GSH- and pH-responsive drug delivery system constructed by water-soluble pillar[5]arene and lysine derivative for controllable drug release

Article abstract of DOI:10.1039/c5cc01393c

Novel GSH- and pH-responsive supramolecular vesicles constructed by an amphiphilic inclusion complex formed from water-soluble pillar[5]arene and lysine derivative have been successfully developed, which can efficiently encapsulate anticancer drug MTZ and show rapid MTZ-release in a simulated acidic tumor environment with high GSH concentration, and exhibit potent antitumor activity.

Full text of DOI:10.1039/c5cc01393c

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GSH- and pH-responsive drug delivery system
constructed by water-soluble pillar[5]arene and
lysine derivative for controllable drug release†
Cite this:DOI: 10.1039/c5cc01393c
Received 14th February 2015,
Accepted 9th March 2015
Xuan Wu,a Yan Li,b Chen Lin,a Xiao-Yu Hu*a and Leyong Wang*a
DOI: 10.1039/c5cc01393c
www.rsc.org/chemcomm
Novel GSH- and pH-responsive supramolecular vesicles constructed
Pillararenes, as a new generation of macrocyclic molecules,
by an amphiphilic inclusion complex formed from water-soluble have received great attention since they were firstly reported in
pillar[5]arene and lysine derivative have been successfully developed, 2008.6 Due to their unique symmetrical and rigid structure, easy
which can efficiently encapsulate anticancer drug MTZ and show modification and excellent properties in host–guest chemistry,7
rapid MTZ-release in a simulated acidic tumor environment with high pillararenes have been widely used to construct various interest-
GSH concentration, and exhibit potent antitumor activity.
ing supramolecular systems, including mechanically interlocked
molecules,8 chemosensors,9 metal cation separation,10 artificial
Nano drug delivery systems (DDS) have attracted tremendous transmembrane channels,11 nanostructures,12 and supramole-
attention for their unique properties in cancer therapies, cular polymers.13 Recently, Li reported the binding behavior
including better efficacy against resistant tumors and fewer between lysine and water-soluble pillar[5]arenes (WP5) in aque-
side effects over conventional free drugs.1 Therefore, it is highly ous solution, where a 1 : 1 host–guest inclusion complex could
desirable to design smart drug delivery systems which cannot be formed.14 WP5, similar with water-soluble pillar[6]arenes
only efficiently encapsulate drugs and shield it from degrada- (WP6), has been demonstrated to show pH-responsiveness and
tion under physiological condition, but also can achieve a rapid good biocompatibility in aqueous media.15 Furthermore, disulfide
release in the specific tumor microenvironment. Vesicles have bond is sensitive to glutathione (GSH), which is of great importance
been widely applied in developing novel drug delivery systems due to for the construction of stimuli-responsive DDS due to the specific
their unique structures and outstanding abilities of encapsulating acidic tumor microenvironment with the presence of high GSH
and controllable releasing drugs under different conditions.2 Up to concentration.16 Therefore, we envisioned that if a disulfide bond-
now, various molecular building blocks have been exploited for containing hydrophobic tail was introduced to modify lysine, a more
constructing vesicles, and most of them were based on structural stable and amphiphilic host–guest inclusion complex would be
stable polymeric materials3 with both hydrophilic and hydrophobic achieved driven by the cooperative hydrophobic and electrostatic
ends. However, supramolecular chemistry provides a much interactions. In addition the obtained supramolecular amphiphile
easier way to construct diversified supramolecular amphiphiles could further self-assemble into well-defined supramolecular nano-
with stimuli-responsiveness by virtue of weak and reversible carriers, which will show dual GSH- and pH-responsiveness, so they
non-convalent interactions,4 especially host–guest interaction,5 might have potential application for drug delivery. To the best of our
which is of great interest and importance for the development knowledge, although disulfide bond-containing GSH-responsive
of smart drug delivery systems.
drug delivery systems have been well studied, particularly in poly-
meric systems and mesoporous silica systems,17 few researches have
focused on the construction of supramolecular vesicles based on the
host–guest interactions. Herein, we designed a novel pillararene-
based drug delivery system based on the host–guest complexation of
WP5 and a disulfide bond-containing lysine derivative G, which
showed dual GSH- and pH-responsiveness, and could be used for
controllable releasing of anticancer drug MTZ in the acidic tumor
microenvironment with high GSH concentration, implying its
promising future for cancer therapy (Scheme 1).
a Key Laboratory of Mesoscopic Chemistry of MOE, Center for Multimolecular
Organic Chemistry, School of Chemistry and Chemical Engineering,
Nanjing University, Nanjing 210093, China. E-mail: lywang@nju.edu.cn;
Fax: +86 25 83597090; Tel: +86 25 83592529
b State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory of Biomaterials
and Devices, School of Biological Science and Medical Engineering,
Southeast University, Nanjing 210096, China
† Electronic supplementary information (ESI) available: Experimental details,
1H NMR, 13C NMR, Job plots and association constant for the host–guest
complex, TEM, DLS and z-potential results, and images of living HepG2 cells.
See DOI: 10.1039/c5cc01393c
WP5 was synthesized according to the reported literature,18
and lysine derivative G was obtained by using lysine as starting
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Scheme 1 Schematic illustration of the formation of supramolecular
vesicles and their stimuli-responsive drug release.
Fig. 2 (a) TEM images of WP5*G aggregates, (b) DLS result of WP5*G
aggregates, (c) the zeta potential of WP5*G aggregates ([WP5] = 0.024 mM
and [G] = 0.072 mM, [G]/[WP5] = 3 : 1). (d) TEM image of WP5*G
aggregates after adding GSH. (e) Image of the Tyndall effect (right: the
solution of WP5*G aggregates, left: the solution of WP5*G aggregates
after adding GSH).
(for details see Fig. S23, ESI†). Based on this best molar ratio, the
critical aggregation concentration (CAC) for WP5*G was deter-
mined to be 1.00 Â 10À5 M by measuring the concentration-
dependent conductivity of the solution (Fig. S24, ESI†).
The aqueous solution of WP5 and G in the best molar ratio
exhibited an obvious Tyndall effect (Fig. 2e), indicating the existence
of abundant nanoparticles. Furthermore, in order to investigate the
size and morphology of these nanoparticles formed by WP5*G
supramolecular amphiphile, dynamic light scattering (DLS) and
transmission electron microscopy (TEM) were carried out (Fig. 2a
and b). The DLS result showed that the formed aggregates had a
narrow size distribution, and the average diameter was 112 nm,
and TEM images indicated the hollow spherical morphology with
an average diameter around 100 nm, indicating the formation of
Fig. 1 1H NMR spectra (400 MHz, D2O, 298 K) of (a) MG (6 mM), (b) MG +
WP5 ([MG] = 6 mM, [WP5] = 9 mM), and (c) WP5 (9 mM).
material (Scheme S1, ESI†). Since G exhibits poor water solu- a vesicular structure. On the basis of our previously work,12d–g the
bility, a model guest MG was used to investigate the host–guest z-potential of the formed supramolecular vesicles was a very impor-
complexations of WP5*G by 1H NMR (Fig. 1), from which tant parameter to evaluate their stability. Therefore, considering the
remarkable upfield chemical shifts and broadening effect of the repulsive-force-induced increasing-stability of vesicles, the molar
methylene protons (Ha–e) of MG were observed in the presence of ratio of 3 : 1 [G]/[WP5] (z-potential = À26.7 mV, Fig. 2c) was used
WP5 due to the inclusion-induced shielding effects,19 indicating for further investigation of their stimuli-responsive behavior.
the inclusion of lysine moiety of MG into the WP5 cavity. Subse-
Subsequently, the stimuli-responsive behavior of the obtained
quently, the 1 : 1 binding stoichiometry between WP5 and MG was supramolecular vesicles was further investigated, and it was found
proved by Job’s plot method (Fig. S21, ESI†). Moreover, based on that the above WP5*G supramolecular vesicles showed a character-
the 1H NMR titration experiments, the association constant (Ka) of istic GSH-responsive behavior due to the cleavage of the disulfide
WP5*MG was further estimated to be (1.87 Æ 0.38) Â 103 MÀ1 bond in guest G under GSH-stimulus. As shown in Fig. 2, upon
(Fig. S22, ESI†), which was approximated as the Ka value between adding GSH to the WP5*G vesicular solution, the obvious Tyndall
WP5 and G. All the above results showed that a stable 1 : 1 WP5*G effect disappeared (Fig. 2e), and meanwhile, no vesicle could be
inclusion complex was formed as shown in Scheme 1.
observed in the TEM image (Fig. 2d). Moreover, after adjusting the
After the accomplishment of the above amphiphilic WP5*G pH of the WP5*G vesicular solution to 5.0, the Tyndall effect
supramolecular complex in aqueous solution, we further investi- disappeared and no vesicle could be found by TEM any more
gated the amphiphilic assembly of such supramolecular inclusion (Fig. S25, ESI†), due to the precipitation of WP5 as its acid form
complex by using the steady-state fluorescence measurement out of the acidic aqueous solution. All the above results clearly
employing pyrene as probe according to the literature.20 Accord- showed that such WP5*G supramolecular vesicles exhibited good
ingly, the best molar ratio of WP6 and G for the formation of GSH- and pH-responsiveness. These properties endow them
supramolecular aggregates was determined to be 5 : 1 ([G]/[WP5]) with the ability to encapsulate drugs at neutral condition and
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release them in response to an acidic environment with high
GSH concentration similar to that of tumor cells, making the
obtained WP5*G supramolecular vesicles suitable for con-
trolled anticancer drug release.
In the following study, mitoxantrone (MTZ), an hydrophilic
anticancer drug,21 was used as a model drug to investigate the
MTZ encapsulation efficiency of the above supramolecular vesicles
as well as their release behavior. To prepare MTZ-loaded vesicles,
an aqueous solution of MTZ was added quickly to an aqueous
solution containing WP5 and G ([G]/[WP5] = 2.5 : 1, 1% EtOH was
added to improve the solubility of G). After standing overnight,
the unloaded MTZ was removed by dialysis against pure water
until water outside the dialysis tube exhibited negligible MTZ
fluorescence. As shown in Fig. 3a, the UV-Vis absorption of the
MTZ-loaded vesicular solution from 610 to 660 nm became much
stronger than the unloaded vesicles, which represents the char-
acteristic absorption peak of MTZ. Meanwhile, compared with the
transparent light blue solution of free MTZ, the MTZ-loaded
vesicular solution turned to royal purple with a light opalescence,
and upon adding GSH to the above vesicular solution (Fig. 3a) or
adjusting the solution pH to 5.0 (Fig. S28, ESI†), the characteristic
absorption peak of MTZ became much stronger, indicating the
encapsulated MTZ molecules were released from the vesicle
cavities. Moreover, TEM images (Fig. 3c and d) and DLS results
(Fig. S26, ESI†) showed that MTZ-loaded vesicles were much larger
in size (B210 nm) than those of the unloaded vesicles (B112 nm),
further confirming that MTZ molecules were successfully loaded
into the vesicle cavities.22 Subsequently, according to the UV-Vis
spectra, the MTZ-encapsulation efficiency was calculated to be
89%, which was much higher than that of the previously reported
study,12f and meanwhile, zeta potential measurements showed that
such MTZ-loaded supramolecular vesicles also had a good stability
(z-potential = À27 mV, Fig. S27, ESI†), indicating their potential
application for drug delivery.
Fig. 4 The time-dependent MTZ release efficiency of MTZ-loaded vesi-
cles under different conditions: (a) in aqueous solutions (pH = 7) contain-
ing different concentrations of GSH, (b) in aqueous solutions in the
presence of 4 mM GSH under different pH values.
conditions (pH = 7.0), almost no release of MTZ could be
observed. However, when a different amount of GSH was added
to the MTZ-loaded vesicular solution, MTZ was released rapidly
in significant amounts with the cumulative release amount of
54% with the GSH concentration of 1 mM, 69% ([GSH] = 4 mM),
and 79% ([GSH] = 10 mM) within 45 min, respectively. On the
other hand, when low pH and GSH stimulus were simultaneously
exerted on the MTZ-loaded vesicles, a burst release of MTZ could
be observed during the initial 10 min due to the very fast
disaggregation of vesicles under dual GSH- and pH-stimuli, and
the cumulative amount of released MTZ was up to 81% ([GSH] =
4 mM, pH = 5.0) after 45 min (Fig. 4b). Since the microenvironment
of tumor cells is acidic with the presence of high GSH concen-
tration, the rapid release of MTZ from MTZ-loaded vesicles can be
selectively triggered in the tumor tissues, which is extremely signi-
ficant for the specific targeted therapy and makes the MTZ-loaded
vesicles ideal candidate in DDS.
To further investigate the anticancer efficiency of MTZ-loaded
supramolecular vesicles with the controlled release of MTZ, MTT
assay was then carried out. Initially, HepG2 cancer cells were
incubated with black vesicles, free MTZ, and MTZ-loaded vesicles,
respectively (the concentration of MTZ was 0.7 mg mLÀ1), and the
relative cell viability in different groups was recorded after incuba-
tion for 24 h, 48 h, and 72 h, respectively. As shown in Fig. 5, it was
found that the relative cell viability of the MTZ-loaded vesicle group
against cancer cells was only about 10% after 72 h, which showed
better therapeutic effects than the free MTZ group (26%). A rational
explanation is that for the blank vesicle group, the relative cell
viability also decreased to about 61% after incubation for 72 h,
indicating that the blank vesicles also had a certain cytotoxic effect.
Subsequently, the release behavior of MTZ from the MTZ-
loaded vesicles was investigated upon GSH stimulus or/and in
acidic pH environment. As shown in Fig. 4a, under neutral
Fig. 3 (a) UV-Vis spectra of blank vesicles (black line), MTZ-loaded
vesicles (red line), and MTZ-loaded vesicles after adding GSH (green line).
(b) Images of MTZ-loaded vesicular solution (right) and free MTZ solution
(left). (c) and (d) TEM images of MTZ-loaded vesicles.
Fig. 5 Anticancer activity of blank vesicles, free MTZ, and MTZ-loaded
vesicles in HepG2 cancer cells at different times.
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pillararene-based supramolecular vesicles based on the host–guest
complexation between WP5 and a lysine derivative G, which
exhibited dual GSH- and pH-responsiveness. Furthermore, drug
loading and in vitro releasing experiments demonstrated that MTZ
could be successfully encapsulated by such supramolecular vesicles
and the resulting MTZ-loaded vesicles exhibit excellent GSH- and
pH-responsiveness, and can efficiently release the encapsulated
MTZ in an acidic environment with high GSH concentration
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candidate for cancer therapy. Finally, cytotoxicity experiments
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potent antitumor activity. Further studies on the active targeting
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