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

Higher blood 25(OH)D level may reduce the breast cancer risk: evidence from a Chinese population based case-control study and meta-analysis of the observational studies.

Experimental data suggest a protective effect of vitamin D on breast cancer; however, epidemiologic results remain inclusive. With a Chinese population-based case-control study and meta-analysis of the observational studies, we here systematically evaluated the association of blood 25(OH)D level and breast cancer risk. With 593 breast cancer cases and 580 cancer-free controls from Shanghai, China, we found that 80% of the normal women had severe vitamin D deficiency (less than 20 ng/mL) and 15.2% had mild deficiency (20 to 30 ng/mL) and only 4.8% of women had sufficient vitamin D level (>30 ng/mL) while the proportion was 96.1%, 3.2% and 0.7% respectively for the breast cancer patients. Compared to those with the lowest quartile of plasma 25(OH)D level, women with highest quartile 25(OH)D level showed a significant decreased breast cancer risk (Q4 vs.Q1: OR = 0.10, 95% CI = 0.06-0.15) and every 1 ng/ml increment of plasma 25(OH)D level led to a 16% lower odds of breast cancer (OR = 0.84, 95% CI = 0.81-0.87; P<0.001). From the meta-analysis of the observational studies, we found that women with highest quantile of blood 25(OH)D level was associated with a significantly reduced breast cancer risk compared to those with lowest quantile of blood 25(OH)D level for the 11 nested case-control and retrospective studies (pooled OR = 0.86, 95% CI = 0.75-1.00) and 10 case-control studies (7 population based, OR = 0.35, 95% CI = 0.24-0.52; 3 hospital based, OR = 0.08, 95% CI = 0.02-0.33). These results suggest that vitamin D may have a chemo-preventive effect against breast cancer

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

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

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