Glutathione and endosomal pH-responsive hybrid vesicles fabricated by zwitterionic polymer block poly(l-aspartic acid) as a smart anticancer delivery platform

Abstract

Zwitterionic hybrid block copolymer based nanocarriers are ideal candidates for drug delivery applications due the higher resistance to nonspecific protein adsorption in complex media compared to nonionic polymers. Especially, zwitterionic poly(2-methacryloyloxyethyl phosphorylcholine) p(MPC) based nanocarriers can maintain its stability during circulation in complex media, such as serum. Thus, a series of bioreducible and pH-responsive zwitterionic/amphiphilic block copolymers, poly(2-methacryloyloxyethyl phosphorylcholine)50-block-poly(l-aspartic acid)n (p(MPC)50–b–p(AA)n) (n=10, 25, 50, 75), bearing a degradable disulfide linker have been synthesized and exploited as dual-stimuli-responsive drug delivery vehicle of the chemotherapeutic drug, doxorubicin (Dox). Dox was successfully loaded into uniform vesicles (∼100nm) fabricated from p(MPC)50–b–p(AA)n and the release performance was investigated under different pH conditions and with a range of concentrations of the reducing agent, 1,4-dithiothreitol (DTT). At physiological conditions, increasing concentrations of DTT resulted in faster Dox release from vesicles. Dox release at elevated DTT concentrations was more effective at pH5.5 than at pH7.5. Blank vesicles were non-toxic over a wide concentration range when tested in normal cell lines (0.01–100μg/mL). Vesicles efficiently encapsulated Dox and the dual stimuli-responsive disassembly results demonstrated controlled and sustained release of Dox tin 4T1 cancer cells to confer dose-dependent cytotoxicity. Thus, the bioreducible and pH sensitive vesicles appear to be a promising theranostic platform for drug delivery applications.