γ-Glutamyl Transferase/Glutathione Cascade-Responsive Unimolecular Nanoprodrug for Precise Cancer Chemotherapy

Nanoprodrug, utilizing precisely engineered nanomaterial as both a carrier and a caging agent, enables targeted delivery and precise release of toxic antitumor drugs into tumor tissues. To further promote the stability and tumor selectivity, a series of hyperbranched polymer-based unimolecular nanoprodrugs were prepared and analyzed. The toxic drug camptothecin was covalently conjugated to the nanostructures through glutathione cleavable linkers to allow for potent release in tumors. A γ-glutamyl transferase responsive moiety was decorated on the nanoprodrugs to tune the surface charges and promote cancer cell uptake. By combining the advantages of stimuli-responsiveness and the stable polymeric nanostructure, the optimized nanoprodrug showed satisfactory cancer/normal cell selectivity, safety, and anticancer efficacy both in vitro and in vivo.