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Engineering POLYTAC Nanoparticles for Bioorthogonal Click Reaction-Enforced Protein Degradation and Breast Cancer Therapy

Haijun Yu,Jing Gao,Qiwen Zhu,Bo Hou,Lei Yang,Xing Jiang,Zhifeng Zou,Xutong Li,Zhiai Xu,Tianfeng Xu,Mingyue Zheng,Huixiong Xu

Published 2022 in Unknown venue

ABSTRACT

PROteolysis TArgeting Chimeras (PROTACs) have been extensively explored for targeted protein degradation and cancer therapy. However, clinic translation of the conventional small molecular PROTACs is challenged by their unfavorable pharmacokinetic profiles and the systemic toxicity due to on-target but off-tumor protein degradation. Herein we presented a tumor microenvironment-activatable polymeric PROTAC (namely POLYTAC) nanoplatform for tumor-specific PROTAC delivery and combinatory cancer therapy. The POLYTAC nanoparticles were engineered by integrating metalloproteinase-liable poly(ethylene glycol) shell, intracellular acidity-responsive hydrophobic core and reduction-activatable PROTACs into one nanoplatform. The resultant POLYTAC nanoparticles can specifically accumulate at the tumor site and release the PROTACs inside the tumor cells for protein degradation. The POLYTAC nanoparticles can be further engineered for bioorthogonal click reaction-enforced tumor-specific delivery of the PROTACs. In combination with photodynamic therapy, we demonstrated that the bioorthogonal POLYTAC nanoparticles remarkably suppressed tumor growth by synergistically inducing cellular apoptosis of the tumor cells in mouse model of MDA-MB-231 breast cancer. The POLYTAC approach might pave the way for tumor-targeted protein degradation and translation of PROTAC-based cancer therapy.

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