Abstract：
Cancer cells show unique redox homeostasis. Glutathione (GSH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) play essential roles as coenzymes of multiple key antioxidant enzymes. Coenzyme depletion offers a unique opportunity for cancer treatment by inducing oxidative stress. Here, we report an innovative hybrid nanocarrier for cancer redox therapy via selective depletion of GSH and NADPH. The nanocarrier core is a sorafenib-loaded porous zeolitic imidazole framework (ZIF-65), and the shell is epigallocatechin gallate (EGCG)-Fe3+ complex (EF). The nitroimidazole ligand in ZIF-65 could selectively deplete NADPH under hypoxia. Sorafenib diminished GSH by inhibiting cystine import and GSH biosynthesis. EGCG can reduce Fe3+ to Fe2+, which aids the generation of hydroxyl radicals via the Fenton reaction. The reversible coordination between nitroimidazole and Zn2+, EGCG, and Fe3+ enables triggered cargo release in acidic lysosomes. Tailored nanocarriers induced the depletion of both coenzymes (GSH and NADPH) and boosted reactive oxygen species in a 4T1 murine cancer cell line. The altered redox balance eventually resulted in efficient apoptotic cell death. The current work offers a novel means of redox cancer therapy via the selective depletion of key antioxidant enzymes in hypoxic cells.
摘要：
癌细胞显示出独特的氧化还原稳态。谷胱甘肽(GSH)和还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)是多种关键抗氧化酶的辅酶。辅酶耗竭通过诱导氧化应激为癌症治疗提供了独特的机会。这里,我们报道了一种通过选择性消耗GSH和NADPH用于癌症氧化还原治疗的创新混合纳米载体。纳米载体核心是负载索拉非尼的多孔沸石咪唑骨架（ZIF-65），壳是表没食子儿茶素没食子酸酯（EGCG）-Fe3复合物（EF）。ZIF-65中的硝基咪唑配体可以在缺氧下选择性地耗尽NADPH。索拉非尼通过抑制胱氨酸导入和GSH生物合成来减少GSH。EGCG可以将Fe3+还原为Fe2+，这有助于通过Fenton反应产生羟基自由基。硝基咪唑与Zn2+的可逆配位,EGCG,和Fe3+能够在酸性溶酶体中触发货物释放。定制的纳米载体诱导了两种辅酶（GSH和NADPH）的消耗，并增强了4T1鼠癌细胞系中的活性氧。改变的氧化还原平衡最终导致有效的凋亡性细胞死亡。目前的工作提供了一种通过选择性消耗低氧细胞中关键的抗氧化酶来治疗氧化还原癌症的新方法。
