A Concerted Redox- and Light-Activated Agent for Controlled Multimodal Therapy against Hypoxic Cancer Cells.
A Concerted Redox- and Light-Activated Agent for Controlled Multimodal Therapy against Hypoxic Cancer Cells.
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用于针对缺氧癌细胞的受控多模式治疗的协同氧化还原和光激活剂。
DOI：
10.1002/adma.202210363
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Liu J
中科院分区：
文献类型：
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作者：
Liu J
缺氧代表了癌症治疗的显著可开发的靶点，仅在实体人类肿瘤中遇到，并且与癌症抗性和复发高度相关。在这里，缺氧激活的线粒体积累的Ru（II）多吡啶前药与共轭偶氮（Az）和氮芥（NM）功能，RuAzNM，报告。该前药对缺氧癌细胞具有多模式治疗诊断特性。缺氧细胞微环境中的偶氮基团的还原导致产生两种伯胺产物，一种是游离苯胺芥子气，另一种是多吡啶RuNH 2络合物。因此，苯胺芥触发活性氧（ROS）和mtDNA交联的产生。同时，所得到的生物学上良性的磷光RuNH 2产生诊断信号并发出光疗激活的信号。这种多模式治疗作用最终提高ROS水平，消耗还原型烟酰胺腺嘌呤二核苷酸（NADH）和三磷酸腺苷（ATP），并诱导线粒体膜损伤、mtDNA损伤和最终细胞凋亡。这种独特的策略允许在缺氧细胞和多细胞球体中实现受控的多模式治疗诊断，使RuAzNM成为一种高度选择性和有效的癌细胞选择性治疗诊断剂（对于缺氧HepG 2癌细胞的IC 50 = 2.3 μ m，对于常氧THL-3正常细胞的IC 50 = 58.2 μ m）。这是第一份关于开发金属基化合物作为缺氧多模式治疗诊断剂的报告。
Hypoxia represents a remarkably exploitable target for cancer therapy, is encountered only in solid human tumors, and is highly associated with cancer resistance and recurrence. Here, a hypoxia‐activated mitochondria‐accumulated Ru(II) polypyridyl prodrug functionalized with conjugated azo (Az) and nitrogen mustard (NM) functionalities, RuAzNM, is reported. This prodrug has multimodal theranostic properties toward hypoxic cancer cells. Reduction of the azo group in hypoxic cell microenvironments gives rise to the generation of two primary amine products, a free aniline mustard, and the polypyridyl RuNH2complex. Thus, the aniline mustard triggers generation of reactive oxygen species (ROS) and mtDNA crosslinking. Meanwhile, the resultant biologically benign phosphorescent RuNH2gives rise to a diagnostic signal and signals activation of the phototherapy. This multimodal therapeutic effect eventually elevates ROS levels, depletes reduced nicotinamide adenine dinucleotide (NADH) and adenosine triphosphate (ATP), and induces mitochondrial membrane damage, mtDNA damage, and ultimately cell apoptosis. This unique strategy allows controlled multimodal theranostics to be realized in hypoxic cells and multicellular spheroids, making RuAzNM a highly selective and effective cancer‐cell‐selective theranostic agent (IC50= 2.3 µmfor hypoxic HepG2 cancer cells vs 58.2 µmfor normoxic THL‐3 normal cells). This is the first report of a metal‐based compound developed as a multimodal theranostic agent for hypoxia.