کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2501220 | 1557327 | 2015 | 9 صفحه PDF | دانلود رایگان |
Multidrug resistance (MDR) is one of the major obstacles to the successful treatment of breast cancer. The overexpression of drug efflux transporters such as P-glycoprotein (P-gp) and of anti-apoptotic proteins like survivin are the major causes of MDR. Here, we developed a gambogic acid (GA)-loaded mixed micelle system made of poly(ethylene glycol)-poly(l-histidine)-poly(d,l-lactide-co-glycolide) (PEG-pHis-PLGA) and d-α-tocopheryl polyethylene glycol 1000 (TPGS) that is potentially useful for overcoming MDR by integrating the beneficial effects of pH-sensitive behavior, P-gp inhibition, and down-regulation of anti-apoptotic proteins. The therapeutic potential and mechanism of action of GA-loaded pH-sensitive mixed micelles were examined in drug-sensitive human breast MCF-7 and drug-resistant MCF-7/ADR cells. The resulting GA-loaded mixed micelles with an average size of 190.1 nm were stable at pH 7.4, but dissociated rapidly in a weakly acidic environment (pH 5.5). The GA-loaded mixed micelles increased the cell cytotoxicity against both MCF-7 and MCF-7/ADR cells, which was associated with enhanced apoptosis. In addition, the GA-loaded mixed micelles down-regulated the expression of the anti-apoptotic proteins survivin and Bcl-2, and inhibited the expression and activity of P-gp in MCF-7/ADR cells. Our results indicate that this system could overcome drug resistant in breast cancer by targeting distinct mechanisms, which may facilitate the translation of the GA-mediated effects into clinical benefits.
Schematic representation of the preparation of gambogic acid-loaded pH-sensitive mixed micelles and the mechanisms of action.Figure optionsDownload high-quality image (151 K)Download as PowerPoint slide
Journal: International Journal of Pharmaceutics - Volume 495, Issue 2, 30 November 2015, Pages 840–848