Morphology-tunable and pH-responsive supramolecular self-assemblies based on AB2-type host–guest-conjugated amphiphilic molecules for controlled drug delivery

Article abstract of DOI:10.3762/bjoc.15.188

Although stimuli-responsive supramolecular self-assemblies have been constructed, the controlled drug delivery induced by morphology transitions of these supramolecular self-assemblies on the basis of host–guest-conjugated monomers (HGCMs) are few reporte

Full text of DOI:10.3762/bjoc.15.188

Morphology-tunable and pH-responsive supramolecular
self-assemblies based on AB2-type host–guest-conjugated
amphiphilic molecules for controlled drug delivery
Yang Bai*1,2, Cai-ping Liu1, Di Chen1,3, Long-hai Zhuo1, Huai-tian Bu1 and Wei Tian*2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 1925–1932.
1Shaanxi Key Laboratory of Chemical Additives for Industry, College
of Chemistry and Chemical Engineering, Shaanxi University of
Science and Technology, Xi’an 710021, China, 2MOE Key Laboratory
of Material Physics and Chemistry under Extraordinary Conditions
and Shaanxi Key Laboratory of Macromolecular Science and
Technology, School of Science, Northwestern Polytechnical
University, Xi’an, 710072, China and 3Institute of Basic Medical
Sciences, Xi’an Medical University, Xi’an 710021, China
doi:10.3762/bjoc.15.188
Received: 30 April 2019
Accepted: 30 July 2019
Published: 13 August 2019
This article is part of the thematic issue "Novel macrocycles – and old
ones doing new tricks".
Email:
Guest Editor: W. Jiang
Yang Bai* - baiyang@sust.edu.cn; Wei Tian* -
happytw_3000@nwpu.edu.cn
© 2019 Bai et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
β-cyclodextrin; controlled drug delivery; host–guest interaction;
stimuli-responsive; supramolecular self-assemblies
Abstract
Although stimuli-responsive supramolecular self-assemblies have been constructed, the controlled drug delivery induced by mor-
phology transitions of these supramolecular self-assemblies on the basis of host–guest-conjugated monomers (HGCMs) are few re-
ported. In this paper, the self-assembly behaviors of AB2-type HGCMs, e.g., β-cyclodextrin-benzimidazole2 (β-CD-BM2), were in-
vestigated at neutral and acidic pH conditions, respectively. Specifically, β-CD-BM2 first self-assembled into fan-shaped supramo-
lecular self-assemblies with a hydrodynamic diameter of 163 nm at neutral pH, whereas they were further dissociated into spheri-
cal supramolecular self-assemblies with a size of 52 nm under acidic conditions. This morphology transition process was utilized to
conduct a two-stage DOX delivery under neutral and acidic pH. Basic cell experiments demonstrated that the drug-loaded β-CD-
BM2-based supramolecular self-assemblies with varied morphology could inhibit cancer cell proliferation, indicating their poten-
tial application in the field of drug delivery.
Introduction
Supramolecular self-assemblies based on noncovalent interac- smart materials [8-10], etc. As one common noncovalent inter-
tions with dynamic nature and reversible property have at- action [11], host–guest interaction has been used to effectively
tracted increasing attention in the fields of biomedicine [1-7], create stimuli-responsive supramolecular self-assemblies with
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regulated self-assembly morphologies due to their response to guest moieties have been used to construct intramolecular com-
various external stimuli, such as temperature [12], light [13-15], plexes [36], cyclic oligomers [37], supramolecular polymers
redox [16-18], and pH [19,20]. In addition, β-cyclodextrin [23,38-40], gels [41,42], etc. However, AB-type HGCMs were
(β-CD), pillararene and cucurbituril have been utilized as host still limited to obtain non-spherical stimuli-responsive supramo-
units to construct these stimuli-responsive supramolecular self- lecular self-assemblies with a tunable morphology transition
assemblies [21-27]. For example, β-CD can form inclusion ability. According to the literature [43,44], some nonspherical
complexes with guests such as azobenzene [28,29], ferrocene supramolecular self-assemblies seemed to be more efficient in
[30,31] and benzimidazole [32-34] to construct light-, redox-, the cellular internalization. Thus, we intend to design AB2-type
and pH-responsive supramolecular self-assemblies. In the amphiphilic HGCMs to form nonspherical supramolecular self-
abovementioned self-assemblies; however, host and guest units assemblies on the basis of their asymmetric host–guest unit
have to be synthesized individually, or were incorporated into number. Thus, an effective and controlled release of drugs
different moieties or polymer chains as terminal or side groups. might be realized due to tunable morphology transitions and
Thus, the preparation procedures of the stimuli-responsive stimuli-responsive properties of supramolecular self-assemblies.
supramolecular self-assemblies were fairly complicated, and
their self-assembly behaviors could hardly effectively be regu- On the basis of the considerations described above, herein we
lated.
report on pH-responsive supramolecular self-assemblies by
utilizing β-CD-benzimidazole2 (β-CD-BM2) as AB2-type
Alternatively, host–guest-conjugated monomers (HGCMs) amphiphilic HGCMs for the delivery and controlled release of
which gather host and guest units into one molecule have been doxorubicin (DOX). β-CD-BM2 was first synthesized by click
studied and attracted many attentions in the field of self- reaction (Scheme 1a). β-CD-BM2 formed fan-shaped self-
assembly [35]. AB-type HGCMs containing one host and other assemblies (FSSAs) at neutral pH through host–guest interac-
Scheme 1: Schematic illustration of the construction of β-CD-BM2-based supramolecular self-assemblies, their morphology transitions and drug
release behaviors. (a) Chemical structure of β-CD-BM2; (b) DOX-loaded fan-shaped self-assemblies (FSSAs); (c) Slow release of DOX from DOX-
loaded FSSAs at pH 7.4; (d) Fast release of DOX from DOX-loaded spherical self-assemblies (SSAs) at pH 5.0.
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tions between β-CD and BM. DOX was used as a model drug of 1496.5236. On the basis of the above results, AB2-type
encapsulated into FSSAs (Scheme 1a,b). The slow release of host–guest-conjugated amphiphilic monomer β-CD-BM2 has
DOX from DOX-loaded FSSAs was observed at pH 7.4 been successfully synthesized.
(Scheme 1b,c). On the contrary, the release rate of DOX in-
Supramolecular self-assembly behavior of
creased evidently when the solution pH value was adjusted to
5.0, accompanied with morphology transitions from FSSAs to β-CD-BM2
spherical self-assemblies (SSAs) due to the pH-induced dissoci- The morphology of the self-assembly and the size of β-CD-
ation of β-CD/BM inclusion complexes (Scheme 1c,d), and the BM2-based supramolecular self-assemblies under neutral and
hydrophilic–hydrophobic interaction-induced formation of acidic pH were first investigated by employing transmission
spherical micelles with BM units as inner hydrophobic core and electron microscopy (TEM) and dynamic light scattering
β-CD moieties as outer hydrophilic shell. The basic cell experi- (DLS). The prepared β-CD-BM2 were dissolved under neutral
ments confirmed that the pH-responsive supramolecular self- pH solution to form FSSAs. TEM revealed that these FSSAs
assemblies based on β-CD-BM2 have a potential application in had an average diameter (Dav) of 120 nm (Figure 1a,c), which
the field of drug delivery.
was close to the hydrodynamic diameter (Dh) of 163 nm deter-
mined by DLS (Figure 1e). Furthermore, the pH-induced self-
assembly morphology transition process were further studied.
When the pH value of the FSSAs solution was adjusted to 5.0,
SSAs (Figure 1b,d) with a Dav of 40 nm and Dh of 52 nm were
formed instead of FSSAs.
Results and Discussion
Synthesis of the host–guest-conjugated
amphiphilic molecule β-CD-BM2
β-CD-N3(-OTs) was first prepared according to our previous
work [45], and then a substitution reaction was performed to
obtain the functionalized β-CD molecule containing two azide
groups (β-CD-(N3)2). The FTIR spectrum of β-CD-(N3)2
(Figure S1A-b, Supporting Information File 1) showed the ap-
pearance of azido absorption peaks at 2103 cm−1. Character-
istic signals of protons a, b and c in the -OTs group of β-CD-
N3(-OTs) at δ = 7.4–7.7 and 2.4 disappeared in the 1H NMR
spectrum (Figure S1B-b, Supporting Information File 1). The
above results confirmed that the substitution reaction has been
successfully conducted. Subsequently, BM-Alk was synthe-
sized by the alkylation reaction between benzimidazole and
propargyl bromide according to the literature [46]. The appear-
ance of the alkynyl absorption peaks at 2127 cm−1 in the FTIR
spectrum (Figure S1A-a, Supporting Information File 1) and the
characteristic signals for BM and propargyl groups in 1H NMR
spectrum (Figure S1B-c, Supporting Information File 1),
accompanied with the GC–MS results (156.1), indicated the
successful preparation of BM-Alk.
The 1H NMR spectra in D2O or D2O/DCl was performed to
explore the internal structure of supramolecular self-assemblies
(Figure 2). As shown in Figure 2b, the proton peak ratios of
Finally, the targeted monomer β-CD-BM2 was synthesized
through the click reaction between β-CD-(N3)2 and excess
BM-Alk (Scheme 1a). As can be seen from the FTIR spectrum
of β-CD-BM2 in Figure S1A-c (Supporting Information File 1),
the absorption peaks of the azido group at 2103 cm−1 and the
alkynyl group at 2127 cm−1 disappeared simultaneously. Char-
acteristic signals for β-CD at δ = 3.1–3.9, 4.3–4.9 and 5.6–5.9
and protons of BM at δ = 7.0–8.4 could be observed obviously
in the 1H NMR spectrum of β-CD-BM2 (Figure S1B-d, Sup-
porting Information File 1). Furthermore, the molecular weight
of β-CD-BM2 (Figure S1C, Supporting Information File 1)
measured by high-resolution mass spectrometry was 1497.5266
[M + H+], which was in accordance with the theoretical value
Figure 1: Typical TEM images (a–d) and DLS curves (e) of β-CD-BM2-
based supramolecular self-assemblies at pH 7.4 (a, c, e) and pH 5.0
(b, d, e), respectively.
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Figure 2: 1H NMR spectra of β-CD-BM2-based supramolecular self-assemblies in DMSO-d6 (a), D2O (b) and DCl/D2O (c), respectively.
2,4,3,5,6-H protons of β-CD to BM protons in D2O was 3.75, interaction of β-CD and protonated BM decreased correspond-
which is slightly bigger than that of 3.46 in DMSO-d6 ingly, resulting in a self-assembly morphology transition from
(Figure 2a) due to the shielding effect of host–guest inclusion. fan-shaped to spherical structures. Furthermore, 2D NOESY,
The proton peak ratios of 2,4,3,5,6-H protons of β-CD to BM UV–vis and fluorescence spectroscopy were employed to
protons in DCl/D2O was 24.96 (Figure 2c), which is bigger than confirm the above proposed mechanism. Firstly, the 2D
that of the ratio of 3.75 in D2O (Figure 2b). The evident weak- NOESY spectra of solutions of supramolecular self-assemblies
ening of BM signals in DCl/D2O indicated that the core layer of further testified the inclusion interaction between β-CD and
supramolecular self-assemblies was mainly attributed to the unprotonated/protonated BM. As shown in Figure 3a, the
hydrophobic BM moiety. This result revealed that the hydro- signals from the BM protons (H protons of the benzene ring)
phobic BM formed the “core”, whereas the hydrophilic β-CD were correlated with the signals of the inner 3-H and 5-H
formed the shell layer of SSAs in DCl/D2O due to the pH-in- protons of β-CD in neutral aqueous solution, indicating the for-
duced dissociation of β-CD/BM inclusion complexes. In addi- mation of the host–guest inclusion complexes between the
tion, the shift of the BM signals to lower field when the pH β-CD and the BM moieties. On the contrary, the 2D NOESY
value was changed from neutral to acidic pH also confirmed the spectra of SSAs showed no correlation peak between the signals
above result.
of the protons of BM and the inner 3-H and 5-H protons of
β-CD at pH 5.0 (Figure 3b). Second, the UV–vis results
On the basis of the abovementioned results, a possible morphol- (Figure 3c) showed that the absorption band at λ = 248 nm de-
ogy transition mechanism of β-CD-BM2-based supramolecular creased and the absorption band at λ = 281, 273 nm shifted to
self-assemblies in different pH solutions was proposed. In 275, 268 nm when the solution pH was changed from 7.5 to 5.0,
neutral aqueous solution, the host–guest interaction between owing to the protonation of BM inclusion complexes. In addi-
β-CD and BM in β-CD-BM2 were enhanced, and further driven tion, the fluorescence spectra indicated that the maximum emis-
by β-CD-BM2 to form the FSSAs. While the BM could be sion wavelength shifted from 297 nm at pH 7.4 to 370 nm at pH
protonated in the acidic environment [47], so the host–guest 5.0 (Figure 3d), indicating as well the protonation of BM inclu-
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Figure 3: 2D NMR NOESY spectra in D2O (a) and D2O/DCl (b), UV–vis spectra (c) and fluorescence spectra (d) of β-CD-BM2-based supramolecular
self-assemblies at pH 7.4 and 5.0.
sion complexes. These results further proved that the self- changed from 7.4 to 5.0. The cumulative release amounts of
assembly morphology transitions of supramolecular self-assem- DOX correspondingly increased from 42% to 98%. The above
blies was driven by the pH-induced dissociation of host–guest result may be attributed to the pH-induced morphology transi-
interactions between BM and β-CD.
tions from FSSAs to SSAs on the basis of the dissociation of
host–guest interactions between β-CD and BM.
Controlled release behaviors of drug-loaded
supramolecular self-assemblies
Cellular toxicity of drug-loaded
β-CD-BM2-based SSAs were used as nanocarriers for drug supramolecular self-assemblies
delivery. Doxorubicin (DOX) was first loaded into FSSAs with The biocompatibility of drug-free supramolecular self-assem-
a drug-loaded content of 8.2%. To confirm the pH-induced con- blies is of crucial importance for the further use of these materi-
trolled release behavior, a two-stage DOX-release process was als as drug carriers. Herein, the biocompatibility of β-CD-BM2-
conducted at different pH conditions. Release curves of DOX based FSSAs towards PC-3 cells was investigated with differ-
from DOX-loaded FSSAs are shown in Figure 4. The release ent concentrations after incubation for 48 h. The result did not
rate of DOX was suppressed at pH 7.4, and only about 42% of show any cytotoxicity against PC-3 cells (Figure 5a). The
DOX was released within 24 h. In contrast, the release rate of viability of PC-3 cells could reach 84% even when the concen-
DOX was evidently increased when the solution pH value was tration of FSSAs was up to 240 μg/mL, indicating a good bio-
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Intracellular uptake of drug-loaded
supramolecular self-assemblies
Confocal laser scanning microscopy (CLSM) was further
utilized to confirm the intracellular uptake of DOX-loaded
FSSAs (Figure 6). The PC-3 cells treated with DOX-loaded
FSSAs indicated Hoechst 33342 blue fluorescence in their
nuclei and DOX red fluorescence in their cytosol after incuba-
tion. Moreover, the intensity of DOX red fluorescence was in-
creased when the incubation time was prolonged from 1 h to
4 h. This result indicated that DOX-loaded FSSAs were inter-
nalized into PC-3 cells and DOX could be released from the
FSSAs under endosome acidic conditions. Thus, DOX-loaded
FSSAs could be considered to deliver and release DOX in
cancer cells.
Figure 4: Cumulative release curves of DOX-loaded β-CD-BM2 based
SSAs at pH 7.4 and 5.0, respectively.
Conclusion
In summary, an AB2-type host–guest-conjugated amphiphilic
monomer, β-cyclodextrin-benzimidazole2 (β-CD-BM2), was
compatibility. An MTT assay was then conducted to evaluate successfully prepared to construct pH-responsive supramolecu-
the potential of supramolecular self-assemblies as intelligent lar self-assemblies. On the basis of the pH-induced association
drug release carriers within a biological environment. The cellu- and disassociation of β-CD/BM complexes, these supramolecu-
lar toxicity of DOX-loaded FSSAs and free DOX·HCl against lar self-assemblies with adjustable morphology and size were
PC-3 cells was further investigated. As shown in Figure 5b, obtained. The fan-shaped supramolecular self-assemblies were
DOX-loaded FSSAs displayed reduced cytotoxicity against first obtained based on the host–guest interaction between β-CD
PC-3 cells in comparison with free DOX·HCl. The in vitro half- and BM, then further dissociated under acidic conditions into
maximal inhibitory concentration (IC50) values of DOX-loaded spherical supramolecular self-assemblies with smaller size. The
FSSAs and free DOX·HCl after incubation for 48 h were 1.44 morphology transitions can be utilized to realize a two-stage
and 0.91 μg/mL, respectively. The results further certified that drug release. The uptake of the DOX-loaded supramolecular
the fast intracellular drug-release process of DOX-loaded self-assemblies performed efficiently and the cellular toxicity
FSSAs provided a large intracellular drug dose and high cyto- through inhibiting cell proliferation was high. All these results
toxicity. All these results suggested that DOX-loaded FSSAs indicate that these supramolecular self-assemblies might have a
presented a potential application in controlled drug delivery.
potential application in the field of controlled release.
Figure 5: (a) Cell viability of PC-3 cells after incubated with β-CD-BM2 based FSSAs for 48 h. (b) In vitro cytotoxicity of DOX-loaded β-CD-BM2 based
FSSAs and free DOX·HCl against PC-3 cells after incubation for 48 h.
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Figure 6: CLSM images of PC-3 cells incubated with the FSSAs and free DOX·HCl at a concentration of 5 μg/mL. From left to right: Hoechst 33342
(blue), DOX (red) and a merge of two images. (A) Free DOX·HCl, 4 h; (B) FSSAs, 1 h; (C) FSSAs, 4 h.
3. Yi, S.; Zheng, J.; Lv, P.; Zhang, D.; Zheng, X.; Zhang, Y.; Liao, R.
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Acknowledgements
This work was supported by the National Science Foundation of
China (No. 21801162 and 21674086), Natural Science Basic
Research Plan in Shaanxi Province of China (2018JZ2003) and
Scientific Research Program Funded by Shaanxi Provincial
Education Department Program (No. 17JK0103).
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