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

Abstract

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.