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/DOXR) 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. To combat multidrug resistance in cancers, a pH‐sensitive, doxorubicin (DOX)‐loaded mixed‐micelle system is prepared. A green‐fluorescence dye is used to demonstrate that the drug carried by the micelle escapes from the endosomal compartment (see picture). In vitro tests against wild‐type and DOX‐resistant ovarian carcinoma cell lines suggest that the micelles effectively kill both types.