramolecular vesicles being triggered by poly-
amines of metabolic carcinogens. The application of the dual
stimuli of pH 5.0 and HDA resulted in an increase in the
release efficiency of the cargo to about 90%. The simulta-
neous application of pH 5.0, GSH, and HDA resulted in the
release efficiency being enhanced up to 95% (Figure 3d). It is
clear that the supramolecular vesicles have promising appli-
cations in the delivery of drugs to tumors.
Figure 3. Controlled release of Ru(bipy)3Cl2 from the supramolecular
vesicles of CPA[6] (7.5ꢀ10À5 m) and G1 (1.5ꢀ10À4 m) upon triggering
by various stimuli: a) GSH; b) pH, CO2 bubbling, and pH/GSH;
c) Zn2+; d) HDA, pH/HDA, and pH/GSH/HDA.
to 73% at 5 mm GSH. On the other hand, the cargo was
clearly released from the supramolecular vesicles upon
decreasing the pH value from 7.4 to 5.0, with a release
efficiency of about 70% (Figure 3b). In this case, CPA[6] was
protonated and insoluble, thus the electrostatic interactions
were weakened, which resulted in dethreading of the
benzimidazolium moiety of G1 from the protonated CPA[6]
and the disassembly of the supramolecular vesicles (Figur-
es S19b, S20b, and S21). The combination of the dual stimuli
of pH 5.0 and GSH resulted in the release efficiency of the
cargo being enhanced to up to 93% (Figure 3b).
Recently, CO2-switchable supramolecular aggregates
have attracted much attention.[15] To date, only two cases of
CO2-switchable supramolecular amphiphiles composed of
tertiary-amine-substituted PA[6] and sulfonate amphiphiles
have been reported. In these cases, the supramolecular
vesicles were formed upon bubbling of CO2.[8] However, the
supramolecular vesicles in our case were disassembled to
release the encapsulated cargo upon bubbling with CO2, with
a release efficiency of about 45% (Figure 3b). Taking into
account that pKa1 = 6.38, the pH value of the saturated H2CO3
solution, the calculated pKa = 2.09 of fully protonated CPA[6]
with 12 carboxyl groups, and the measured pKa = 1.82 of
hydroquinone-O,O’-diacetic acid (Tables S1–S3), the CPA[6]
would be partially protonated. This resulted in a weakening of
the electrostatic interactions between CPA[6] and G1 and the
disassembly of the supramolecular vesicles for cargo release
(Figures S19c, S20c, and S22). This is the first example of
a CO2-triggered controlled release from supramolecular
vesicles.
The antitumor drug doxorubicin (DOX) was further
loaded within the supramolecular vesicles of CPA[6] and
G1, with an encapsulation efficiency and loading efficiency of
DOX of 17.7% and 17.4%, respectively. The application of
the dual stimuli of pH 5.0 and GSH caused the DOX to be
released through disassembly/disruption of the supramolec-
ular vesicles (Figure S25). The cell viabilities of human liver
cancer cells (HepG2) incubated with supramolecular vesicles
of CPA[6] and G1 without and with DOX loading for 24 and
48 h were studied by the MTT assay (Figure S26). The
cytotoxicity analyses indicate that CPA[6] and G1 were only
slightly cytotoxic and that DOX was released from the
supramolecular vesicles in the microenvironments of the
tumor cells. The apoptosis of HepG2 cells and human normal
liver cells (LO2) incubated with the DOX-loaded supra-
molecular vesicles for 24 and 48 h was studied by flow
cytometry (Figures S27–S30). The total apoptotic ratios of
both HepG2 and LO2 cells increased with the increase in the
DOX concentration and incubation time, but the total
apoptotic ratios of the HepG2 cells were significantly higher
than those of LO2 cells (Figure S31). The flow cytometry
analyses indicate that the microenvironments of tumor cells
are favorable for the release of DOX from the internalized
supramolecular vesicles for cell apoptosis. Furthermore, high
content imaging analyses showed that the red fluorescence
emitted from DOX gradually became stronger and the red
area gradually expanded as the incubation time increased
(Figure 4). The light-magenta areas observed in the merged
fluorescence images arise from the overlap of the red color
from DOX and the blue color from cell nuclei stained with
DAPI. This observation indicates that DOX was released in
the microenvironments of tumor cells and the released DOX
entered the cell nuclei for apoptosis. It is clear that the smart
stimuli-responsive supramolecular vesicles have promising
applications in drug therapy of tumors.
The carboxylate groups of CPA[6] can be chelated by
many divalent metal ions, and Zn2+ ions were found to have
a high binding affinity for CPA[6].[5] The presence of Zn2+
resulted in a decrease in the number of negative charges on
CPA[6], a weakening of the electrostatic interactions between
CPA[6] and G1, and the disassembly of the supramolecular
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Novel supramolecular vesicles based on host–guest inter-
actions were constructed from CPA[6] and disulfide-linked
benzimidazolium amphiphiles, and the microstructures of the
CPA-based supramolecular vesicles were clearly elaborated
for the first time. The supramolecular vesicles underwent
controlled drug release in response to the five triggers of
GSH, pH, CO2, Zn2+, and HDA. This is the first case that one
smart PA-based supramolecular vesicle was integrated with
five stimuli-responsive attributes to meet diverse require-
ments for controlled drug release. Importantly, each of the
five stimuli is closely related to microenvironments of tumors
and diseases of the human body. The smart stimuli-responsive
supramolecular vesicles have promising applications in drug
therapy of tumors and relevant diseases.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: drug delivery · host–guest systems · pillararenes ·
supramolecular chemistry · vesicles
Manuscript received: December 9, 2016
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Supramolecular Vesicles
Trigger happy: Coassembly of carboxyl-
ate-substituted pillar[6]arenes and disul-
fide-linked benzimidazolium amphiphiles
led to supramolecular vesicles that could
be triggered by glutathione, pH, CO2,
Zn2+, and hexanediamine to release an
encapsulated drug. The five stimuli are
closely related to microenvironments of
tumors and diseases of the human body.
The microstructures of the supramolec-
ular vesicles were also clearly elaborated.
L. Jiang, X. Huang, D. Chen, H. Yan, X. Li,
X. Du*
&&& — &&&
Supramolecular Vesicles Coassembled
from Disulfide-Linked Benzimidazolium
Amphiphiles and Carboxylate-Substituted
Pillar[6]arenes that Are Responsive to Five
Stimuli
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!