促进 ROS 介导的溶酶体膜透化以治疗癌症铁死亡,Advanced Healthcare Materials

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促进 ROS 介导的溶酶体膜透化以治疗癌症铁死亡
Advanced Healthcare Materials ( IF 10.0 ) Pub Date : 2022-11-21 , DOI: 10.1002/adhm.202202150
Ying Chen _{1,

2} , Zengqiu Yang _{1,

2} , Sibu Wang _{1,

2} , Qin Ma _{1,

2} , Lingyan Li _{1,

2} , Xingjie Wu _{1,

2} , Qianqian Guo _{1,

2} , Ling Tao _{1,

2} , Xiangchun Shen _{1,

2}

Affiliation

由于过氧化氢酶不足、溶酶体中大量还原铁和低酸性环境，通过基于芬顿反应的活性氧 (ROS) 生成诱导溶酶体膜透化 (LMP) 最近在癌症治疗中引起了越来越多的关注。然而，溶酶体膜受到高度糖基化的膜蛋白的保护，并且几种内溶酶体损伤反应机制可以快速修复受损的溶酶体。为了产生足够的 ROS 并导致溶酶体膜完全破裂，开发了一种溶酶体靶向 ROS 诱导剂，即N- (3-氨基丙基) 吗啉接枝交联硫辛酸囊泡并负载维生素 C (VC@ ^{N3AM cLAVs)。}VC@ ^N3AMcLAVs 在溶酶体中高效积累并通过溶酶体谷胱甘肽转化为两个氧化还原对 LA/DHLA（二氢硫辛酸，LA 的还原形式）和 VC/DHA（脱氢抗坏血酸，VC 的氧化形式），不仅可以产生大量的H ₂ O ₂通过促氧化作用同时也通过相互间的循环氧化还原反应加速铁的转化，使生成的H ₂ O ₂高效转化为剧毒的•OH。体外和体内实验均表明 VC@ ^N3AMcLAVs 可以有效地增强 ROS 的产生并促进 LMP，最终通过铁死亡途径启动肿瘤细胞的不可逆死亡，因此代表了一种潜在的用于癌症治疗的抗癌药物。

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Boosting ROS-Mediated Lysosomal Membrane Permeabilization for Cancer Ferroptosis Therapy

Due to the deficient catalase, abundant reduced iron and low acidic environment in lysosomes, inducing lysosomal membrane permeabilization (LMP) through Fenton reaction-based reactive oxygen species (ROS) generation recently attracts increasing attention in cancer therapy. However, the lysosomal membranes are protected by highly glycosylated membrane proteins and several endolysosomal damage-response mechanisms can rapidly repair the injured lysosomes. To produce sufficient ROS and cause complete lysosomal membranes rupture, a lysosome-targeted ROS inducer, N-(3-Aminopropyl) morpholine grafted cross-linked lipoic acid vesicles with vitamin C-loading (VC@^N3AMcLAVs), is developed. VC@^N3AMcLAVs efficiently accumulate in lysosomes and convert into two redox couples LA/DHLA (dihydrolipoic acid, reduced form of LA) and VC/DHA (dehydroascorbic acid, oxidized form of VC) by the lysosomal glutathione, which can not only produce a large amount of H₂O₂ by pro-oxidant action but also accelerate iron transformation through the cyclic redox reactions between each other and cause the efficient conversion of the generated H₂O₂ into highly toxic •OH. Both in vitro and in vivo experiments demonstrate that VC@^N3AMcLAVs can effectively enhance ROS production and boost LMP, finally initiation irreversible death of tumor cells via ferroptosis pathway, thus representing a potential anticancer drug for cancer therapy.

更新日期：2022-11-21

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