Multi-functionalized micelles facilitate intracellular doxorubicin delivery for reversing multidrug resistance of breast cancer

Intracellular doxorubicin (DOX) pumping out of cells through P-glycoprotein (P-gp) transporter lead to the reduction of intracellular DOX levels and induce multidrug resistance (MDR). A hyaluronic acid-deoxycholic acid-histidine and Pluronic F127 (PF127) mixed micellar system, named HA-DOCA-His-PF micelles, functionalized with active targeted endocytosis mediated via CD44 receptor, intracellular triggered DOX release under endosome-pH, and combined with PF127 mediated P-gp efflux inhibition was developed for sufficiently intracellular DOX delivery and MDR reversion. The DOX/HA-DOCA-His-PF drug-loaded micelles displayed endosomal pH-mediated self-assembly/disassembly characteristics, triggered DOX release under an endosomal (pH 5.5) environment, and demonstrated enhanced cytotoxicity and superior MDR reversion performance against drug-resistant MCF-7/Adr tumor cells. Importantly, superior antitumor activity of DOX/HA-DOCA-His-PF micelles was presented on the growth inhibition of MCF-7/Adr bearing tumor, by...