pH-, redox dual-sensitive poly(β-amino ester)-g-TPGS copolymer nanoparticles for drug delivery and inhibition of multidrug resistance in cancer

To overcome multidrug resistance (MDR) in P-glycoprotein (P-gp) overexpressed cancer cells, poly(β-amino ester)-g-d-α-tocopheryl polyethylene glycol 1000 (C32-g-TPGS) copolymers were synthesized by Michael-type step polymerization. These copolymers could self-assemble into nanoparticles (NPs) and encapsulate paclitaxel (PTX) effectively. Due to the tertiary amine groups and disulfide linkages in the copolymers, the NPs exhibited a pH-, redox dual-sensitive structure change as well as the drug release behavior. The NPs were stable under normal physiological environment while they dissociated in a weakly acidic (pH 5.5) or reductive (10 mM DTT) environment and release the incorporated PTX quickly. Although the cell cytotoxicity of the PTX-loaded C32-g-TPGS NPs had no advantage over Taxol against drug-sensitive human ovarian A2780 cells, they did show improved cytotoxicity in drug-resistant A2780/T cells and the IC50 decreased 2 to 4-fold compared to that of Taxol, which presented a feasible way to enhance the therapeutic effect of antitumor drugs in MDR tumors.