生物正交化学
化学
蛋白质降解
点击化学
两亲性
蛋白质水解
生物化学
组合化学
共聚物
酶
有机化学
聚合物
作者
Jing Gao,Bo Hou,Qiwen Zhu,Lei Yang,Xingyu Jiang,Zhengting Zou,Xutong Li,Tianfeng Xu,Mingyue Zheng,Yi‐Hung Chen,Zhiai Xu,Huixiong Xu,Haijun Yu
标识
DOI:10.1038/s41467-022-32050-4
摘要
Abstract 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.
科研通智能强力驱动
Strongly Powered by AbleSci AI