MOF负载Weel抑制剂实现p53突变胆囊癌的合成致死靶向治疗

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

作者机构：Department of General SurgerySir Run-Run Shaw HospitalZhejiang UniversityHangzhou 310016China School of MedicineZhejiang UniversityHangzhou 310058China National Engineering Research Center of Innovation and Application of Minimally Invasive InstrumentsSir Run-Run Shaw HospitalZhejiang UniversityHangzhou 310016China School of Materials Science and EngineeringZhejiang UniversityHangzhou 310058China Department of ChemistryZhejiang UniversityHangzhou 310016China Department of PathologySir Run-Run Shaw HospitalZhejiang UniversityHangzhou 310016China International CollegeZhejiang UniversityHangzhou 310058China Institute of Advanced Magnetic Materials and International Research Center for EM MetamaterialsCollege of Materials&Environmental EngineeringHangzhou Dianzi UniversityHangzhou 310018China Zhejiang Provincial Key Laboratory for Advanced Drug Delivery SystemsCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China National Key Laboratory of Advanced Drug Delivery and Release SystemsZhejiang UniversityHangzhou 310058China Liangzhu LaboratoryZhejiang UniversityHangzhou 311121China Jinhua Institute of Zhejiang UniversityJinhua 321299China MOE Key Laboratory of Macromolecular Synthesis and FunctionalizationDepartment of Polymer Science and EngineeringZhejiang UniversityHangzhou 310027China 

出 版 物：《Science Bulletin》 (科学通报（英文版）)

年 卷 期：2024年第69卷第9期

页      面：1286-1301页

核心收录：

学科分类：0831[工学-生物医学工程（可授工学、理学、医学学位）] 0710[理学-生物学] 1007[医学-药学(可授医学、理学学位)] 1004[医学-公共卫生与预防医学(可授医学、理学学位)] 100706[医学-药理学] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 0817[工学-化学工程与技术] 0703[理学-化学] 100214[医学-肿瘤学] 0836[工学-生物工程] 0702[理学-物理学] 10[医学] 

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) 

主　　题：Synthetic lethality Nanomedicine Sonodynamic therapy Gallbladder cancer Metal-organic frameworks DNA damage response 

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 ***,estrone-targeted ADA-encapsulated metal–organic frameworks(ADA@MOF-EPL)for GBC synthetic lethal treatment by inducing conditional factors are *** 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 *** 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 *** conditional factor induced by ADA@MOF-EPL further enhances the antitumor efficacy while significantly reducing systemic ***,ADA@MOF-EPL demonstrates similar antitumor abilities in other p53-mutated solid tumors,revealing its potential as a broad-spectrum antitumor drug.