Reduction-Cleavable Polymeric Vesicles with Efficient Glutathione-Mediated Drug Release Behavior for Reversing Drug Resistance

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

Forest plot of the highest quantile versus lowest quantile blood 25(OH)D level and breast cancer risk.

<p>Forest plot of the highest quantile versus lowest quantile blood 25(OH)D level and breast cancer risk.</p

Characteristics of the studies included in the meta-analysis of blood 25(OH)D and breast cancer risk.

*<p>Abbreviations: OR, odds ratio; 95% CI, 95% confidence interval; BMI, body mass index; HRT, hormone replacement therapy; PTH, parathyroid hormone; WHI, women’s health initiative.</p>#<p>Odds ratio for the highest versus lowest category of blood 25(OH)D level.</p

The odds ratios for breast cancer risk by plasma 25(OH)D concentration.

*<p>The OR was adjusted by age, age at first birth, age at menarche, use of contraceptive, menopausal status, first-degree relatives’ history of breast cancer and season of blood collection.</p

Working flow chart for selection of studies included in meta-analysis.

<p>Working flow chart for selection of studies included in meta-analysis.</p

The baseline characters for the participants in the study.

<p>The baseline characters for the participants in the study.</p