Reduction-Cleavable
Polymeric Vesicles with Efficient Glutathione-Mediated Drug Release
Behavior for Reversing Drug Resistance
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Abstract
In
the treatment of cancer, multidrug resistance (MDR) has been the major
obstacle to the success of chemotherapy. The underlying mechanism
relies on the overexpression of drug-efflux transporters that prevent
the intracellular transport of the drug. In this study, reduction-cleavable
vesicles were designed and developed with efficient glutathione-mediated
drug-release behavior for reversing drug resistance. Polymeric vesicles
were self-assembled from triblock copolymers with disulfide-bond-linked
poly(ethylene glycol) (PEG) and poly(ε-benzyloxycarbonyl-l-lysine) (PzLL). Observations from transmission electron microscopy
(TEM) and confocal laser scanning microscopy (CLSM) outline an obvious
hollow structure surrounded by a thin outer layer, indicating the
successful formation of the vesicles. Using fluorescently detectable
doxorubicin hydrochloride (DOX·HCl) as the model drug, a significant
acceleration of drug release regulated by glutathione (GSH) was found
(>3-fold difference). Upon incubation of the DOX·HCl-loaded
polymeric vesicles with the HeLa cervical cancer cell line exposed
to glutathione, an enhanced nuclear accumulation of DOX·HCl was
observed, elicited by the preferred disassembly of the vesicle structure
under reducing conditions. Importantly, by using the gemcitabine hydrochloride
(GC·HCl)-resistant breast cancer cell line MDA-MB-231, it was
found that cell viability was significantly reduced after treatment
with GC·HCl-loaded polymeric vesicles, indicating that these
vesicles can help to reverse the drug resistance