Cyclodextrin-containing redox-responsive nanogels: Fabrication of a modular targeted drug delivery system

Among various nanoscale drug delivery systems, biodegradable polymeric nanogels present a viable platform for targeted cancer therapy. Herein, we report the fabrication of a modular redox-responsive nanogel system obtained through host-guest interaction-directed self-assembly of dextran-based polymers. The self-assembly of beta-cyclodextrin (beta-CD) and adamantane (Ada) in an aqueous environment is harnessed to fabricate nanogels. Importantly, utilization of a disulfide-containing bis-adamantane-based crosslinker leads to redox-responsive degradation of nanogels upon exposure to glutathione (GSH), an endogenous reducing agent. Nanogels loaded with doxorubicin (DOX) could be further conjugated with an adamantane-containing cyclic peptide-based targeting moiety through non-covalent interactions. In vitro drug release, cytotoxicity and cellular internalization studies were undertaken. Enhanced drug release from nanogels was observed under acidic and reductive glutathione-containing environment. While the empty nanogels were not cytotoxic, drug-loaded nanogels showed cytotoxicity against MDA-MB-231 breast cancer cells. The highest amount of cytotoxicity was observed in GSH-enriched cells when targeted with the targeting group containing drug-loaded nanogels.