Tumor-targeted PROTAC prodrug nanoplatform enables precise protein degradation and combination cancer therapy  

作　　者：Zhi-feng Zou Lei Yang Hui-jun Nie Jing Gao Shu-min Lei Yi Lai Fan Zhang Ernst Wagner Hai-jun Yu Xiao-hua Chen Zhi-ai Xu 

机构地区：[1]School of Chemistry and Molecular Engineering,East China Normal University,Shanghai,200241,China [2]State Key Laboratory of Chemistry Biology&Center of Pharmaceutics,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203,China [3]School of Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing,210023,China [4]Department of Chemistry,Fudan University,Shanghai,20043,China [5]Department of Pharmacy,Ludwig-Maximilians-Universität,81377,München,Germany [6]School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou,310024,China

出　　处：《Acta Pharmacologica Sinica》2024年第8期1740-1751,共12页中国药理学报（英文版）

基　　金：Financial supports from the National Natural Science Foundation of China(22074043,U22A20328,22177120);Science and Technology Commission of Shanghai Municipality(20430711800 and 23ZR1475000);the Sino German Workshop grant(W-0005,LMU/Fudan U)were appreciated.

摘　　要：Proteolysis targeting chimeras(PROTACs)have emerged as revolutionary anticancer therapeutics that degrade disease-causing proteins.However,the anticancer performance of PROTACs is often impaired by their insufficient bioavailability,unsatisfactory tumor specificity and ability to induce acquired drug resistance.Herein,we propose a polymer-conjugated PROTAC prodrug platform for the tumor-targeted delivery of the most prevalent von Hippel-Lindau(VHL)-and cereblon(CRBN)-based PROTACs,as well as for the precise codelivery of a degrader and conventional small-molecule drugs.The self-assembling PROTAC prodrug nanoparticles(NPs)can specifically target and be activated inside tumor cells to release the free PROTAC for precise protein degradation.The PROTAC prodrug NPs caused more efficient regression of MDA-MB-231 breast tumors in a mouse model by degrading bromodomain-containing protein 4(BRD4)or cyclin-dependent kinase 9(CDK9)with decreased systemic toxicity.In addition,we demonstrated that the PROTAC prodrug NPs can serve as a versatile platform for the codelivery of a PROTAC and chemotherapeutics for enhanced anticancer efficiency and combination benefits.This study paves the way for utilizing tumor-targeted protein degradation for precise anticancer therapy and the effective combination treatment of complex diseases.

关 键 词：proteolysis-targeting chimeras tumor-targeted delivery precise protein degradation combination therapy triple-negative breast cancer 

分 类 号：R730.5[医药卫生—肿瘤]