Doxorubicin-loaded polymeric micelle overcomes multidrug resistance of cancer by double-targeting folate receptor and early endosomal pH.

An optimized, pH-sensitive mixed-micelle system conjugated with folic acid is prepared in order to challenge multidrug resistance (MDR) in cancers. The micelles are composed of poly(histidine (His)-co-phenylalanine (Phe))-b-poly(ethylene glycol) (PEG) and poly(L-lactic acid) (PLLA)-b-PEG-folate. Core-forming, pH-sensitive hydrophobic blocks of poly(His-co-Phe) of varying composition are synthesized. The pH sensitivity of the micelles is controlled by the copolymer composition and is fine tuned to early endosomal pH by blending PLLA(3K)-b-PEG(2K)-folate in the presence of a basic anticancer drug, doxorubicin (DOX). In vitro tests are conducted against both wild-type (A2780) and DOX-resistant ovarian carcinoma cell lines. A mixed-micelle system composed of poly(His-co-Phe (16 mole%))-b-PEG (80 wt%) and PLLA-b-PEG-folate (20 wt%) is selected to target early endosomal pH. DOX-loaded micelles effectively kill both wild-type sensitive (A2780) and DOX-resistant ovarian MDR cancer-cell lines (A2780/DOX(R)) through an instantaneous high dose of DOX in the cytosol, which results from active internalization, accelerated DOX release triggered by endosomal pH, and an endosomal membrance disruption.