PDF(Pubmed)
Abstract：
Ferroptosis has received ever-increasing attention due to its unparalleled mechanism in eliminating resistant tumor cells. Nevertheless, the accumulation of toxic lipid peroxides (LPOs) at the tumor site is limited by the level of lipid oxidation. Herein, by leveraging versatile sodium alginate (ALG) hydrogel, a localized ferroptosis trigger consisting of gambogic acid (GA), 2,2\'-azobis [2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH), and Ink (a photothermal agent), was constructed via simple intratumor injection. Upon 1064 nm laser irradiation, the stored AIPH rapidly decomposed into alkyl radicals (R•), which aggravated LPOs in tumor cells. Meanwhile, GA could inhibit heat shock protein 90 (HSP90) to reduce the heat resistance of tumor cells, and forcefully consume glutathione (GSH) to weaken the antioxidant capacity of cells. Systematic in vitro and in vivo experiments have demonstrated that synchronous consumption of GSH and increased reactive oxygen species (ROS) facilitated reduced expression of glutathione peroxidase 4 (GPX4), which further contributed to disruption of intracellular redox homeostasis and ultimately boosted ferroptosis. This all-in-one strategy has a highly effective tumor suppression effect by depleting and generating fatal active compounds at tumor sites, which would pave a new route for the controllable, accurate, and coordinated tumor treatments.
摘要：
Ferroptosis因其在消除耐药肿瘤细胞方面无与伦比的机制而受到越来越多的关注。然而，毒性脂质过氧化物(LPO)在肿瘤部位的积累受到脂质氧化水平的限制。在这里，通过利用多功能海藻酸钠（ALG）水凝胶，由藤黄酸（GA）组成的局部铁中毒触发剂，2,2'-偶氮双[2-(2-咪唑啉-2-基)丙烷]二盐酸盐(AIPH),和墨水（光热剂），通过简单的瘤内注射构建。在1064nm激光照射下，储存的AIPH迅速分解成烷基(R•)，这加重了肿瘤细胞中的LPO。同时,GA能抑制热休克蛋白90(HSP90)降低肿瘤细胞的耐热性,并强制消耗谷胱甘肽（GSH）以削弱细胞的抗氧化能力。系统的体外和体内实验表明，GSH的同步消耗和活性氧（ROS）的增加促进了谷胱甘肽过氧化物酶4（GPX4）的表达降低，这进一步导致了细胞内氧化还原稳态的破坏，并最终促进了铁细胞凋亡。这种多合一策略通过在肿瘤部位消耗和产生致命的活性化合物而具有高度有效的肿瘤抑制作用，这将为可控的，准确,和协调的肿瘤治疗。
