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Near-Infrared Light Irradiation Induced Mild Hyperthermia Enhances Glutathione Depletion and DNA Interstrand Cross-Link Formation for Efficient Chemotherapy
ACS Nano ( IF 15.8 ) Pub Date : 2020-10-21 , DOI: 10.1021/acsnano.0c03781 Jimei Zhang 1, 2, 3 , Baochang Zhao 4 , Shizhu Chen 5, 6 , Yongchao Wang 2, 7 , Yuxuan Zhang 2, 7 , Yufei Wang 2, 7 , Dengshuai Wei 7, 8 , Lingpu Zhang 7, 8 , Guanghua Rong 9 , Yuhua Weng 10 , Jifu Hao 3 , Binglong Li 3 , Xue-Qin Hou 3 , Xiaoxu Kang 7, 8 , Yao Zhao 11 , Fuyi Wang 7, 11 , Yongxiang Zhao 12 , Yingjie Yu 7, 8 , Qin-Pei Wu 1 , Xing-Jie Liang 2, 7 , Haihua Xiao 7, 8
ACS Nano ( IF 15.8 ) Pub Date : 2020-10-21 , DOI: 10.1021/acsnano.0c03781 Jimei Zhang 1, 2, 3 , Baochang Zhao 4 , Shizhu Chen 5, 6 , Yongchao Wang 2, 7 , Yuxuan Zhang 2, 7 , Yufei Wang 2, 7 , Dengshuai Wei 7, 8 , Lingpu Zhang 7, 8 , Guanghua Rong 9 , Yuhua Weng 10 , Jifu Hao 3 , Binglong Li 3 , Xue-Qin Hou 3 , Xiaoxu Kang 7, 8 , Yao Zhao 11 , Fuyi Wang 7, 11 , Yongxiang Zhao 12 , Yingjie Yu 7, 8 , Qin-Pei Wu 1 , Xing-Jie Liang 2, 7 , Haihua Xiao 7, 8
Affiliation
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DNA alkylating agents generally kill tumor cells by covalently binding with DNA to form interstrand or intrastrand cross-links. However, in the case of cisplatin, only a few DNA adducts (<1%) are highly toxic irreparable interstrand cross-links. Furthermore, cisplatin is rapidly detoxified by high levels of intracellular thiols such as glutathione (GSH). Since the discovery of its mechanism of action, people have been looking for ways to directly and efficiently remove intracellular GSH and increase interstrand cross-links to improve drug efficacy and overcome resistance, but there has been little breakthrough. Herein, we hypothesized that the anticancer efficiency of cisplatin can be enhanced through iodo-thiol click chemistry mediated GSH depletion and increased formation of DNA interstrand cross-links via mild hyperthermia triggered by near-infrared (NIR) light. This was achieved by preparing an amphiphilic polymer with platinum(IV) (Pt(IV)) prodrugs and pendant iodine atoms (iodides). The polymer was further used to encapsulate IR780 and assembled into Pt–I–IR780 nanoparticles. Induction of mild hyperthermia (43 °C) at the tumor site by NIR light irradiation had three effects: (1) it accelerated the GSH-mediated reduction of Pt(IV) in the polymer main chain to platinum(II) (Pt(II)); (2) it boosted the iodo-thiol substitution click reaction between GSH and iodide, thereby attenuating the GSH-mediated detoxification of cisplatin; (3) it increased the proportion of highly toxic and irreparable Pt-DNA interstrand cross-links. Therefore, we find that mild hyperthermia induced via NIR irradiation can enhance the killing of cancer cells and reduce the tumor burden, thus delivering efficient chemotherapy.
中文翻译：
近红外光诱导的轻度高热可增强谷胱甘肽的耗竭和DNA链间交联形成，从而实现高效化学疗法。
DNA烷化剂通常通过与DNA共价结合形成链间或链内交联而杀死肿瘤细胞。但是，就顺铂而言，只有少数DNA加合物（<1％）是高毒性的不可修复的链间交联。此外，顺铂被高水平的细胞内硫醇如谷胱甘肽（GSH）快速解毒。自从发现其作用机理以来，人们一直在寻找直接有效地去除细胞内GSH并增加链间交联以提高药物疗效和克服耐药性的方法，但是几乎没有突破。这里，我们假设，顺铂的抗癌效率可通过碘-硫醇点击化学介导的GSH损耗来增强和增加的DNA的形成链间交联通过由近红外（NIR）光触发的轻度高温。这是通过制备具有铂（IV）（Pt（IV））前药和碘原子侧基（碘化物）的两亲聚合物来实现的。该聚合物进一步用于封装IR780，并组装成Pt-I-IR780纳米颗粒。通过NIR光辐照在肿瘤部位诱导轻度高温（43°C）具有三种作用：（1）促进了GSH介导的聚合物主链中Pt（IV）还原为铂（II）（Pt（II ））; （2）促进了GSH和碘化物之间的碘硫醇取代点击反应，从而减弱了GSH介导的顺铂解毒作用；（3）增加了高毒性和不可修复的Pt-DNA链间交联的比例。因此，我们发现通过 近红外辐射可以增强癌细胞的杀伤力并减轻肿瘤负担，从而提供有效的化学疗法。
更新日期：2020-11-25
中文翻译：
近红外光诱导的轻度高热可增强谷胱甘肽的耗竭和DNA链间交联形成，从而实现高效化学疗法。
DNA烷化剂通常通过与DNA共价结合形成链间或链内交联而杀死肿瘤细胞。但是，就顺铂而言，只有少数DNA加合物（<1％）是高毒性的不可修复的链间交联。此外，顺铂被高水平的细胞内硫醇如谷胱甘肽（GSH）快速解毒。自从发现其作用机理以来，人们一直在寻找直接有效地去除细胞内GSH并增加链间交联以提高药物疗效和克服耐药性的方法，但是几乎没有突破。这里，我们假设，顺铂的抗癌效率可通过碘-硫醇点击化学介导的GSH损耗来增强和增加的DNA的形成链间交联通过由近红外（NIR）光触发的轻度高温。这是通过制备具有铂（IV）（Pt（IV））前药和碘原子侧基（碘化物）的两亲聚合物来实现的。该聚合物进一步用于封装IR780，并组装成Pt-I-IR780纳米颗粒。通过NIR光辐照在肿瘤部位诱导轻度高温（43°C）具有三种作用：（1）促进了GSH介导的聚合物主链中Pt（IV）还原为铂（II）（Pt（II ））; （2）促进了GSH和碘化物之间的碘硫醇取代点击反应，从而减弱了GSH介导的顺铂解毒作用；（3）增加了高毒性和不可修复的Pt-DNA链间交联的比例。因此，我们发现通过 近红外辐射可以增强癌细胞的杀伤力并减轻肿瘤负担，从而提供有效的化学疗法。
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