A nanodrug to combat cisplatin-resistance by protecting cisplatin with p-sulfonatocalix[4]arene and regulating glutathione S-transferases with loaded 5-fluorouracil

Article abstract of DOI:10.1039/c9cc03012c

A nanodrug that can effectively combat cisplatin-resistant A549/CDDP cells was developed by protecting cisplatin from glutathione (GSH) detoxification trough a host-guest interaction between cisplatin and p-sulfonatocalix[4]arene. The enzymatic activity o

Full text of DOI:10.1039/c9cc03012c

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A nanodrug to combat cisplatin-resistance by protecting cisplatin
with p-sulfonatocalix[4]arene and regulating glutathione S-
transferases with loaded 5-fluorouracil
Received 00th January 20xx,
Accepted 00th January 20xx
Xin Dai,a,b Xueying Zhou,a Chunyan Liao,a Yongchao Yao,a Yunlong Yu,a and Shiyong Zhang*,a
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
nanodrug that can effectively combat cisplatin-resistant
A549/CDDP cells was developed by protecting cisplatin from
glutathione (GSH) detoxification trough a host-guest interaction
between cisplatin and p-sulfonatocalix[4]arene. The enzymatic
activity of glutathione S-transferases (GSTs) was also regutated by
loaded 5-fluorouracil (5-FU).
Cisplatin was approved by the U.S. Food and Drug
Administration (FDA) for clinical application early in 1978.
However, patients receiving this chemotherapy usually suffer
from severe drug resistance.1 Studies on the mechanism of
cisplatin resistance have revealed that while the highly
reactive Pt (II) can facilitate intercalation of DNA to exert
cytotoxicity, it can also be easily inactivated by various
sulfhydryl-containing molecules in vivo, such as human serum
albumin (HSA), metallothionein (MT), and especially
glutathione (GSH) in tumor cells.2 GSH complexes with cisplatin
in the form of dimers by -SH occupying the drug’s active site of
the leaving group Cl-, which causes drug efflux and the inability
to form cisplatin-DNA adducts, thus blocking the apoptosis
induced by failure of the DNA mismatch repair pathway.3
Notably, clinical studies have indicated that detoxification of
GSH is associated with glutathione S-transferases (GSTs),
which are overexpressed in resistant cells and can catalyse the
detoxification.4 To overcome GSH/GSTs pathway-induced
resistance to cisplatin, there are two strategies that should
both be pursued: making cisplatin itself more resistant to
sulfhydryl detoxification without impairing its cytotoxicity, and
modulating intracellular GSH or GST levels by various means.
Thanks to advances in nanomedicine, it is possible to
simultaneously combine these two strategies into one
nanodrug carrier to achieve a synergistic effect.5 Nanodrug
carriers are now widely used in the delivery of platinum drugs
Scheme 1. Schematic illustrations of the preparation of Pt-
cCAV5-FU (A) and the mechanism to combat cisplatin-resistant
A549/CDDP cells (B).
in vivo, for they can improve the solubility of hydrophobic
drugs and enrich them in tumor tissues through enhanced
permeability and retention (EPR) effects, thereby optimizing
the biological distribution and reducing systemic toxicity.
There have been several reports about nanoparticle platforms
used to overcome GSH/GSTs pathway-induced cisplatin
resistance by combining the two strategies simultaneously. As
a typical example, Ling et al. co-delivered Pt (IV) prodrugs and
poly (disulfide amide) polymers within nanoparticles
constructed by lipid-PEG to combat cisplatin-resistant
A2780cis ovarian cancer.6 Li et al. reported an ethacrynic acid-
modified Pt (IV) prodrug in lipid-PEG micelles, which
significantly enhanced antitumor outcomes against cisplatin-
resistant BEL7404-CP20 liver cancer cells both in vitro and in
vivo.7 As a key part of these combination strategies, the
cisplatin was covalently modified into Pt (IV) prodrugs, which
compared to Pt (II) are much more resistant to deactivation by
a. National Engineering Research Centre for Biomaterials, and college of chemistry,
Sichuan University, 29 Wangjiang Road, Chengdu 610064, China. E-mail:
szhang@scu.edu.cn
b. Zunyi Medical and Pharmaceutical College Pingan Road, Xinpu District, Zunyi
56300, China.
Electronic
Supplementary
Information
(ESI)
available:
See
DOI:
10.1039/x0xx00000x
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reductants.8 However, this prodrug strategy of covalently
modifying cisplatin is time-consuming and costly. Besides, due
to the need to add adjuvants such as PEG, the effective drug
loading of these models is relatively low, and the loose nano-
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DOI: 10.1039/C9CC03012C
assemblies may also be unstable in
environment.
a physiological
Recent studies have shown that supramolecular
chemotherapies utilizing macrocyclic molecules to non-
covalently protect drugs can effectively prolong their half-
lives.9 For example, protected by p-sulfonatocalix[4]arene, the
half-life of the new platinum drug ME5SS can be prolonged by
as much as 3.2 times in a sulfhydryl-rich environment
compared to the unprotected drug while maintaining
cytotoxicity.10 Inspired by these promising results, we herein
report a supramolecular nanodrug that can protect cisplatin
Fig. 1 Characteristics of Pt-cCAV5-FU. Distribution of the
hydrodynamic diameter sizes of CAM, Pt-CAV, Pt-cCAV, and Pt-
cCAV5-FU (A). Vesicle structure verification with fluorescence
leakage tests by encapsulating Phloxine B (B). Zeta potentials
of CAM, Pt-CAV, Pt-cCAV, and Pt-cCAV5-FU; [1] = 2 mM (C).
Representative TEM of Pt-cCAV5-FU (D).
and simultaneously deliver
a GST regulator to combat
GSH/GSTs pathway-induced cisplatin resistance. As shown in
Scheme 1, cisplatin can co-assemble with 1 by a host–guest
interaction, then
1 evolves into a cisplatin-induced p-
sulfonatocalix[4]arene vesicle (Pt-CAV) in water, while it forms
a p-sulfonatocalix[4]arene micelle (CAM) structure when 1
self-assembles alone. Crosslinked Pt-CAV (Pt-cCAV) can be
easily obtained by crosslinking Pt-CAV with a linker containing
an ester bond. Through the successful protection to cisplatin in
a sulfhydryl environment by the calixarene cavity of 1,
nanoparticles showed good cytotoxicity both to human non-
small cell lung cancer (A549) cells and their cisplatin-resistant
derivative, A549/CDDP. Furthermore, when the soluble GST
regulator 5-FU was loaded in the inner hydrophilic region of
Pt-cCAV, the resulting Pt-cCAV5-FU further regulated GSTs and
effectively reversed the drug resistance of A549/CDDP. This
novel nanodrug possesses the advantages of good
biocompatibility, high loading of cisplatin, and high stability in
a physiological environment, thus giving it great potential to
combat GSH/GSTs pathway-induced cisplatin resistance.
Calixarenes are third-generation macrocyclic molecules,
among which calix[4]arenes have been studied most
extensively for their applications in medicine.11 The
calix[4]arene can be endowed with excellent water solubility
and has good biocompatibility when modified with sulfonic
groups on the upper rim (p-sulfonatocalix[4]arenes).12 To
make them self-assemble into nanocarriers in water, we
modified the lower rim of p-sulfonatocalix[4]arenes with 6-
bromo-1-hexene to construct amphiphilic molecule 1 (see
Supporting Information for the synthetic route).
by neutral cisplatin and 1 in a ratio of 1:1, suggesting the
hydrophobic cavity of 1 is the binding site (Fig. S1). A series of
ratios of cisplatin to 1 were tested, and when the ratio of
cisplatin to 1 was < 1.0, they could not co-assemble well and
had inhomogeneous particle sizes and a high polydispersity
index (PDI). When the ratio was ≥ 1.0, the final loading amount
of cisplatin could not be further increased (Table S1),
confirming the formation of 1:1 host–guest complexes
between cisplatin and 1. When no cisplatin was added, 1 self-
assembled into micelle structures (CAM, Scheme 1), and the
hydration kinetic radii were reduced to 29.0 nm. In order to
further clarify the binding mode of cisplatin to molecule 1, we
set a control group with cisplatin and 4 eq. of sodium 4-(hex-5-
en-1-yloxy) benzenesulfonate 5, which is the monomer of 1.14
It was found that the vesicle structure was not assembled by
[cisplatin + 5] as confirmed by the DLS and fluorescence
leakage test (Fig. S2). This result indicated that the “guest-
induced assembly” could only be achieved through the
hydrophobic binding of cisplatin to the preorganized
hydrophobic cavity of 1.15
Pt-cCAV was obtained by triggering a “thiol-ene” click
reaction at the hydrophobic region of Pt-CAV in the presence
of compound 2 (see Supporting Information for details). The
1
successful crosslinking was confirmed by H NMR, where 81%
of double bonds were consumed, and all peaks became broad
(Fig. S4), and gel permeation chromatography (GPC), where a
By dissolving 1 in water and adding cisplatin at a ratio of
1:1, a very clear and transparent solution of Pt-CAV was
obtained. Dynamic light scattering (DLS) showed that the
hydration kinetic radii of the Pt-CAV were about 58.8 nm (Fig.
1A). The vesicle structure was confirmed by fluorescence
leakage assays, where the surfactant Triton X-100 destroyed
the assembly of Pt-CAV, and the maxima of excitation and
emission fluorescence intensity of the indicator Phloxine B
increased more than 6 times (Fig. 1B).13 MALDI-TOF-MS
spectrum showed that the host–guest complex assembled only
great increase in molecular weight was determined [Mn
=
56916 g mol−1, and PDI = 2.061 (Fig. S5)]. Dilution experiments
showed that Pt-cCAV maintained a stable particle size upon
dilution, as low as 10 μg mL-1 in water, while Pt-CAV
disintegrated when below 60 μg mL-1 (Fig. S6A). When
incubated in 10% fetal bovine serum, Pt-cCAV kept well after 1
h, but no reasonable particle size could be detected under the
same conditions for Pt-CAV (Fig. S6B). These results suggested
high tolerance of crosslinked nanoparticles for extremely
dilute concentrations or
environment.16
a
complex bloodstream
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The final Pt-cCAV5-FU was prepared with the same
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DOI: 10.1039/C9CC03012C
procedure as for Pt-cCAV, except for employing a solution
containing 5-FU instead of pure water. DLS showed that 5-FU
entrapment did not disturb the particle size of Pt-cCAV (Fig.
1A). 5-FU entrapment also did not change the zeta potential of
Pt-cCAV (Fig. 1C). Representative transmission electron
microscopy (TEM) images showed that nanoparticles of Pt-
cCAV5-FU were spherical in shape without adhesion or
aggregation (Fig. 1D), with a diameter of 70 nm, which was
consistent with the DLS results. Inductively coupled plasma
(ICP) tests showed that the loading content of cisplatin was 13
wt%. Encapsulation percentage (EN%) assays showed that the
maximum encapsulation percentage of 5-FU was 19% (Table.
S2), and the final molar ratio of cisplatin to 5-FU in Pt-cCAV5-FU
was calculated to be 4.04:1.
The human non-small cell lung cancer cell line A549 and its
cisplatin-resistant derivative A549/CDDP were chosen to test
the effectiveness of Pt-cCAV5-FU by comparison with cisplatin,
Fig. 2 Regulatory effect of Pt-cCAV5-FU on GSTs and cell uptake
of Pt-cCAV5-FU by A549 and A549/CDDP. Western blots of GST-
π expression (A) and GST activity of of A549/CDDP cells (B)
after treatment with cisplatin, Pt-cCAV, and Pt-cCAV5-FU for 12
h at a Pt concentration of 50 μM; no treatment was the
control. Platinum content in the genomic DNA of A549 and
A549/CDDP cells after incubation with Pt-cCAV and Pt-cCAV5-FU
at a Pt concentration of 50 μM for 12 h (C). The relative cell
uptake efficiency of DiI-labeled Pt-cCAV5-FU under different
inhibitors; chlorpromazine inhibits the endocytosis pathway
mediated by clathrin, genistein inhibits the endocytosis
pathway mediated by caveolin, and amiloride inhibits the
endocytosis pathway mediated by micropinocytosis (D). The
flow cytometric profiles (E) and mean fluorescence intensity
(F) of DiI-labeled Pt-cCAV5-FU after 2, 6, and 12 h incubations
with A549 and A549/CDDP cells, respectively; untreated cells
were used as a control.
Pt-cCAV, and [cisplatin
dependent cell inhibition assays are shown in Fig. S7, and the
corresponding half inhibitory concentrations (IC50 and
+ 5-FU]. Results of 48-h dose-
)
resistance fold are shown in Table 1. Compared with free
cisplatin, the Pt-cCAV group decreased the drug resistance fold
of A549/CDDP from 4.98 to 1.76, suggesting that the
protective effect provided by p-sulfonatocalix[4]arene made
cisplatin more resistant to detoxification by various
intracellular sulfhydryl-containing molecules, including GSH.
When treated with Pt-cCAV5-FU, the drug resistance fold of
A549/CDDP decreased to 0.75, demonstrating that when
loaded with 5-FU, the nanodrug further reduced cell resistance
to cisplatin. Notably, the crosslinked micelles (cCAM, see
Supporting Information for details), equivalent to the pure
carriers in Pt-cCAV,17 showed negligible toxicity to cancer or
normal cells over the whole experimental concentration range
(Fig. S8), suggesting that the toxicity of Pt-cCAV originated
entirely from the guest cargo cisplatin instead of the carriers.
By contrast, the free [cisplatin + 5-FU] combination showed
only a slight reduction in drug resistance (Table 1).
5-FU when used in combination with cisplatin.18 Tominaga et
al. found that a combination of 5-FU and cisplatin effectively
treated
recurrent
oesophageal
cancer
through
immunohistologic assays because of the significantly reduced
expression of GST-π.19 Nishiyama et al. found that GST-π gene
expression is significantly reduced when 5-FU and cisplatin are
combined, which induces synergistic toxicity against cisplatin-
resistant hepatocellular carcinoma HCC-48 cells.20 As shown in
Fig. S9, western blotting showed that A549/CDDP cells indeed
had higher GST-π expression compared to A549 cells. When
A549/CDDP cells were treated with Pt-cCAV, GST-π expression
did not change compared with the control and free cisplatin.
However, GST-π expression was obviously reduced when cells
were treated with Pt-cCAV5-FU (Fig. 2A), which indicated that 5-
FU loaded in nanoparticles downregulated the expression of
GST-π. GST activity experiments further showed that only the
Pt-cCAV5-FU group had the distinct effect of reducing GST
activity in A549/CDDP cells (Fig. 2B), confirming that the
enzymatic activity of GSTs decreased with the significant
inhibition of the GST-π expression level.
Table 1 Comparison of IC50 and derived drug resistance fold of
cisplatin, Pt-cCAV, Pt-cCAV5-FU, and [cisplatin + 5-FU] to A549
and A549/CDDP cells. Data are presented as means ± SD (n =
3).
IC50 (μM)
A549/CDDP
Resistance
Fold
Test Group
A549
Cisplatin
Pt-cCAV
Pt-cCAV5-FU
7.5 ± 0.5
25.7 ± 2.0
18.6 ± 1.2
37.6 ±1.3
45.1 ± 0.5
14.0 ± 2.2
21.0 ± 1.0
4.98
1.76
0.75
3.38
Cisplatin + 5-FU 6.2 ± 0.7
Since free 5-FU showed little toxicity over the whole tested
concentration (Fig. S7), the effect of 5-FU on GST-π expression
and GST activity in A549/CDDP cells was checked to clarify
whether 5-FU reduced cell resistance by inhibiting the GST
pathway. GST-π (a member of the GST family) has been
confirmed in a large number of studies to be the most directly
related marker of cisplatin resistance and is the main target of
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Intuitively, by inhibition of the pathways leading to
cisplatin resistance, the resistance fold of A549/CDDP cells can Foundation of China (No. 51673130) and the Applied Basic
be reduced and ideally approach 1.0. Surprisingly, when Research Project of Sichuan Province (No. 2015JY0279).
treated with Pt-cCAV5-FU, the resistance fold of A549/CDDP
Journal Name
This work was supported by the National NaVtiuewraAlrtSiccleieOnnlcinee
DOI: 10.1039/C9CC03012C
cells decreased to as low as 0.75, suggesting that Pt-cCAV5-FU
was even more toxic to A549/CDDP than A549 cells. The
genomic DNA Pt content test also showed that Pt-cCAV5-FU
resulted in 1.45 times more nuclear platinum in A549/CDDP
than A549 cells (Fig. 2C), which confirmed that Pt-cCAV5-FU
exerted greater cytotoxicity to A549/CDDP cells.21 In order to
determine how the reversal of drug resistance in A549/CDDP
Conflicts of interest
There are no conflicts to declare.
Notes and references
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internalization of the nanoparticles by co-incubating A549 cells
with 1,1’-dioctadecyl-3,3,3’,3’-tetramethylindocarbocyanine
perch-lorate (DiI)-labeled Pt-cCAV5-FU and checking the
inhibition of internalization mechanisms with various inhibitors
(See Supporting Information for details). As shown in Fig. 2D,
compared with chlorpromazine and amiloride, cells treated
with genistein showed the least uptake according to relative
intracellular fluorescence, indicating that the internalization
pathway of Pt-cCAV5-FU was through caveolin-mediated
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cells consistently took in more nanoparticles (Fig. 2E, F).
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results illustrate that Pt-cCAV5-FU not only protected cisplatin
from detoxification by GSH and regulated the enzymatic
activity of GSTs, but was also uptaken faster by A549/CDDP
cells, which facilitated the intracellular accumulation of more
drugs. All of these factors contributed to Pt-cCAV5-FU showing
more toxicity to the resistant cell lines than to non-resistant
cell lines.
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17 Since 1 could not form vesicles alone, the cross-linked micelles
cCAM was used to replace pure carriers in Pt-cCAV or Pt-cCAV5-FU
in in vitro cytotoxicity assay.
In summary,
a supramolecular-based strategy was
successfully used to create the nanodrug Pt-cCAV5-FU. This drug
combats GSH/GSTs pathway-induced cisplatin resistance by
protecting cisplatin from glutathione (GSH) detoxification
through host–guest interactions between cisplatin and p-
sulfonatocalix[4]arene, and by regulating GSTs with loaded 5-
FU. Compared with the free drug, Pt-cCAV reduced the drug
resistance fold of A549/CDDP cells from 4.9 to 1.7, and Pt-
cCAV5-FU further reduced it to 0.75 via 5-FU regulation of GST-
π expression and reduction of GST activity. In addition to the
pathway inhibition, Pt-cCAV5-FU was uptaken faster by
A549/CDDP cells through caveolin-mediated endocytosis,
resulting in higher cytotoxicity to A549/CDDP than A549 cells.
The novel nanodrug Pt-cCAV5-FU thus effectively reversed
A549/CDDP resistance and holds great potential in cancer
therapy.
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