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Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy

文献类型：期刊论文

作者Gao, Jing5,6,7,8; Hou, Bo4,5,6; Zhu, Qiwen5,6; Yang, Lei3; Jiang, Xingyu3; Zou, Zhifeng4,5,6; Li, Xutong5,6; Xu, Tianfeng5,6; Zheng, Mingyue5,6; Chen, Yi-Hung2
刊名NATURE COMMUNICATIONS
出版日期2022-07-26
卷号13期号:1页码:14
DOI10.1038/s41467-022-32050-4
通讯作者Xu, Zhiai(zaxu@chem.ecnu.edu.cn) ; Xu, Huixiong(xu.huixiong@zs-hospital.sh.cn) ; Yu, Haijun(hjyu@simm.ac.cn)
英文摘要PROteolysis TArgeting Chimeras (PROTACs) has been exploited to degrade putative protein targets. However, the antitumor performance of PROTACs is impaired by their insufficient tumour distribution. Herein, we present de novo designed polymeric PROTAC (POLY-PROTAC) nanotherapeutics for tumour-specific protein degradation. The POLY-PROTACs are engineered by covalently grafting small molecular PROTACs onto the backbone of an amphiphilic diblock copolymer via the disulfide bonds. The POLY-PROTACs self-assemble into micellar nanoparticles and sequentially respond to extracellular matrix metalloproteinase-2, intracellular acidic and reductive tumour microenvironment. The POLY-PROTAC NPs are further functionalized with azide groups for bioorthogonal click reaction-amplified PROTAC delivery to the tumour tissue. For proof-of-concept, we demonstrate that tumour-specific BRD4 degradation with the bioorthogonal POLY-PROTAC nanoplatform combine with photodynamic therapy efficiently regress tumour xenografts in a mouse model of MDA-MB-231 breast cancer. This study suggests the potential of the POLY-PROTACs for precise protein degradation and PROTAC-based cancer therapy. Proteolysis targeting chimeras (PROTACs) have emerged as promising cancer therapy agents but have suffered from systemic toxicity issues. Here, the authors report on the creation of polymeric PROTAC nanoparticles for tumour targeting delivery and demonstrate protein degradation in vivo, in combination with photodynamic therapy.
WOS关键词UBIQUITINATION ; DISCOVERY
资助项目National Natural Science Foundation of China[52111530092] ; National Natural Science Foundation of China[51873228] ; National Natural Science Foundation of China[22074043] ; National Natural Science Foundation of China[81725008] ; International Cooperation Project of Science and Technology Commission of Shanghai Municipality[20430711800] ; Science and Technology Commission of Shanghai Municipality[19DZ2251100] ; Shanghai Municipal Health Commission[SHSLCZDZK 03502] ; Shanghai Municipal Health Commission[2019LJ21] ; Scientific Research and Development Fund of Zhongshan Hospital of Fudan University[2022ZSQD07] ; Open Funds of State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, CAS[SIMM2105KF-12]
WOS研究方向Science & Technology - Other Topics
语种英语
出版者NATURE PORTFOLIO
WOS记录号WOS:000832623400014
源URL[http://119.78.100.183/handle/2S10ELR8/301896]  
专题新药研究国家重点实验室
通讯作者Xu, Zhiai; Xu, Huixiong; Yu, Haijun
作者单位1.Fudan Univ, Zhongshan Hosp, Inst Ultrasound Med & Engn, Dept Ultrasound, Shanghai 200032, Peoples R China
2.Wuhan Univ, Inst Adv Studies IAS, Wuhan 430072, Peoples R China
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
4.East China Normal Univ, Sch Chem & Mol Engn, Shanghai 200241, Peoples R China
5.Chinese Acad Sci, Ctr Pharmaceut, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
6.Chinese Acad Sci, State Key Lab Drug Res, Shanghai 201203, Peoples R China
7.Tongji Univ, Shanghai Peoples Hosp 10, Ctr Minimally Invas Treatment Tumor, Ultrasound Res & Educ Inst,Sch Med, Shanghai 200072, Peoples R China
8.Tongji Univ, Dept Med Ultrasound, Shanghai 200072, Peoples R China
推荐引用方式
GB/T 7714		 Gao, Jing,Hou, Bo,Zhu, Qiwen,et al. Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy[J]. NATURE COMMUNICATIONS,2022,13(1):14.
APA Gao, Jing.,Hou, Bo.,Zhu, Qiwen.,Yang, Lei.,Jiang, Xingyu.,...&Yu, Haijun.(2022).Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy.NATURE COMMUNICATIONS,13(1),14.
MLA Gao, Jing,et al."Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy".NATURE COMMUNICATIONS 13.1(2022):14.

入库方式： OAI收割

来源：上海药物研究所

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