1703321 (1 of 9)
2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
A Transformable Chimeric Peptide for Cell Encapsulation
to Overcome Multidrug Resistance
Chi Zhang, Li-Han Liu, Wen-Xiu Qiu, Yao-Hui Zhang, Wen Song, Lu Zhang,
Shi-Bo Wang, and Xian-Zheng Zhang*
C. Zhang, Dr. L.-H. Liu, W.-X. Qiu, Y.-H. Zhang, W. Song,
L. Zhang, S.-B. Wang, Prof. X.-Z. Zhang
Key Laboratory of Biomedical Polymers of Ministry
of Education and Department of Chemistry
Wuhan 430072, P. R. China
Prof. X.-Z. Zhang
The Institute for Advanced Studies
Wuhan 430072, P. R. China
The ORCID identiﬁcation number(s) for the author(s) of this article
can be found under https://doi.org/10.1002/smll.201703321.
Multidrug resistance (MDR) has been one of the biggest obstacles
in antitumor chemotherapy.
Tumor MDR, whether intrinsic or
acquired, widely exists in clinic chemotherapy. Conventional chem-
otherapeutic drugs, for instance, doxorubicin (DOX) and pacli-
taxel (PTX), generally elicit drug resistance and further result in
the ineffectiveness of drugs.
Moreover, drug resistance induced
by one drug often lead to cross-resistance to many other drugs.
The most primary and fundamental reason associated with MDR
is P-glycoprotein (P-gp)-mediated drug efﬂux.
P-gp is a mem-
brane protein, a member of adenosine triphosphate adenosine
Multidrug resistance (MDR) remains one of the biggest obstacles in chemo-
therapy of tumor mainly due to P-glycoprotein (P-gp)-mediated drug efﬂux.
Here, a transformable chimeric peptide is designed to target and self-assemble
on cell membrane for encapsulating cells and overcoming tumor MDR. This
chimeric peptide (C
, denoted as CTGP) with cath-
epsin B-responsive and cell membrane-targeting abilities can self-assemble into
nanomicelles and further encapsulate the therapeutic agent doxorubicin (termed
as CTGP@DOX). After the cleavage of the Gly-Phe-Leu-Gly (GFLG) sequence
by pericellular overexpressed cathepsin B, CTGP@DOX is dissociated and
transformed from spherical nanoparticles to nanoﬁbers due to the hydrophilic–
hydrophobic conversion and hydrogen bonding interactions. Thus obtained
nanoﬁbers with cell membrane-targeting 16-carbon alkyl chains can adhere
ﬁrmly to the cell membrane for cell encapsulation and restricting DOX efﬂux.
In comparison to free DOX, 45-time higher drug retention and 49-fold greater
anti-MDR ability of CTGP@DOX to drug-resistant MCF-7R cells are achieved.
This novel strategy to encapsulate cells and reverse tumor MDR via morphology
transformation would open a new avenue towards chemotherapy of tumor.
5′-triphosphate (ATP) binding cassette trans-
porters in many MDR cells; it acts as an
active drug efﬂux pump for a broad range of
In recent years, extensive
efforts have been devoted to develop novel
drug delivery systems with speciﬁc cellular
internalization pathway and controllable
drug release kinetics to evade P-gp efﬂux and
increase drug bioavailability.
strategy is greatly restricted by the limited
drug bioavailability and fast drug efﬂux.
Recently, it has been reported that tailor-
made peptides can self-assemble into
speciﬁc nanostructures intracellularly to cir-
cumvent P-gp efﬂux and prolong drug reten-
tion time for anti-MDR chemotherapy.
Besides, peptide and peptide derivatives
have been widely used as functional bio-
materials combined with chemotherapeutic
agents for antitumor therapy, owing to their
excellent biocompatibility, potential bioac-
tivity, speciﬁc biological recognition ability,
and easy chemical modiﬁcation.
is more interesting, a series of peptide-based materials could self-
assemble into speciﬁc networks not only intracellularly
Particularly, pericellularly self-assembled
peptide-based materials could even encapsulate cells and further
block cellular mass exchange. Such a cell-encapsulation strategy
was reported to provide a range of promising therapeutic treat-
ments in clinical applications.
By mimicking the natural
structure of bacterial endospores, this strategy could encapsulate
cells in artiﬁcial shells to form “cell-in-shell” structure for modu-
lating cellular metabolism and even control the fate of cells.
Here, we ﬁrst reported a chimeric peptide encapsulated with
DOX to form dense networks on cell membrane via morphology
transformation for encapsulating cells, restricting drug efﬂux
and overcoming tumor MDR. As shown in Scheme 1, the chi-
meric peptide (C
, denoted as
CTGP) was comprised of cathepsin B-responsive Gly-Phe-Leu-
Gly (GFLG) sequence,
hydrophilic polyethylene glycol (PEG)
and Gly-Gly-Gly-His (GGGH) sequence, cell membrane-targeted
hydrophobic 16-carbon alkyl chain
emission (AIE) probe.
In aqueous solution, CTGP could self-
assemble into nanomicelles and further encapsulate DOX to
form peptide-based drug delivery nanosystem (CTGP@DOX).
During blood circulation, CTGP@DOX could keep stable with
the PEG corona of CTGP and further accumulate at tumor site via
enhanced permeability and retention effect. Once encountering
Small 2018, 14, 1703321