Advances in Reactive Oxygen Species Responsive Anti-cancer Prodrugs

Abstract

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 O 2 . Examples include hydrogen peroxide (H 2 O 2 ), superoxide anion ( 2 O − ), hydroxyl radical (HO•), hypochlorite radical (OCl -) and singlet oxygen ( 1 O 2 ). 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.

Redox Control in Acute Lymphoblastic Leukemia: From Physiology to Pathology and Therapeutic Opportunities

“…ROS-responsive anticancer prodrugs, which are designed based on ROS-sensitive linkers, are composed of anticancer drugs, ROS-sensitive linkers, and other functional units. They are designed to mask the original cytotoxic activity of drugs and can respond to high-level tumor-specific ROS in tumor sites to trigger the breakage of sensitive linkers to release active drugs, ultimately achieving the goal of selectively killing tumor cells [ 140 , 141 , 142 ]. Sensitive linkers currently available for the design of ROS-responsive prodrugs include aryl boronic acid or ester, alkyl thioether or selenide, thioketal, peroxalate ester, and aminoacrylate [ 140 ] ( Table 2 ).…”

“…For example, quiescent LSCs have low levels of intracellular ROS that may not be sufficient to activate the prodrug system. Therefore, researchers attach great importance to the compensation strategy of adding ROS promoters (β-lapa, glucose oxidase, photosensitizers, and ascorbic acid) into the ROS prodrug system to provide additional ROS [ 140 ]. However, this ROS compensation strategy should be selective; otherwise, it will promote the generation of ROS in HSCs and lead to unexpected injury.…”

Metal-organic Frameworks (MOF)-based Novel Electrochemiluminescence Biosensing Platform for Quantification of H2O2 Releasing from Tumor Cells

“…研究表明, 肿瘤 细胞分泌的过氧化氢(H 2 O 2 )水平明显高于正常细胞, 被 认为是癌症诊断的生物标志物 [4][5] . 因此, 对细胞分泌 H 2 O 2 的定量检测不仅有助于了解细胞生理和病理的进 展机制, 而且对癌症的早期诊断和及时治疗具有重要意 义 [6][7][8] . 电化学发光(ECL)分析具有灵敏度高、背景信号 低和检测速度快的优点, 是测定细胞分泌的 H 2 O 2 的有 力工具.…”

Macromolecular Effects in Medicinal Chemistry※

“…例如, 通过设计大分子骨架的聚合度、支 化度及柔性链与刚性链的比例等, 可以调控大分子骨架 的尺寸、形貌、亲疏水性等以获得不同的性能 [3][4] ; 对于 小分子药物部分的设计, 尤其是毒副作用大的小分子药 物, 可以修饰成无药理活性的小分子前药, 之后在靶标 部位经刺激还原为有药理活性的小分子原药 [5][6] . 对于 连接基团部分的设计通常是为了实现大分子键合药物 的特异性敏感释放, 以提高药效并降低毒副作用, 常用 的连接基团如亚胺键、腙键、缩醛、硼酯键等可以在低 pH 值下断裂 [7][8][9][10] , 缩硫酮键、苯硼酸等可以在高活性氧 条件下敏感断裂 [11][12][13] , 二硫键可以在高谷胱甘肽的条件 下断裂 [14][15] ; 此外还可以设计乏氧、光、热、超声等敏 感断裂的连接基团 [16][17][18][19] . 增溶域结构(例如聚乙二醇、聚 丙烯酸、透明质酸、聚多糖等)在解决疏水小分子药物 递送方面发挥重要作用, 常用于遮蔽纳米粒子免受蛋白 结合, 延长体内循环时间 [20][21] , 并可以通过调控增溶域 部分的比例, 以获得不同的组装表观性能从而影响体内 递送、组织靶向、细胞吞噬等过程 [22][23] .…”