Adavosertib-encapsulated metal-organic frameworks for p53-mutated gallbladder cancer treatment via synthetic lethality

Shijie Li ¹Sarun Juengpanich ²Win Topatana ¹Tianao Xie ¹Lidan Hou ³Yiyuan Zhu ⁴Jiadong Chen ⁵Yukai Shan ³Yina Han ⁶Ziyi Lu ³Tianen Chen ³Charlie Topatana ⁷Bin Zhang ³Jiasheng Cao ³Jiahao Hu ³Jiafei Yan ³Yingxin Chen ⁸Zhen Gu ⁹Jicheng Yu ¹⁰Xiujun Cai ²Mingyu Chen²

扫码查看

作者信息

1. Department of General Surgery,Sir Run-Run Shaw Hospital,Zhejiang University,Hangzhou 310016,China;School of Medicine,Zhejiang University,Hangzhou 310058,China
2. Department of General Surgery,Sir Run-Run Shaw Hospital,Zhejiang University,Hangzhou 310016,China;School of Medicine,Zhejiang University,Hangzhou 310058,China;National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments,Sir Run-Run Shaw Hospital,Zhejiang University,Hangzhou 310016,China
3. Department of General Surgery,Sir Run-Run Shaw Hospital,Zhejiang University,Hangzhou 310016,China
4. School of Materials Science and Engineering,Zhejiang University,Hangzhou 310058,China
5. Department of Chemistry,Zhejiang University,Hangzhou 310016,China
6. Department of Pathology,Sir Run-Run Shaw Hospital,Zhejiang University,Hangzhou 310016,China
7. International College,Zhejiang University,Hangzhou 310058,China
8. Institute of Advanced Magnetic Materials and International Research Center for EM Metamaterials,College of Materials & Environmental Engineering,Hangzhou Dianzi University,Hangzhou 310018,China
9. Department of General Surgery,Sir Run-Run Shaw Hospital,Zhejiang University,Hangzhou 310016,China;Zhejiang Provincial Key Laboratory for Advanced Drug Delivery Systems,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou 310058,China;National Key Laboratory of Advanced Drug Delivery and Release Systems,Zhejiang University,Hangzhou 310058,China;Liangzhu Laboratory,Zhejiang University,Hangzhou 311121,China;Jinhua Institute of Zhejiang University,Jinhua 321299,China;MOE Key Laboratory of Macromolecu
10. Department of General Surgery,Sir Run-Run Shaw Hospital,Zhejiang University,Hangzhou 310016,China;Zhejiang Provincial Key Laboratory for Advanced Drug Delivery Systems,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou 310058,China;National Key Laboratory of Advanced Drug Delivery and Release Systems,Zhejiang University,Hangzhou 310058,China;Liangzhu Laboratory,Zhejiang University,Hangzhou 311121,China;Jinhua Institute of Zhejiang University,Jinhua 321299,China
折叠

Abstract

Adavosertib(ADA)is a WEE1 inhibitor that exhibits a synthetic lethal effect on p53-mutated gallbladder cancer(GBC).However,drug resistance due to DNA damage response compensation pathways and high toxicity limits further applications.Herein,estrone-targeted ADA-encapsulated metal-organic frame-works(ADA@MOF-EPL)for GBC synthetic lethal treatment by inducing conditional factors are developed.The high expression of estrogen receptors in GBC enables ADA@MOF-EPL to quickly enter and accumulate near the cell nucleus through estrone-mediated endocytosis and release ADA to inhibit WEE1 upon enter-ing the acidic tumor microenvironment.Ultrasound irradiation induces ADA@MOF-EPL to generate reac-tive oxygen species(ROS),which leads to a further increase in DNA damage,resulting in a higher sensitivity of p53-mutated cancer cells to WEE1 inhibitor and promoting cell death via conditional syn-thetic lethality.The conditional factor induced by ADA@MOF-EPL further enhances the antitumor efficacy while significantly reducing systemic toxicity.Moreover,ADA@MOF-EPL demonstrates similar antitumor abilities in other p53-mutated solid tumors,revealing its potential as a broad-spectrum antitumor drug.

Key words

Synthetic lethality/Nanomedicine/Sonodynamic therapy/Gallbladder cancer/Metal-organic frameworks/DNA damage response

引用本文复制引用

基金项目

国家自然科学基金(82202873)

国家自然科学基金(32200566)

浙江省自然科学基金(LQ22H160003)

中央高校基本科研业务费专项(226-2022-00141)

出版年

2024

科学通报(英文版)

中国科学院

科学通报(英文版)

CSTPCD

ISSN：1001-6538

参考文献量64

段落导航