Gambogic acid-loaded pH-sensitive mixed micelles for overcoming breast cancer resistance.
Nyckelord
Abstrakt
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.