A bioresponsive diselenide-functionalized hydrogel with cascade catalytic activities for enhanced local starvation- and hypoxia-activated melanoma therapy.

Glutathione (GSH) consumption-enhanced cancer therapies represent important potential cancer treatment strategies. Herein, we developed a new multifunctional diselenide-crosslinked hydrogel with glutathione peroxidase (GPx)-like catalytic activity for GSH depletion-enhanced glucose oxidase (GOx)-mediated tumor starvation and hypoxia-activated chemotherapy. By increasing acid and H2O2 during GOx-induced tumor starvation, the degradation of the multiresponsive scaffold could be promoted, which led to accelerated release of the loaded drugs. Meanwhile, the overproduced H2O2 led to accelerated intracellular GSH consumption under the cascade catalysis of small molecular selenides released from the degraded hydrogel, further enhancing the curative effect of in situ H2O2 and subsequent multimodal cancer treatment. Following the GOx-induced amplification of hypoxia, tirapazamine (TPZ) was transformed into the highly toxic benzotriazinyl radical (BTZ·), exhibiting enhanced antitumor activity. This GSH depletion-augmented cancer treatment strategy effectively boosted GOx-mediated tumor starvation and activated the hypoxia drug, leading to significantly enhanced local anticancer efficacy. STATEMENT OF SIGNIFICANCE: There has been a growing interest in depleting intracellular GSH as a potential strategy for improving ROS-based cancer therapy. Herein, a bioresponsive diselenide-functionalized dextran-based hydrogel with GPx-like catalytic activity was developed for GSH consumption-enhanced local starvation- and hypoxia-activated melanoma therapy. Results showed that the overproduced H2O2 led to accelerated intracellular GSH consumption under the cascade catalysis of small molecular selenides released from the degraded hydrogel, further enhancing the curative effect of in situ H2O2 and subsequent multimodal cancer treatment.