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

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外文摘要：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.

外文关键词：

Synthetic lethalityNanomedicineSonodynamic therapyGallbladder cancerMetal-organic frameworksDNA damage response

作者：

Shijie Li、Sarun Juengpanich、Win Topatana、Tianao Xie、Lidan Hou、Yiyuan Zhu、Jiadong Chen、Yukai Shan、Yina Han、Ziyi Lu、Tianen Chen、Charlie Topatana、Bin Zhang、Jiasheng Cao、Jiahao Hu、Jiafei Yan、Yingxin Chen、Zhen Gu、Jicheng Yu、Xiujun Cai、Mingyu Chen

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作者单位：

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

School of Materials Science and Engineering,Zhejiang University,Hangzhou 310058,China

Department of Chemistry,Zhejiang University,Hangzhou 310016,China

Department of Pathology,Sir Run-Run Shaw Hospital,Zhejiang University,Hangzhou 310016,China

International College,Zhejiang University,Hangzhou 310058,China

Institute of Advanced Magnetic Materials and International Research Center for EM Metamaterials,College of Materials & Environmental Engineering,Hangzhou Dianzi University,Hangzhou 310018,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

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基金：

国家自然科学基金国家自然科学基金浙江省自然科学基金中央高校基本科研业务费专项

项目编号：

8220287332200566LQ22H160003226-2022-00141

出版年：

2024

DOI：

10.1016/j.scib.2024.02.039

科学通报(英文版)

中国科学院

科学通报(英文版)

CSTPCD

ISSN：1001-6538

年,卷(期)：2024.69(9)

参考文献量64