Introducing urea into tirapazamine derivatives to enhance anticancer therapy  

作　　者：Yajun Xu Jianlin Lv Chaoying Kong Ya Liu Kun Wang Zhaohui Tang Xuesi Chen 

机构地区：[1]Key Laboratory of Polymer Ecomaterials,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences,Changchun 130022,China [2]School of Applied Chemistry and Engineering,University of Science and Technology of China,Hefei 230026,China

出　　处：《National Science Review》2024年第4期239-247,共9页国家科学评论（英文版）

基　　金：This work was supported by the Ministry of Science and Technology of China(2022YFE0110200);the National Natural Science Foundation of China(52025035);the Jilin Provincial International Cooperation Key Laboratory of Biomedical Polymers Grant(20210504001GH).

摘　　要：Tirapazamine(TPZ)has been approved for multiple clinical trials relying on its excellent anticancer potential.However,as a typical hypoxia-activated prodrug(HAP),TPZ did not exhibit survival advantages in Phase III clinical trials when used in combination therapy due to the insufficient hypoxia levels in patients’tumors.In this study,to improve the therapeutic effects of TPZ,we first introduced urea to synthesize a series of urea-containing derivatives of TPZ.All urea-containing TPZ derivatives showed increased hypoxic cytotoxicity(9.51–30.85-fold)compared with TPZ,while maintaining hypoxic selectivity.TPZP,one of these derivatives,showed 20-fold higher cytotoxicity than TPZ while maintaining a similar hypoxic cytotoxicity ratio.To highly efficiently deliver TPZP to the tumors and reduce its side effects on healthy tissues,we further prepared TPZP into a nanodrug with fibrin-targeting ability:FT11-TPZP-NPs.CA4-NPs,a vascular disrupting agent,was used to increase the fibrin level within tumors and exacerbate tumor hypoxia.By being combined with CA4-NPs,FT11-TPZP-NPs can accumulate in the hypoxia-aggravated tumors and activate sufficiently to kill tumor cells.After a single-dose treatment,FT11-TPZP-NPs+CA4-NPs showed a high inhibition rate of 98.1%against CT26 tumor models with an initial volume of∼480 mm3 and four out of six tumors were completely eliminated;it thereby exerted a significant antitumor effect.This study provides a new strategy for improving the therapeutic effect of TPZ and other HAPs in anticancer therapy.

关 键 词：TIRAPAZAMINE vascular disrupting agent hypoxia-activated prodrug combretastatin A4 UREA 

分 类 号：R914[医药卫生—药物化学]