School of Biomedical Engineering, Anhui Medical University, Hefei, 230032, China.
Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan, 430072, China.
Adv Healthc Mater. 2023 Jan;12(3):e2202045. doi: 10.1002/adhm.202202045. Epub 2022 Oct 27.
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.
阿霉素（Dox）介导的活性氧（ROS）生成用于线粒体凋亡，这被确定为一种新的细胞毒性机制，除了通过核 DNA 复制干扰而建立的机制之外。然而，这种机制对 Dox 治疗的贡献远远小于后者。这种新发现的途径将使 Dox 治疗的作用类似于单独使用 Dox 的化学动力疗法（CDT）和化疗相结合的作用，将得到放大。一锅纳米构建（HEBD）是基于在水介质中由表没食子儿茶素没食子酸酯（EGCG）、丁硫氨酸亚砜（BSO）和甲醛之间的化学反应驱动组装而制造的，然后进行 Dox 吸附。酸性肿瘤微环境由于希夫碱键的断裂而允许 EGCG、BSO 和 Dox 的释放。HEBD 中的 EGCG 成分负责靶向线粒体并破坏线粒体电子传递链（mETC），以迫使电子泄漏，有利于 Dox 捕获电子产生更多的 ROS。EGCG 诱导的 mETC 破坏导致线粒体呼吸抑制，减轻肿瘤细胞中的缺氧，而 BSO 抑制谷胱甘肽的生物合成，以防止 ROS 被氧化还原消耗，进一步增强 Dox 诱导的 CDT。这种放大 Dox 介导的联合治疗中 CDT 途径的策略可以大大提高抗肿瘤效果，延长荷瘤小鼠的寿命，降低心脏毒性和转移的风险。
