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

Abstract

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.