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A region-confined PROTAC nanoplatform for spatiotemporally tunable protein degradation and enhanced cancer therapy

文献类型：期刊论文

作者Gao, Jing6,7,8,9,10; Jiang, Xingyu5; Lei, Shumin4; Cheng, Wenhao9,10; Lai, Yi9,10; Li, Min9,10; Yang, Lei9,10; Liu, Peifeng3; Chen, Xiao-hua2; Huang, Min1
刊名NATURE COMMUNICATIONS
出版日期2024-08-04
卷号15期号:1页码:18
DOI10.1038/s41467-024-50735-w
通讯作者Yu, Haijun(hjyu@simm.ac.cn) ; Xu, Huixiong(xuhuixiong@126.com) ; Xu, Zhiai(zaxu@chem.ecnu.edu.cn)
英文摘要The antitumor performance of PROteolysis-TArgeting Chimeras (PROTACs) is limited by its insufficient tumor specificity and poor pharmacokinetics. These disadvantages are further compounded by tumor heterogeneity, especially the presence of cancer stem-like cells, which drive tumor growth and relapse. Herein, we design a region-confined PROTAC nanoplatform that integrates both reactive oxygen species (ROS)-activatable and hypoxia-responsive PROTAC prodrugs for the precise manipulation of bromodomain and extraterminal protein 4 expression and tumor eradication. These PROTAC nanoparticles selectively accumulate within and penetrate deep into tumors via response to matrix metalloproteinase-2. Photoactivity is then reactivated in response to the acidic intracellular milieu and the PROTAC is discharged due to the ROS generated via photodynamic therapy specifically within the normoxic microenvironment. Moreover, the latent hypoxia-responsive PROTAC prodrug is restored in hypoxic cancer stem-like cells overexpressing nitroreductase. Here, we show the ability of region-confined PROTAC nanoplatform to effectively degrade BRD4 in both normoxic and hypoxic environments, markedly hindering tumor progression in breast and head-neck tumor models. Antitumor performance of PROteolysis-TArgeting Chimeras (PROTACs) is limited by their targeting ability and retention to tumor sites. Here the authors design the reactive oxygen species (ROS)-activatable and hypoxia-responsive PROTAC nanoparticles with selective penetration into tumors for degradation of BRD4 to suppress breast and head and neck cancer progression.
WOS关键词STEM-CELLS ; TUMOR HETEROGENEITY ; RESISTANCE ; UBIQUITINATION ; STRATEGY ; HYPOXIA ; PRODRUG
资助项目National Natural Science Foundation of China (National Science Foundation of China)[U22A20328] ; National Natural Science Foundation of China (National Science Foundation of China)[22074043] ; National Natural Science Foundation of China (National Science Foundation of China)[32311530041] ; National Natural Science Foundation of China[23ZR1475000] ; National Natural Science Foundation of China[20430711800] ; National Natural Science Foundation of China[19DZ2251100] ; Science and Technology Commission of Shanghai Municipality[SHSLCZDZK 03502] ; Shanghai Municipal Health Commission[2022ZSQD07] ; Scientific Research and Development Fund of Zhongshan Hospital of Fudan University ; Shanghai Advanced Research Institute, CAS ; Shanghai Institute of Materia Medica, CAS
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001283931200001
出版者NATURE PORTFOLIO
源URL[http://119.78.100.183/handle/2S10ELR8/312679]  
专题新药研究国家重点实验室
通讯作者Yu, Haijun; Xu, Huixiong; Xu, Zhiai
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Shanghai Jiao Tong Univ, Renji Hosp, Shanghai Canc Inst, State Key Lab Syst Med Canc,Sch Med, Shanghai 200032, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
5.East China Normal Univ, Sch Chem & Mol Engn, Shanghai 200241, Peoples R China
6.Tongji Univ, Shanghai Peoples Hosp 10, Ctr Minimally Invas Treatment Tumor, Sch Med, Shanghai 200072, Peoples R China
7.Tongji Univ Sch Med, Shanghai Peoples Hosp 10, Dept Med Ultrasound, Shanghai 200072, Peoples R China
8.Fudan Univ, Zhongshan Hosp, Inst Ultrasound Med & Engn, Dept Ultrasound, Shanghai 200032, Peoples R China
9.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Pharmaceut, Shanghai 201203, Peoples R China
10.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Gao, Jing,Jiang, Xingyu,Lei, Shumin,et al. A region-confined PROTAC nanoplatform for spatiotemporally tunable protein degradation and enhanced cancer therapy[J]. NATURE COMMUNICATIONS,2024,15(1):18.
APA Gao, Jing.,Jiang, Xingyu.,Lei, Shumin.,Cheng, Wenhao.,Lai, Yi.,...&Xu, Zhiai.(2024).A region-confined PROTAC nanoplatform for spatiotemporally tunable protein degradation and enhanced cancer therapy.NATURE COMMUNICATIONS,15(1),18.
MLA Gao, Jing,et al."A region-confined PROTAC nanoplatform for spatiotemporally tunable protein degradation and enhanced cancer therapy".NATURE COMMUNICATIONS 15.1(2024):18.

入库方式： OAI收割

来源：上海药物研究所

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