活性氧响应型抗肿瘤前药研究进展

doi:10.6023/A20040116

摘要/Abstract

活性氧（ROS）在机体信号转导和代谢中起着至关重要的作用，而ROS水平的升高与多种病变（癌症和炎症等）息息相关，基于肿瘤组织高水平ROS开发的肿瘤特异杀伤性前药策略，在增强药效和药物选择性方面提供了一种新颖的方法.本综述介绍了目前用于构建抗肿瘤前药的ROS敏感键：芳基硼酸/酯、烷基硫/硒醚、硫缩酮、过氧草酸酯、氨基丙烯酸酯、噻唑烷酮和α-酮酰胺等，并且详叙了基于这些敏感键设计的前药在抗肿瘤方向上的应用，同时探讨了现有ROS响应型前药系统的研究进展和局限性，并对未来的研究方向进行了展望.

关键词: 活性氧, ROS响应, 前药, 药物递送, 肿瘤治疗

Reactive oxygen species (ROS) are categorized as a class of instantaneous intermediate products of oxygen, which are usually produced by a single electron continuous reduction of O₂. Examples include hydrogen peroxide (H₂O₂), superoxide anion (O₂^-), hydroxyl radical (HO·), hypochlorite radical (OCl^-) and singlet oxygen (¹O₂). The endogenous ROS arise from three major resources:mitochondrial electron transport chain (Mito-ETC), endoplasmic reticulum (ER) and NADPH oxidase (NOX). The produced ROS play vital roles in physiological functions including modulation of functions of proteins, regulation of cell signaling, mediation of inflammation, and elimination of pathogens. However, the cumulative ROS level in vivo could elicit oxidative stress, which is implicated in a multitude of diseases including cancer, autoimmune diseases, inflammation, cardiovascular diseases, neurodegenerative diseases. This abnormal biochemical alteration in tumors has inspired researchers to exploit the relatively high levels of ROS for development of ROS-responsive prodrug systems. In recent years, ROS-responsive prodrug systems based on a spectrum of ROS-sensitive linkers have been designed and developed with aim of precision tumor therapy. Herein, in this review, we would like to illustrate ROS-sensitive linkers developed to date including arylboronic acid or ester, alkyl thioether or selenide, thioketal, peroxalate ester, aminoacrylate, thiazolidinone and α-ketoamide, and elucidate the underlying molecular oxidation mechanism. Furthermore, the design of ROS-responsive prodrugs based on these sensitive linkers and their applications in anti-cancer therapy were reviewed. Additionally, the existing problems and the future research perspectives of prodrug systems were also discussed.

Key words: reactive oxygen species, ROS-responsive, prodrug, drug delivery, anti-cancer therapy

引用此文

张留伟, 陈麒先, 王静云. 活性氧响应型抗肿瘤前药研究进展[J]. 化学学报, 2020, 78(7): 642-656.

Zhang Liuwei, Chen Qixian, Wang Jingyun. Advances in Reactive Oxygen Species Responsive Anti-cancer Prodrugs[J]. Acta Chimica Sinica, 2020, 78(7): 642-656.

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