Hypoxia-induced activity loss of a photo-responsive microtubule inhibitor azobenzene combretastatin A4  

作　　者：Yang An Chao Chen Jundong Zhu Pankaj Dwivedi Yanjun Zhao Zheng Wang 

机构地区：[1]School of Pharmaceutical Science&Technology,Tianjin Key Laboratory for Modem Drug Delivery&High Efficiency,Collaborative Innovation Center of Chemical Science and Engineering(Tianjin),Tianjin University,Tianjin 300072,China [2]School of Engineering Science,University of Science and Technology of China,Hefei 230027,China

出　　处：《Frontiers of Chemical Science and Engineering》2020年第5期880-888,共9页化学科学与工程前沿（英文版）

基　　金：The work was financially supported by the National Natural Science Foundation of China(Grant No.21650110447).

摘　　要：The conformation-dependent activity of azo-benzene combretastatin A4(Azo-CA4)provides a unique approach to reduce the side-effects of chemotherapy,due to the light-triggered conformation transition of its azobenzene moiety.Under hypoxic tumor microenviron-ment,however,the high expression of azoreductase can reduce azobenzene to aniline.It was postulated that the Azo-CA4 might be degraded under hypoxia,resulting in the decrease of its anti-tumor activity.The aim of this study was to verify such hypothesis in HeLa cells in vitro.The quantitative drug concentration analysis shows the ratio-metric formation of degradation end-products,confirming the bioreduction of Azo-CA4.The tubulin staining study indicates that Azo-CA4 loses the potency of switching off microtubule dynamics under hypoxia.Furthermore,the cell cycle analysis shows that the ability of Azo-CA4 to induce mitotic arrest is lost at low oxygen content.Therefore,the cytotoxicity of Azo-CA4 is compromised under hypoxia.In contrast,combretastatin A4 as a positive control maintains the potency to inhibit tubulin polymer-ization and break down the nuclei irrespective of light irradiation and oxygen level.This work highlights the influence of hypoxic tumor microenvironment on the anti-tumor potency of Azo-CA4,which should be considered during the early stage of designing translational Azo-CA4 delivery systems.

关 键 词：HYPOXIA microtubule inhibitor drug delivery azo-combretastatin A4 PHOTO-RESPONSIVE 

分 类 号：R730[医药卫生—肿瘤]