阿霉素
活性氧
细胞凋亡
丁硫胺
线粒体
化学
药理学
谷胱甘肽
化疗增敏剂
癌症研究
心脏毒性
生物化学
肿瘤微环境
细胞毒性
生物
体外
化疗
毒性
酶
有机化学
遗传学
肿瘤细胞
作者
Tao Liu,Cheng‐Feng Xiong,Lin‐Jun Zhang,Guan‐Hua Jiao,Hui Shi,Jun Feng,Xian‐Zheng Zhang
标识
DOI:10.1002/adhm.202202045
摘要
Doxorubicin (Dox)-mediated generation of reactive oxygen radicals (ROS) for mitochondrial apoptosis is identified as a new cytotoxic mechanism in addition to the well-established one via nuclear DNA replication interference. However, this mechanism contributes far less than the latter to Dox therapy. This newly identified pathway to make Dox therapy function like the combination of chemodynamic therapy (CDT) and chemotherapy-mediated by Dox alone would be amplified. One-pot nanoconstruction (HEBD) is fabricated based on the chemical reactions driven assemblies among epigallocatechin gallate (EGCG), buthionine sulfoximine (BSO) and formaldehyde in aqueous mediums followed by Dox adsorption. Acid tumor microenvironments allow the liberation of EGCG, BSO, and Dox due to the breakage of Schiff base bonds. EGCG component in HEBD is responsible for targeting mitochondria and disrupting mitochondrial electron transport chain (mETC) to compel electrons leakage in favor of their capture by Dox to produce more ROS. EGCG-induced mETC disruption results in mitochondrial respiration inhibition with alleviated hypoxia in tumor cells while BSO inhibits glutathione biosynthesis to protect ROS from redox depletion, further boosting Dox-induced CDT. This strategy of amplifying CDT pathway for the Dox-mediated combined therapy could largely improve antitumor effect, extend lifespan of tumor-bearing mice, reduce risks of cardiotoxicity and metastasis.
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