癌细胞表现出独特的氧化还原平衡。谷胱甘肽（GSH）和还原型烟酰胺腺嘌呤二核苷酸磷酸（NADPH）作为多种关键抗氧化酶的辅酶扮演着重要角色。辅酶耗竭通过诱导氧化应激提供了癌症治疗的独特机会。本文报道了一种新颖的混合纳米载体，通过选择性耗竭GSH和NADPH实现癌症氧化还原疗法。纳米载体核心是索拉非尼载药的多孔沸石咪唑骨架（ZIF-65），外壳是表油酸儿茶酚酸（EGCG）-铁（Fe3+）复合物（EF）。ZIF-65中的硝基咪唑配体可以在缺氧条件下选择性耗竭NADPH。索拉非尼通过抑制半胱氨酸进口和GSH生物合成来减少GSH。EGCG可以还原Fe3+为Fe2+，从而通过芬顿反应促进羟自由基的产生。硝基咪唑和Zn2+、EGCG和Fe3+之间的可逆配位促使在酸性溶酶体中触发货物释放。量身定制的纳米载体诱导了GSH和NADPH辅酶的耗竭，并在4T1小鼠癌细胞系中增强了活性氧物种。改变的氧化还原平衡最终导致有效的凋亡细胞死亡。本研究提供了一种通过选择性耗竭缺氧细胞中的关键抗氧化酶来实现氧化还原癌症治疗的新手段。版权所有©2023 Elsevier Inc.。保留所有权利。

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.Copyright © 2023 Elsevier Inc. All rights reserved.