MOF负载Weel抑制剂实现p53突变胆囊癌的合成致死靶向治疗  

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

作　　者：郦仕杰 Sarun Juengpanich Win Topatana 谢天傲 侯丽丹 朱怡远 陈佳东 单煜凯 韩依纳 陆子毅 陈天恩 Charlie Topatana 张斌 曹佳胜 胡家豪 严加费 陈迎鑫 顾臻 俞计成 蔡秀军 陈鸣宇 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(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 Macromolecular Synthesis and Functionalization,Department of Polymer Science and Engineering,Zhejiang University,Hangzhou 310027,China)

机构地区：[1]Department of General Surgery,Sir Run-Run Shaw Hospital,Zhejiang University,Hangzhou 310016,China [2]School of Medicine,Zhejiang University,Hangzhou 310058,China [3]National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments,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]Zhejiang Provincial Key Laboratory for Advanced Drug Delivery Systems,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou 310058,China [10]National Key Laboratory of Advanced Drug Delivery and Release Systems,Zhejiang University,Hangzhou 310058,China [11]Liangzhu Laboratory,Zhejiang University,Hangzhou 311121,China [12]Jinhua Institute of Zhejiang University,Jinhua 321299,China [13]MOE Key Laboratory of Macromolecular Synthesis and Functionalization,Department of Polymer Science and Engineering,Zhejiang University,Hangzhou 310027,China

出　　处：《Science Bulletin》2024年第9期1286-1301,共16页科学通报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82202873,32200566);the Natural Science Foundation of Zhejiang Province(LQ22H160003);the Fundamental Research Funds for the Central Universities(2262022-00141)。

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 frameworks(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 entering the acidic tumor microenvironment.Ultrasound irradiation induces ADA@MOF-EPL to generate reactive 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 synthetic 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.

关 键 词：Synthetic lethality NANOMEDICINE Sonodynamic therapy Gallbladder cancer Metal-organic frameworks DNA damage response 

分 类 号：R735.8[医药卫生—肿瘤]