Reversion of multidrug resistance by co-encapsulation of vincristine and verapamil in PLGA nanoparticles

Multidrug resistant (MDR) cancer may be treated using combinations of encapsulated cytotoxic drugs and chemosensitizers. To optimize the effectiveness of this combinational approach, poly(D,L-lactide-co-glycolide acid) (PLGA) nanoparticles formulations capable of delivering a cytotoxic drug, vincristine, a chemosensitizer, verapamil, or their combination were prepared via combining O/W emulsion solvent evaporation and salting-out method. Moreover, this work evaluated a number of approaches for the administration of chemosensitizer-cytotoxic drug combinations in a systematic fashion. The results showed that the administration sequence of anticancer drug and chemosensitizer was critical for maximal therapeutic efficacy and the simultaneous administration of vincristine and verapamil could achieve the highest reversal efficacy. In addition, PLGA nanoparticles (PLGANPs) showed moderate MDR reversal activity on MCF-7/ADR cells resistant to vincristine. The dual-agent loaded PLGA nanoparticles system resulted in the similar cytotoxicity to one free drug/another agent loaded PLGANPs combination and co-administration of two single-agent loaded PLGANPs, which was slightly higher than that of the free vincristine/verapamil combination. Co-encapsulation of anticancer drug and chemosensitizer might cause lower normal tissue drug toxicity and fewer drug-drug interactions. Therefore, we speculate that PLGANPs simultaneously loaded with anticancer drug and chemosensitizer might be the most potential formulation in the treatment of drug resistant cancers in vivo. (C) 2009 Elsevier B.V. All rights reserved.