Thermo and pH dual-controlled charge reversal amphiphilic graft copolymer micelles for overcoming drug resistance in cancer cells

Currently, multidrug resistance (MDR) is the major challenge of nanotechnology in cancer treatment. In this study, a series of amphiphilic poly(styrene-co-maleic anhydride)-graft-poly(2-(N,N-dimethylamino)ethyl methacrylate) graft copolymer [PSMA₈₉-g-P(DMA₁₆-co-SD)] micelles were prepared. PSMA₈₉-g-P(DMA₁₆-co-SD) graft copolymers were first synthesized by grafting different amounts of sulfadimethoxine (SD) onto PSMA₈₉-g-P(DMA₁₆-co-SD). The PSMA₈₉-g-P(DMA₁₆-co-SD₅₆) micelles exhibited a thermo and pH dual-controlled charge reversal properties without cleavage of chemical bonds. The surface charge of PSMA₈₉-g-P(DMA₁₆-co-SD₅₆) micelles reversed from positive to negative after the solution temperature increased from 25 °C to 37 °C at pH 7.4. However, when the pH value was adjusted to 6.8 at 37 °C, the surface charge became positive again. The thermo and pH dual-controlled charge reversal not only resulted in a controlled doxorubicin (DOX) release but also effectively enhanced the cellular uptake of DOX-loaded PSMA₈₉-g-P(DMA₁₆-co-SD₅₆) micelles through electrostatic absorptive endocytosis. MTT assay demonstrated that DOX-loaded PSMA₈₉-g-P(DMA₁₆-co-SD₅₆) micelles showed the highest inhibition growth of DOX-resistant ovarian carcinoma (A2780/Dox^R) cells with pH 6.8 at 37 °C among those with pH 7.4 at 37 °C and pH 7.4 at 25 °C, leading to higher efficiency in overcoming MDR of A2780/Dox^R cells. Therefore, PSMA₈₉-g-P(DMA₁₆-co-SD₅₆) micelles can be used as intelligent drug-delivery systems to overcome MDR of cancer cells.