Cross-Linking of Thiolated Paclitaxel–Oligo(p-phenylene vinylene) Conjugates Aggregates inside Tumor Cells Leads to “Chemical Locks” That Increase Drug Efficacy

Article abstract of DOI:10.1002/adma.201704888

How to reduce the resistance of certain tumor cells to paclitaxel (PTX) and related taxoid anticancer drugs is a major challenge for improving cure rates. An oligo(p-phenylenevinylene) unit with thiol groups and a PTX unit (OPV-S-PTX), which enhances drug efficacy and reverses resistance is thus designed. The mechanism involves diffusion of OPV-S-PTX into the cell, where π–π interactions lead to aggregation. Cross-linking of the aggregates via oxidation of thiol groups is favored in tumor cells because of the higher reactive oxygen species (ROS) concentration. Cross-linked aggregates “chemically lock” the multichromophore particle for a more persistent effect. The IC₅₀ of OPV-S-PTX for tumor cell line A549 is reduced down to 0.33 × 10^?9m from that observed for PTX itself (41 × 10^?9m). Enhanced efficacy by OPV-S-PTX is proposed to proceed via acceleration of microtubule bundle formation. A549/T-inoculated xenograft mice experiments reveal suppression of tumor growth upon OPV-S-PTX treatment. Altogether, these results show that the internal cross-linking of OPV-S-PTX through ROS provides a means to discriminate between tumor and healthy cells and the formation of the chemically locked particles enhances drug efficacy and helps in reducing resistance.

Full text of DOI:10.1002/adma.201704888

CommuniCation
Drug Resistance
www.advmat.de
Cross-Linking of Thiolated Paclitaxel–Oligo(p-phenylene
vinylene) Conjugates Aggregates inside Tumor Cells Leads
to “Chemical Locks” That Increase Drug Efficacy
Lingyun Zhou, Fengting Lv, Libing Liu, Guizhi Shen, Xuehai Yan,* Guillermo C. Bazan,*
and Shu Wang*
and unusual mechanism of action. PTX
How to reduce the resistance of certain tumor cells to paclitaxel (PTX) and
related taxoid anticancer drugs is a major challenge for improving cure
rates. An oligo(p-phenylenevinylene) unit with thiol groups and a PTX unit
(OPV-S-PTX), which enhances drug efficacy and reverses resistance is thus
designed. The mechanism involves diffusion of OPV-S-PTX into the cell,
where π–π interactions lead to aggregation. Cross-linking of the aggregates
via oxidation of thiol groups is favored in tumor cells because of the higher
reactive oxygen species (ROS) concentration. Cross-linked aggregates “chemi-
cally lock” the multichromophore particle for a more persistent effect. The
can promote polymerization of tubulin,
stabilize microtubules, alter normal cel-
lular function, and induces formation of
abnormal mitotic spindles, finally leading
to apoptosis of tumor cells.[2] Paclitaxel
and other taxoid drugs have been used to
treat a variety of solid tumors,[3,4] especially
breast and ovarian cancer.[3,5,6] Despite this
success, PTX can be resisted by certain
tumors through three major mechanisms:
(1) alteration of target, specifically, the
expression of the β-tubulin isotypes[7] or
irregular polyglutamylation of tubulin;[8]
(2) reduced drug uptake by altered extra-
cellular circumstances[9] or decreased
metabolic activity;[10] (3) enhanced drug
efflux based on a variety of ATP-binding
cassette (ABC) superfamily proteins,
ABCC2 (MRP2) mainly for PTX.[11,12] The
latter two are widely recognized reasons of
multidrug resistance for PTX.[13–16]
IC50 of OPV-S-PTX for tumor cell line A549 is reduced down to 0.33 × 10−9
m
from that observed for PTX itself (41 × 10−9 m). Enhanced efficacy by OPV-
S-PTX is proposed to proceed via acceleration of microtubule bundle forma-
tion. A549/T-inoculated xenograft mice experiments reveal suppression of
tumor growth upon OPV-S-PTX treatment. Altogether, these results show
that the internal cross-linking of OPV-S-PTX through ROS provides a means
to discriminate between tumor and healthy cells and the formation of the
chemically locked particles enhances drug efficacy and helps in reducing
resistance.
Substantial research has been dedi-
cated to finding ways to reduce anticancer
A number of upcoming therapeutic systems to treat cancer fail
due to tumor recurrence, the majority of which comprise cells
with a developed ability to resist chemotherapeutic drugs.[1]
In view that this problem is appearing with higher frequency
and involves a wide range of chemotherapeutic drugs, the
multidrug resistance challenge has been brought to the fore-
front of anticancer research. Among a wide range of anticancer
drugs, Paclitaxel (PTX) is known for its broad applicability
drug resistance. The ABC family of protein inhibitors[1,17] and
tubulin tyrosine ligase-like enzymes[18] have demonstrated
some progress. Another approach is to rapidly increase intra-
cellular drug concentration through drug delivery strategies.
The enhanced permeability and retention (EPR) effect is fea-
tured in tumor biology because of abnormally formed tumor
vessels that allow nanocarriers containing chemotherapeutics
to accumulate inside solid tumor cells. Nanocarriers conjugated
L. Zhou, F. Lv, L. Liu, S. Wang
Beijing National Laboratory for Molecular Sciences
Key Laboratory of Organic Solids
Institute of Chemistry
Chinese Academy of Sciences
Beijing 100190, P. R. China
G. Shen, X. Yan
State Key Laboratory of Biochemical Engineering
Institute of Process Engineering
Chinese Academy of Sciences
Beijing 100190, P. R. China
E-mail: yanxh@ipe.ac.cn
E-mail: wangshu@iccas.ac.cn
G. C. Bazan
L. Zhou, F. Lv, L. Liu, S. Wang
University of Chinese Academy of Sciences
Beijing 100049, P. R. China
Departments of Chemistry and Biochemistry and Materials
Center for Polymers and Organic Solids
University of California
Santa Barbara, CA 93106-9510, USA
E-mail: bazan@chem.ucsb.edu
The ORCID identification number(s) for the author(s) of this article
can be found under https://doi.org/10.1002/adma.201704888.
DOI: 10.1002/adma.201704888
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with groups that bind to overexpressed antigens or to receptors
on the target cells can also induce receptor-mediated endocy-
tosis and then enter cells.[19–21] Cell-penetrating transporters
could in theory more effectively deliver drugs into cells.[22]
Within this context, our group has used cationic water-soluble
oligo(p-phenylene vinylene) (OPV) derivatives to enhance the
cell penetration of doxorubicin under illumination.[23] How-
ever, mechanistic aspects of the overall process remain poorly
defined and the cytotoxicity concurrently increased causing
undesirable side effects.
and more than 100-fold, respectively. To test that thiols are
critical in the particle size increase, we tested the precursor
of OPV-SH, namely, OPV-NH2 in Figure 1a, as a control. No
obvious size change was observed for OPV-NH2 with the same
H2O2 treatment (Figure S1, Supporting Information). These
results indicate that OPV-SH assemblies can be cross-linked
with each other via oxidative linking of the thiol groups.[36]
The cytotoxicity of OPV-SH was first evaluated on tumor cells
(A549, MCF-7), PTX-resistant drug cells (A549/T and MCF-7m),
and normal cells (HPF). As shown in Figure S2 (Supporting
Information), OPV-SH exhibits little toxicity toward these cell
lines. We next examined the distribution, localization, and time
requirement for OPV-SH to enter cells. Human lung carcinoma
cells A549/T, a paclitaxel-resistant cell line, were incubated with
2.5 × 10−6 m OPV-SH for different times, and were then imaged
by confocal laser scanning microscopy (Figure S3, Supporting
Information). The fluorescence of OPV-SH could not be detected
within the first 30 min; however, after 2 h incubation the charac-
teristic emission appears within the cytosol of cells (Figure S3a,
Supporting Information). The emission intensity increases with
incubation time with no observable distortion in cell shape, sug-
gesting that OPV-SH aggregation does not interfere with cell
growth and are nontoxic at a concentration of 2.5 × 10−6 m. Neg-
ligible changes in the brightness and shape of the fluorescent
signals occur after 12 h, which indicates the absence of further
OPV-SH incorporation into the cells. Lyso-tracker, a fluorescent
dye, and OPV-SH were co-incubated with cells. As illustrated in
Figure S3c (Supporting Information), OPV-SH and Lyso-tracker
displayed poor colocalization, which demonstrates that OPV-SH
does not locate in lysosomes, even though positively charged
molecules are prone to electrostatic binding with negatively
charged organelles or lysosomes and particles endocytosed into
cells are more likely trapped in lysosomes. Considering the low
molecular weight and the presence of positively charged imida-
mide functionalities, it is likely that OPV-SH is transferred by
an active transport mechanism, or by way of cell-penetrating
peptides (CPPs),[37] rather than endocytosis.
Intracellular molecular assembly provides
a plausible
strategy to accumulate specific molecules inside target cells,
and substantial progress has been accomplished in the con-
text of cell imaging, drug delivery, cell killing, and overcoming
drug resistance.[24–32] Molecular assemblies nonetheless are
difficult to form and to maintain within an intracellular envi-
ronment because of the inherent complexity of the overall cell
system. Because of their biocompatibility and low cytotoxicity,
OPV derivatives have been used in biological applications,
including imaging and photodynamic treatments.[33,34] More to
the point, they undergo aggregation through π–π stacking and
hydrophobic interactions between the aromatic backbones.[35]
Based on these considerations, we disclose here a novel
PTX-OPV conjugate with reactive thiol groups (OPV-S-PTX),
which significantly and unexpectedly enhances PTX efficacy,
and thereby enables to reverse drug resistance. OPV-S-PTX
assembles inside cells and then cross-links via the thiol func-
tionalities in the presence of reactive oxygen species (ROS) to
yield nano/microparticles. This cross-linking process occurs in
the cytoplasm of cancer cells, but not in healthy mammalian
cells, and provides the basis to inhibit diffusion of the drug
from the cells and to improve efficacy. As a result, the IC50 of
OPV-S-PTX for tumor cell line A549 is reduced by 124 times
in comparison to that of PTX itself, and even for the paclitaxel-
resistant tumor cell line A549/T, the IC50 value exhibits nearly
a 90-fold reduction.
We first designed and synthesized a positively charged OPV
grafted with thiol groups (OPV-SH) (Figure 1a,c), which is
water-soluble, fluorescent, and able to effectively penetrate cell
membranes. Complete details on the synthesis and molecular
characterization are provided in the Supporting Information.
OPV-SH exhibits an optical absorption maximum at 418 nm,
an emission maximum at 538 nm (Figure 1b), and a quantum
yield of 8% in water. The aggregation of OPV-SH in aqueous
solution, see Figure 2a, was studied through a combination
of techniques. Dynamic light scattering (DLS) measurements,
scanning electron microscopy (SEM), and transmission elec-
tron microscopy (TEM) were employed to probe the particle
size of the aggregates in solution (Figure 2b). DLS measure-
ments show particles with a diameter of ≈10 nm at a concen-
tration of 2.5 µm. SEM and TEM images indicate that OPV-SH
assembled into 6 nm belt-shaped structures. This organization
is mediated through hydrophobic interactions and π–π stacking,
and the amphiphilic characteristics[35] of OPV-SH. In a second
process, the molecules within the aggregates are locked upon
oxidation with each other through disulfide cross-linking to
form nano/microparticles. As shown by DLS, SEM, and TEM
results (Figure 2b,c), after the addition of an equivalent or
excess amount of H2O2, the particle sizes increase by 20-fold
The confocal laser scanning microscopy images in Figure 3a
show aggregates within the cells when OPV-SH was incubated
with A549/T, A549, and MCF-7m cells, but not with normal
293T and HPF cell lines (Figure 3a, Figure S4a, Supporting
Information). The formation and observation of OPV-SH aggre-
gates therefore can distinguish between tumor and normal
cells. This cell-specific self-aggregation and cross-linking
between molecules is tentatively attributed to the higher con-
centrations of ROS in tumor versus normal cells.[38] We
measured and calculated the ROS capacity of each cell line as
exhibited in Figure 3b, which obviously showed that tumor
cell expressed more ROS compared to normal cells. (Detailed
measurements and calculation of ROS capacity can be found
in the Experimental Section.) OPV-SH molecules can pene-
trate healthy cells, which is supported by the observation that
OPV-SH at concentrations > 64 µM decreases cell viability
(Figure S2, Supporting Information). However, the lower level
of ROS concentration does not allow for effective oxidation
of the thiol groups and OPV-SH molecules diffuse out of the
cells. Only through cross-linking does one obtain the persis-
tence presence inside cells. Indeed, it was possible to observe
aggregated OPV-SH inside A549/T cells for 10 d (Figure S4c,
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Figure 1. a) Synthesis route to OPV-SH, PTT-S-PTX, and OPV-S-PTX. b) Emission and absorption spectra of OPV-SH. c) 1H-NMR spectra of OPV-SH,
Acr-PTX, and OPV-S-PTX.
Supporting Information). Additionally, upregulating the ROS
level led to apparent aggregation of OPV-SH in normal cell line
HPF and downregulating the ROS level caused a remarkable
reduction of aggregation in cancer cell line A549 (Figure S4b,
Supporting Information). For comparison, the small molecule
Lyso-Tracker almost vanished in 2 d. In control experiments,
under the same conditions, OPV-NH2 could image the whole
cytoplasm, but then it diffused out the cell (Figure S5, Sup-
porting Information). OPV-NH2 lacks suitable functionalities
for cross-linking, therefore cells are able to eliminate the small-
sized particles and passed them onto offspring. Hence, the
thiol group is essential for triggering cross-linking within the
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Figure 2. a) The concept schematic diagram elucidates that OPV-SH forms small-sized assemblies via hydrophobic interaction and π–π stacking, and
the assemblies are cross-linked with each other after sulfydryl groups were oxidized to disulfides, for instance, by addition of H2O2. b) Represetative
SEM (above) and TEM (below) images obtained for OPV-SH assemblies. 1 and 2 are the images of OPV-SH without addition of H2O2. 3 and 4 are the
images of OPV-SH (2.5 × 10−6 m) with equivalent amount of H2O2. 5 and 6 are the images of OPV-SH (2.5 × 10−6 m) with excess addition (100 times)
of H2O2. The scale bars are 500 nm for 1, 3, and 5; 200 nm for 2, 4, and 6. c) Hydrodynamic diameter of OPV-SH with or without addition of H2O2
measured by DLS.
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Figure 3. a) CLSM images of A549/T, A549, MCF-7m, 293T, and HPF incubated with 2.5 × 10−6 m OPV-SH for 12 h. The scale bars are 7 µm. b) ROS
capacity scatter graph and box graph of A549/T, A549, MCF-7m, 293T, and HPF. c) The concept schematic diagram below elucidates how did OPV-SH
and OPV-S-PTX function in cell. Free PTX was easily expelled by efflux protein (Pgp or ABCB2) and at the beginning the OPV-SH and OPV-S-PTX were
free in cytosol (left). With the OPV-SH and OPV-S-PTX molecules accumulated in cytosol, assemblies formed followed by sulfydryl groups oxidized
by ROS and oxidizing substances in cytosol (middle). The cross-linked assemblies were not easily expelled and remained function in cell, inducing
microtube bundles formation and cell apoptosis (right). d) IC50 of OPV-S-PTX and PTX for A549, A549/T, MCF-7m, and HPF cells.
cells, which ultimately prevents excretion by the cells. The first
aggregate process is mediated by hydrophobic interactions, it is
reversible. So, for the amine-containing oligomers, that effect
is reversible and the aggregates decrease in size (or dissipate) if
the equilibrium drives monomers out of the cell. Cross-linking
provides another avenue of aggregations, which is irreversible.
The cross-linked aggregates are not prone to equilibrium (they
are chemically bonded) and must remain within the cell.
Facile drug penetration into cells and difficult removal from
tumor cytoplasm may provide a useful drug-resistant cancer
strategy. Selective aggregation in tumor cells could reduce
the side effect encountered that normal cells also be harmed
in chemotherapy. These features led us to covalently bind
paclitaxel to the OPV-SH and to study the resulting effects on
the resistance by cancer cells. OPV-SH molecules were cova-
lently bound with an equivalent amount of acrylyl-containing
PTX (Acr-PTX in Figure 1a) through a Michael addition reac-
tion to afford the desired target species OPV-S-PTX (Figure 1c,
the double bond in the acryloyl group disappeared). For a com-
parison with molecules that lack conjugated backbones, pentae-
rythritol tetrakis(2-mercaptoacetate) (PTT-SH) was also linked
with Acr-PTX (PTT-S-PTX). The thiol groups in both OPV-SH
and OPV-S-PTX can be oxidized to yield disulfide bonds by
taking advantage of intracellular ROS, ultimately yielding a
cross-linked assembly. Since on average OPV-S-PTX retains
three unreacted thiol groups aggregation by cross-linking
with ROS can still occur. Note that the OPV backbone is able
to effectively stack into ordered and compact structures that
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promote minimum surface contact with the aqueous environ-
ment, and that the linking group that brings together the PTX
molecule to the OPV backbone is hydrophilic, thus it is reason-
able that the PTX molecules are present predominantly on the
periphery of the aggregate. In this way, PTX molecules are not
easily expelled and can maintain drug efficacy (Figure 3c). In
order to validate the above-mentioned hypothesis, the cytotox-
icity of OPV-S-PTX on several tumor cell lines and HPF cell
line was studied and compared with that of PTX.
As shown in Figure 3d and Figure S6 (Supporting Infor-
mation), the calculated IC50 of OPV-S-PTX for A549/T is
0.087 × 10−6 m, ≈90 times lower than that of PTX (7.8 × 10−6 m).
When incubated with multidrug-resistant human breast cancer
cells MCF-7m, OPV-S-PTX also showed improved drug effi-
cacy (Figures S6 and S7, Supporting Information, IC50 for
OPV-S-PTX 6.7 × 10−6 m, for PTX 30.2 × 10−6 m). As predicted,
OPV-S-PTX enhances tumor depression, not only for regular
tumor cells (A549, MCF-7) but also for PTX-resistant drug
cells (A549/T and MCF-7m). Moreover, as shown in Figure S6
(Supporting Information), OPV-S-PTX exhibits lower cytotox-
icity to normal cells relative to PTX. Presumably OPV-S-PTX
does not effectively aggregate/cross-link in HPF cells and is not
effectively retained. This lower toxicity of OPV-S-PTX toward
normal cells may ultimately reduce risk of side effects for tax-
ane-based chemotherapy.
The molecular mechanism of OPV-S-PTX for enhanced anti-
tumor efficacy was explored by studying its effect on tumor
cell microtubules. The multivalent interaction of the OPV-S-
PTX assembly with microtubules should be more stable than
the interaction of a single paclitaxel molecule. As shown in
Figure S8 (Supporting Information), immunofluorescence
images show that OPV-S-PTX indeed accelerates the therapeutic
effect of paclitaxel. Microtubule bundles formed within 4 h
after incubated with OPV-S-PTX, and cell apoptosis started after
12 h, on account of cell shrinkage and nuclear fragmentation.
For cells dosed with paclitaxel, bundles could not be observed
until 48 h and the cellular morphology is well maintained.
Any assisting assembling role by using OPV-SH in combina-
tion with OPV-S-PTX was also examined (Figure S9, Supporting
Information). When OPV-S-PTX is used at concentrations
lower than 0.25 × 10−6 m, one finds that the overall aggrega-
tion/cross-linking process is ineffective thereby affecting the
mode of action. However, the addition of 2 or 10 µM OPV-SH,
leads to substantial decreases in cell viability, leading to an
improvement in drug efficiency of 40%. Since OPV-SH exhibits
minor toxicity, the additional component only acts as adjunctive
role for assisting OPV-S-PTX assembly.
To demonstrate the pivotal role of the OPV backbone for the
ROS-induced assembly formation, we introduced PTT-SH, a
molecule possessing same number of thiol groups but with the
Figure 4. a) Real-time in vivo imaging in tumor site after OPV-S-PTX was uptaken for 10 min to 48 h. Note: Fluorescence at tumor site in the blank
group is resulted from the tumor on itself grown from paclitaxel resistance tumor cells. b) Growth of tumors in xenograft mice. A549/T cells were
subcutaneously injected into BALB/c nude mice (n = 6). Size of tumors and weight of mice were measured daily for two weeks. Weight variation curves
and tumor growth curves were constructed to compare relative weight and tumor volumes among saline-, Taxol-, and OPV-S-PTX-injected groups
(** indicates P-value < 0.05).
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absence of conjugated aromatic rings, and compared the results
with those obtained with OPV-SH. By reacting PTT-SH with
Acr-PTX under a similar protocol for preparing OPV-S-PTX,
PTT-S-PTX was afforded (Figure 1a). It shows obviously
impaired PTX efficacy even with addition of PTT-SH
(Figure S10, Supporting Information). Thus, the ability of OPV
backbones to self-assemble through π–π stacking is a critical
element of aggregate formation.
Acknowledgements
The authors are grateful to the National Natural Science Foundation
of China (Nos. 91527306, 21533012, and 21373243), and the Strategic
Priority Research Program of the Chinese Academy of Sciences
(XDA09030306).
Conflict of Interest
The antitumor activity of OPV-S-PTX was evaluated on
A549/T-inoculated xenograft mice. OPV-S-PTX was adminis-
tered by tail-vein injections every 2–7 d, followed by one week
observation, with Taxol and normal saline as the control. Real-
time imaging was acquired at different time intervals after the
mouse had been infected with OPV-S-PTX. The mouse was
anesthetized each time before it was pictured. Images of the
tumor site show that after injection, the drug began to accu-
mulate, and could not be totally metabolized in 2 d (Figure 4a).
For the distribution of OPV-S-PTX in tumor, liver and kidney
were illustrated by fluorescent images of ex vivo dissected
organs of the control and OPV-S-PTX-injected xenograft mice
(Figure S11, Supporting Information). It is worth noting that
ex vivo dissected organs and optical fluorescent images were
cast on MCF-7 xenograft mice. Due to metabolization and
removal through urination, OPV-S-PTX fluorescence was
observed in normal tissues, specifically the liver and kidney.
Tumor size and mouse weight were measured every day
(Figure 4b,c). Tumor growth was remarkably suppressed by
OPV-S-PTX treatment, and showed a better tumor inhibition
rate (54%) compared with PTX (25%) (Figure S12, Supporting
Information). Since, as mentioned above, OPV-S-PTX localizes
in tumor cell and normal cell are less affected the weight loss
of mice injected with OPV-S-PTX is reduced compared to treat-
ment with PTX.
The authors declare no conflict of interest.
Keywords
antitumor, assembly inside cells, chemical locks, drug resistance,
supramolecular paclitaxel
Received: August 25, 2017
Revised: November 12, 2017
Published online:
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