Shaofeng Lou, Xiuyuan Zhang, Mingming Zhang, Shenglu Ji, Weiwei Wang, Ju Zhang, Chen Li, Deling Kong

A reductase-cleavable and thermo-responsive star-shaped polymer nanogel was prepared via an "arm-first" atom transfer radical polymerization approach. The nanogel consists of a thermo- and redox-sensitive core and a zwitterionic copolymer block. The dual sensitive core is composed of poly(N-isopropylacrylamide) that is formed by disulfide crosslinking of N-isopropylacrylamide. The zwitterionic copolymer block contains a poly(sulfobetaine methacrylate) component, a known anti-adsorptive moiety that extends blood circulation time, and a lactose motif of poly(2-lactobionamidoethyl methacrylamide) that specifically targets the asialoglycoprotein receptors (ASGP-Rs) of hepatoma. Doxorubicin (DOX) was encapsulated into the cross-linked nanogels via solvent extraction/evaporation method and dialysis; average diameter of both blank and DOX-loaded nanogels was ~120 nm. The multi-responsiveness of nanogel drug release in different temperatures and redox conditions was assessed. After 24 h, DOX release was only ~20% at 30°C with 0 mM glutathione (GSH), whereas over 90% DOX release was observed at 40°C and 10 mM GSH, evidence of dual responsiveness to temperature and reductase GSH. The IC50 value of DOX-loaded nanogels was much lower in human hepatoma (HepG2) cells compared to non-hepatic HeLa cells. Remarkably, DOX uptake of HepG2 cells differed substantially in the presence and absence of galactose (0.31 vs 1.42 µg/mL after 48 h of incubation). The difference was non-detectable in HeLa cells (1.21 vs 1.57 µg/mL after 48 h of incubation), indicating that the overexpression of ASGP-Rs leads to the DOX-loaded lactosylated nanogels actively targeting hepatoma. Our data indicate that the lactose-decorated star-shaped nanogels are dual responsive and hepatoma targeted, and could be employed as hepatoma-specific anti-cancer drug delivery vehicle for cancer chemotherapy.