Mitochondria-targeted ROS- and GSH-responsive diselenide-crosslinked polymer dots for programmable paclitaxel release

Abstract

Enhancing therapeutic efficacy of drugs from reactive oxygen species (ROS) and glutathione (GSH)-responsive matrix and minimizing toxic effects on normal cells remains a challenge in programmable anticancer drug delivery. Herein, ROS- and GSH-responsive paclitaxel (PTX)-loaded polymer dot (PD) with mitochondria-targeting capability was designed by constructing diselenide linkage and triphenylphosphonium (TPP) for tunable PTX release and fluorescence for cancer theranostics. PD-TPP nanocarrier could improve the PTX stability after loading (PD-TPP(PTX)), and the cleavage of diselenide bond in the presence of H2O2 and GSH triggered the controllable PTX release, providing higher fluorescence intensity. As the levels of H2O2 and GSH are higher in cancer cells compared to normal cells, PTX was selectively released from PD-TPP in cancer cells, reducing cell viability (∼25%) and causing enhanced apoptosis of cancer cells compared to normal cells. The PD-TPP(PTX) selectivity was also reflected by distinct fluorescence intensity in HeLa and PC-3 cells (cancer) compared to CHO-K1 cells (normal). Furthermore, conjugated TPP promoted the PD-TPP(PTX) accumulation in mitochondria due to specific targeting of TPP towards mitochondria, allowing PTX release in mitochondria of cancer cells. Hence, this approach could be a potential strategy to enhance therapeutic efficacy of cancer drugs and minimize the side effects on normal cells.