Polymeric Micelles Targeting Tumor pH

This chapter introduces polymeric micelles for the triggered release either by slightly acidic extracellular pH (pH_e) or by early endosomal pH. Triggered release by tumor pH_e may allow localized high-dose therapy, which is effective for sensitive cells. Active intracellular translocation of the micellar carriers via specific interactions, combined with triggered release in early endosomes and endosomolytic activity of destabilized micelle components, has been proven to be effective for treating multidrug-resistant tumors. The high rate of glycolysis in tumor cells, under either aerobic or anaerobic conditions, has been thought to be a major cause of low pH_e. The pH-sensitive micelle-with-folate showed a dramatic effect when tested with drug-resistant tumors in vitro and in vivo, demonstrating a cell-kill rate as that of sensitive cells. In a resistant tumor xenograft model in mice, the tumor was regressed by iv administration of the folate-decorated pH-sensitive micelles with less weight-loss of the treated animal than control animals treated by pH-insensitive micelles and free doxorubicin.