Synthesis of zwitterionic redox-responsive nanogels by one-pot amine-thiol-ene reaction for anticancer drug release application

Zwitterionic polymers with high biocompatibility and extremely low fouling properties have attracted interest as promising nanocarriers for drug delivery. In this work, novel zwitterionic nano-gels were prepared via the facile one-pot “click” reaction of α, ω-functionalized poly(sulfobetaine)s (FPSBs) and cystamine. FPSBs were first synthesized by atom transfer radical polymerization with initiators having furan-maleimide adducts followed by the end-capping reaction with thiolactone derivatives. Subsequently, the thiolactone rings of PSBs could be opened by aminolysis of cystamine crosslinkers and the released thiol-groups reacted with the double-bonds of furan-maleimide moieties to form PSB nanogel networks through the thiol-ene “click” reaction. The nanogels were readily degraded in the presence of glutathione (GSH) as a reducing agent, which was confirmed by the changes in particle size. Doxorubicin (DOX), could be loaded in the core of the nanogels with a high drug loading content of 24.3%. Moreover, the in vitro drug release profile showed a low release (24.8%) of DOX at a physiological environment, whereas there were burst releases of 74.4% and 89.9% in the presence of 5 mM and 10 mM GSH similar to a tumor cytoplasm environment. Cell viability assays demonstrated that the nanogel showed low cytotoxicity against the normal HEK293 cell, while exhibited a high cytotoxic activity towards HeLa cancer cells. These evidences revealed the effective redox responsive characteristics of the PSB nanogels.