首页|Introducing urea into tirapazamine derivatives to enhance anticancer therapy

Introducing urea into tirapazamine derivatives to enhance anticancer therapy

扫码查看
原文链接
  • NETL
  • NSTL
  • 万方数据
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,FT 11-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.

tirapazaminevascular disrupting agenthypoxia-activated prodrugcombretastatin A4urea

Yajun Xu、Jianlin Lv、Chaoying Kong、Ya Liu、Kun Wang、Zhaohui Tang、Xuesi Chen

展开 >

Key Laboratory of Polymer Ecomaterials,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences,Changchun 130022,China

School of Applied Chemistry and Engineering,University of Science and Technology of China,Hefei 230026,China

Ministry of Science and Technology of China国家自然科学基金Jilin Provincial International Cooperation Key Laboratory of Biomedical Polymers Grant

2022YFE01102005202503520210504001GH

2024

10.1093/nsr/nwae038

国家科学评论(英文版)

国家科学评论(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.11(4)
  • 43