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.
摘要：
谷胱甘肽（GSH）消耗增强的癌症疗法代表了重要的潜在癌症治疗策略。在这里，我们开发了一种新型多功能的双硒化物交联水凝胶,其具有类似谷胱甘肽过氧化物酶(GPx)的催化活性,可用于GSH耗竭增强的葡萄糖氧化酶(GOx)介导的肿瘤饥饿和缺氧激活的化疗.通过在GOx诱导的肿瘤饥饿期间增加酸和H2O2，可以促进多响应支架的降解，这导致装载药物的加速释放。同时,在降解水凝胶释放的小分子硒化物的级联催化下，过量产生的H2O2导致细胞内GSH消耗加速，进一步增强原位H2O2和后续多模式癌症治疗的疗效。在GOx诱导的缺氧扩增后，替拉嗪（TPZ）转化为高毒性的苯并三嗪基（BTZ·），表现出增强的抗肿瘤活性。这种GSH消耗增强的癌症治疗策略有效地促进了GOx介导的肿瘤饥饿并激活了缺氧药物，导致局部抗癌功效显著增强。重要性声明：人们对消耗细胞内GSH作为改善基于ROS的癌症治疗的潜在策略越来越感兴趣。在这里，开发了一种具有GPx样催化活性的生物响应性二硒化物功能化葡聚糖基水凝胶,用于GSH消耗增强的局部饥饿和缺氧激活的黑色素瘤治疗.结果表明，在降解水凝胶释放的小分子硒化物的级联催化下，过量产生的H2O2导致细胞内GSH消耗加速，进一步增强原位H2O2和后续多模式癌症治疗的疗效。
