Tumor microenvironment responsive supramolecular glyco-nanovesicles based on diselenium-bridged pillar[5]arene dimer for targeted chemotherapy

Article abstract of DOI:10.1039/d0cc04149a

Supramolecular glyco-nanovesicles (SeSe-(P5)2?Man-NH3+) based on the host-guest complex of a diselenium-bridged pillar[5]arene dimer and a mannose derivative have been successfully developed for the first time, which possessed tumor microenvironment-respo

Full text of DOI:10.1039/d0cc04149a

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DOI: 10.1039/D0CC04149A
COMMUNICATION
Tumor Microenvironment Responsive Supramolecular Glyco-
Nanovesicles Based on Diselenium-Bridged Pillar[5]arene Dimer
for Targeting Chemotherapy
Received 00th January 20xx,
Accepted 00th January 20xx
Yang Wang, Ming Jin, Zelong Chen, Xianjun Hu, Liang Pu, Zhichao Pei and Yuxin Pei*
DOI: 10.1039/x0xx00000x
+
Supramolecular glyco-nanovesicles (SeSe-(P5)2⊃Man-NH3 ) based Attributed to the versatile chemical modifiability and unique
on the host-guest complex of diselenium-bridged pillar[5]arene symmetrical structures,20-23 pillar[n]arenes have been
dimer and mannose derivative have been successfully developed increasingly popular host molecules in supramolecular
for the first time, which possessed tumor microenvironment- chemistry over decade and utilized in the multifunctional SDDS
responsiveness and specific targetability due to their diselenium in recent years.24-31 Most application of pillar[n]arenes is based
bonds and mannose units, respectively.
on monomeric pillar[n]arenes. Until now, another intriguing
category of pillar[n]arenes, bridged pillar[n]arene dimer, are
less reported and rarely investigated in drug delivery systems.32-
Nowadays, in spite of chemotherapy is one of the most effective
treatments for cancer, its clinical application is limited, resulting
from the lack ability of specific targeting or on-demand drug
release.1,2 During the past decades, smart supramolecular drug
delivery systems (SDDS), possessing the stimuli-responsiveness
and targetability, have been developed, based on dynamic self-
assembly process with noncovalent bonds, especially the host-
34
For instance, Wang et al. reported paclitaxel- loaded
nanoparticles based on disulphide-bridged pillar[5]arene dimer
using a microemulsion method without the involvement of any
amphiphilic structures.34 Compared with sulfur, selenium has
guest
interactions.3-7
Furthermore,
the
tumor
microenvironment (TME) is a complex integrated system, which
features high glutathione (GSH) level, low pH, and
overproduced hydrogen peroxide. Therefore, TME could supply
intracellular stimuli for SDDS to realize targeting therapy.8,9
Supramolecular nanovesicles are wildly used as nanocarriers
to encapsulate drugs resulted from their unique cavities. They
are obtained by amphiphilic host-guest complexes with
multifunctional units through dynamic self-assembly, causing
the susceptibility to exogenous or endogenous stimuli
accompanied by changes in morphology.10,11 Carbohydrates, as
attractive hydrophilic biomolecules with good biocompatibility
and specific recognition of glycoproteins, are gaining more
interests in construction of supramolecular glyco-
nanovesicles.12-15 Thus, supramolecular glyco-nanovesicles
composed of carbohydrate derivatives and macrocyclic host
molecules have potential in targeting chemotherapy.16,17
Pillar[n]arenes, as an emerging category of macrocyclic
molecules, composed of hydroquinone units which are
connected by methylene bridges at the para-position.18,19
Scheme 1 Illustration of (A) the construction of supramolecular
glyco-nanovesicles (SeSe-(P5)2⊃Man-NH3 ) and (B) their TME-
responsive targeting chemotherapy.
Shaanxi Key Laboratory of Natural Products & Chemical Biology,
College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100,
P. R. China. E-mail: peiyx@nwafu.edu.cn; Fax: +86-29-8709-1196;
+
Electronic Supplementary Information (ESI) available: See DOI: 10.1039/x0xx00000x
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We mixed Man-NH2 and SeSe-(P5)2 in 800 µL DMSVOie-wd6ArwticitlehO4nliµneL
DOI: 10.1039/D0CC04149A
deuteron-hydrochloric acid via H NMR to verify if there presented
lower electronegativity and a large atomic radius, resulting in the
lower bond energy of diselenium bonds (172 kJ/mol) than disulfide
bonds (240 kJ/mol).35-37 Hence, we supposed that the drug delivery
systems containing diselenium bonds should have more ideal drug
release behavior than disulfide bonds upon TME. And to the best of
our knowledge, there is no report of multifunctional SDDS based on
diselenium-bridged pillar[5]arene dimer for targeting chemotherapy.
In this work, we reported a supramolecular glyco-nanovesicle
1
host-guest interactions between them. As shown in Fig. 1a, it
revealed the obvious upfield chemical shifts of phenyl protons (Ha),
methylene protons (Hb) and slight upfield chemical shifts of methoxy
protons (Hc) of SeSe-(P5)2. Meanwhile, the methylene protons (Hd)
+
adjacent to the ammonium ion of Man-NH3 presented slight
downfield chemical shifts, which indicated the formation of host-
guest complex (Ha-d defined in Fig S3 and S7, ESI†).39 Unlike what we
expected that one mole of SeSe-(P5)2 would combine with two moles
+
(SeSe-(P5)2⊃Man-NH3 ) with TME-responsiveness based on the host-
guest complex of diselenide-containing pillar[5]arene dimer (SeSe-
+
+
of Man-NH3 , the stoichiometry of the SeSe-(P5)2⊃Man-NH3
+
(P5)2) and mannose derivative (Man-NH3 ) for targeting
complexation via Job’s plot method (Fig. S8, S9, ESI†) showed that
+
chemotherapy, where the targetability derives from the mannose
the 1 : 1 binding stoichiometry between SeSe-(P5)2 and Man-NH3 .
+
residue of Man-NH3 , meanwhile TME-responsiveness derives from
We supposed that the possible assembled state should present as Fig.
1b.
the diselenium bonds of SeSe-(P5)2 (Scheme 1). Thereby, the drug-
loaded supramolecular glyco-nanovesicles could not only effectively
target to cancer cells, but also implement TME-responsiveness to on-
demand drug release.
+
To construct SeSe-(P5)2⊃Man-NH3 glyco-nanovesicles based
+
on the complexation between SeSe-(P5)2 and Man-NH3 , a mixed
+
solution of SeSe-(P5)2 and Man-NH3 in H2O/THF (10 : 1 in v/v) was
+
Firstly, SeSe-(P5)2 and Man-NH3 were synthesized by following
sonicated for 1 h and then stood overnight. SEM and TEM images
(Fig. 1c, and d, respectively) indicated the formation of a vesicular
structure with hollow spherical morphology and the film with a
thickness of 4.75 nm, which was matched with the theoretical
calculation value (Fig. 1b). The dynamic light scattering (DLS) analysis
(Fig. S10a, ESI†) showed that the glyco-nanovesicles have an average
size of 270 nm. Furthermore, the critical aggregation concentration
1
previously reported methods,38 and characterized by H NMR (Fig.
S1–S7, ESI†).
(a)
+
(CAC) of SeSe-(P5)2⊃Man-NH3 was quantitatively found to be 10.4
µg/mL through the water surface tension method (Fig. S11, ESI†).
Upon the methyl thiazole tetrazolium (MTT) assay, the
cytotoxicity of glyco-nanovesicles was evaluated. HepG2 human
hepatoma cells, MCF-7 breast cancer cells, and 293T healthy human
+
kidney cells were incubated with SeSe-(P5)2⊃Man-NH3 glyco-
nanovesicles at various concentrations for different time periods.
The relative cell viabilities (Fig. S12, ESI†) showed that even if at high
+
concentration (200 µg/mL) of SeSe-(P5)2⊃Man-NH3 glyco-
nanovesicles the relative cell viabilities were still at high levels,
(b)
(a)
(b)
(d)
(c)
(d)
(c)
+
Fig. 2 (a) SEM images of DOX-loaded SeSe-(P5)2⊃Man-NH3 glyco-
nanovesicles (scale bar: 500 nm); (b) SEM images of DOX-loaded
SeSe-(P5)2⊃Man-NH3+ glyco-nanovesicles in the presence of 10 mM
+
GSH (scale bar: 2000 nm); (c) Zeta potential of SeSe-(P5)2⊃Man-NH3
1
Fig. 1 (a) H NMR spectra (500 MHz, DMSO-d6, 298 K): (top) Man-
NH3+ (25 mM); (middle) SeSe-(P5)2 : Man-NH3+ = 1 : 5; (bottom) SeSe-
(P5)2 (5 mM); (b) The energy-minimized structure of SeSe-
glyco-nanovesicles with or without DOX-loaded; (d) DOX release
profile of the DOX-loaded SeSe-(P5)2⊃Man-NH3+ glyco-nanovesicles
in 2.5 mM GSH and PBS, respectively.
+
(P5)2⊃Man-NH3 (ball and stick mode); (c) SEM image and (d) TEM
image of SeSe-(P5)2⊃Man-NH3+ glyco-nanovesicles.
2 | J. Name., 2012, 00, 1-3
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which revealed the good biocompatibility of the supramolecular And the DLS results (Fig. S10b, ESI†) showed the average size of DOX-
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DOI: 10.1039/D0CC04149A
loaded glyco-nanovesicles increased to 319 nm. In addition, the Zeta
glyco-nanovesicles.
Then, the drug encapsulation efficiency, and stimuli-responsive potential measurements (Fig. 2c) and UV-Vis spectrum (Fig. S14,
release behavior of glyco-nanovesicles were investigated using ESI†) indicated that DOX was successfully encapsulated (ζ-potential
doxorubicin hydrochloride (DOX) as a model anticancer drug. Upon = - 12.6 mV). Furthermore, the drug loading efficiency and loading
+
encapsulating DOX into the cavity of the SeSe-(P5)2⊃Man-NH3
content of the glyco-nanovesicles were determined to be 69.1% and
glyco-nanovesicles (the preparation details were shown in ESI†), 21.3%, respectively.
SEM (Fig. 2a) showed that the morphology of DOX-loaded SeSe-
To investigate the release behavior of DOX from SeSe-
+
+
(P5)2⊃Man-NH3 glyco-nanovesicles changed to irregular (P5)2⊃Man-NH3 glyco-nanovesicles, the change of morphology
nanoparticles. The change of the morphology may result from and the amount of released DOX were monitored upon neutral
the electrostatic and π-π stacking interactions between DOX environment with GSH. As shown in Fig. 2b, the SEM image of the
+
+
and the complex of SeSe-(P5)2⊃Man-NH3 . Furthermore, the SeSe-(P5)2⊃Man-NH3 glyco-nanovesicles showed that the
DOX-loaded glyco-nanovesicles had different morphology compared morphology of the glyco-nanovesicles was intensely changed and
to the spherical vesicles formed by pristine DOX (Fig. S13, ESI†).
clustered into large pieces after incubated with GSH (10 mM). The
DOX release profiles (Fig. 2d) revealed that DOX was inappreciably
released with the cumulative release amount of 13% under neutral
conditions within 72 h. While high cumulative release amount of 62%
within 72 h was obtained upon the neutral environment with 2.5 mM
GSH. The results demonstrated that the DOX-loaded glyco-
nanovesicles had good stability without obvious premature leakage
and exhibited responsiveness to GSH. Compared with the 17% drug
release of paclitaxel-loaded nanoparticles based on disulphide-
bridged pillar[5]arene dimer upon 10 mM GSH for 86 h, which was
reported by Wang et al., SeSe-(P5)2⊃Man-NH3+ glyco-nanovesicles
showed superior drug release efficiency. Moreover, the DOX-
loaded glyco-nanovesicles were incubated with HepG2 cells for 2, 4,
12 h, respectively, and the intracellular DOX fluorescence intensity
was observed with a confocal laser scanning microscope (CLSM) to
investigate the cellular uptake of glyco-nanovesicles. The CLSM
images (Fig. 3a) showed the fluorescence intensity of DOX (red
channel) was increased with the prolongation of incubated time,
meanwhile, the fluorescence of DOX had a good overlap with the
fluorescence of the nuclei (blue channel). The results of semi-
quantitative analysis (Fig. 3b) were matched with the fluorescence
images. This result demonstrated that DOX-loaded glyco-
nanovesicles could be effectively uptake by HepG2 cells, and
released DOX to enter the nuclei. To evaluate the targetability of the
glyco-nanovesicles, HepG2 cells and 293T cells were incubated with
DOX-loaded glyco-nanovesicles for 4 h. As expected, the red
fluorescence of DOX in 293T cells (Fig. S15, ESI†) was much weaker,
compared with that in HepG2 cells. On the other hand, the CLSM
images (Fig. 3c) showed that the fluorescence intensity of DOX was
significant decreased when the HepG2 cells were pre-incubated with
mannose for 4 h. It means that the cellular uptake of HepG2 cells
mediated by mannose to mannose receptors was reduced due
(a)
(b)
(c)
(d)
(e)
(f)
Fig. 3 (a) CLSM images of HepG2 cells incubated with DOX-loaded
SeSe-(P5)2⊃Man-NH3+ glyco-nanovesicles for 2, 4, 12 h, respectively
(DOX concentration: 5 µM, scale bar: 20 µm); (b) Mean fluorescence
intensity of DOX in HepG2 cells (n = 50); (c) CLSM images of HepG2
(a)
(b)
+
cells incubated with DOX-loaded SeSe-(P5)2⊃Man-NH3 glyco-
nanovesicles upon different treatments (with or without pre-
incubation of mannose for 4 h, DOX concentration: 5 µM, scale bar:
20 µm); (d) Mean fluorescence intensity of DOX in HepG2 cells with
different treatments *p < 0.05 (n = 50); (e) Flow cytometry analysis
and (f) mean fluorescence intensity of DOX in HepG2 cells with
different treatments. i: PBS, ii: DOX-loaded glyco-nanovesicles, iii:
DOX-loaded glyco-nanovesicles + Mannose (DOX concentration: 5
µM).
Fig. 4 Cell viability of (a) HepG2 cells and (b) MCF-7 cells incubated
with DOX-loaded SeSe-(P5)2⊃Man-NH3 glyco-nanovesicles at
different DOX concentrations for 24, 48 and 72 h (n = 6).
+
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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8
9
M. Zhang, X. Guo, M. Wang and K. Liu, Journal oVfieCwoAnrttircolelOlendline
to the blocked mannose receptors. The same conclusion could be
drawn from flow cytometry analysis of HepG2 cells (Fig. 3e, f) and
MCF-7 cells (Fig. S16, ESI†) after incubation with PBS, DOX-loaded
glyco-nanovesicles (with or without pre-incubation of mannose for
4 h), respectively.
Release, 2020, 323, 203-224.
DOI: 10.1039/D0CC04149A
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The anticancer efficiency in vitro of DOX-loaded glyco-
nanovesicles was further investigated via MTT assay. The HepG2 and
MCF-7 cells were separately incubated with DOX-loaded glyco-
nanovesicles for different time periods. As shown in Fig. 4, the cell
viabilities of HepG2 and MCF-7 cells were obviously decreased with
the prolongation of incubating time and the increasement of DOX
concentration. Under the same conditions, the cell viability of 293T
cells was higher than the cell viabilities of HepG2 cells and MCF-7
cells, which was likely due to the lower concentration of GSH and
lower expression of mannose receptor in normal cells (Fig. S17, ESI†).
Furthermore, the glyco-nanovesicles effectively reduced the toxicity
of free DOX to 293T cells, although its cytotoxicity to cancer cells was
not as good as that of free DOX owing to the slow release of DOX
from the loaded-vesicles (Fig. S18, ESI†). The results demonstrated
that the glyco-nanovesicles not only had a good killing effect on
cancer cells, but also could reduce the toxicity of drugs to
normal cells.
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In summary, we have successfully designed and fabricated
supramolecular glyco-nanovesicles based on pillar[5]arene dimer via
+
the host-guest interactions between SeSe-(P5)2 and Man-NH3 . The
glyco-nanovesicles possessed TME-responsiveness and targetability
of cancer cell, owing to the diselenium bonds and mannose residue,
respectively. Besides, it had good biocompatibility and could
effectively accumulate in cancer cells to release DOX via the cleavage
of diselenium bonds to achieve selective cytotoxicity. Therefore, this
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
This research work was supported by the National Natural
Science Foundation of China (21772157 and 21877088).
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