Enhanced intercellular retention activity of novel pH-sensitive polymeric micelles in wild and multidrug resistant...

The purpose of this work was to demonstrate the advantage of using pH-sensitive polymeric mixed micelles (PHSM) composed of poly(L: -histidine) (polyHis)/poly(ethylene glycol) (PEG) and poly(L: -lactic acid) (pLLA)/PEG block copolymers with folate conjugation to increase drug retention in wild-type and MDR tumor cells.

Both wild-type and multidrug resistant (MDR) human breast adenocarcinoma (MCF-7) cell lines were used to investigate the accumulation and elimination of doxorubicin (DOX), PHSM with folate (PHSM/f), and pH-insensitive micelles composed of pLLA/PEG block copolymer with folate (PHIM/f).

Cells treated with PHSM/f showed decelerated elimination kinetics compared to cells treated with PHIM/f. MDR cells treated with drug-containing PHSM/f for 30 min retained 80% of doxorubicin (DOX) even after incubation for 24 h in the absence of drug. On the other hand, cells treated with drug-containing PHIM/f retained only 40% of DOX within the same period of time. Flow cytometry and confocal microscopy confirmed these results.

Cellular entry of the micelles occurred via receptor-mediated endocytosis using folate receptors. The pH-induced destabilization of PHSM/f led to rapid distribution of drug and polymer throughout the cells, most likely due to polyHis-mediated endosomal disruption. This reduced the likelihood of drug efflux via exocytosis from resistant tumor cells.