Glutathione‐Scavenging Nanoparticle‐Mediated PROTACs Delivery for Targeted Protein Degradation and Amplified Antitumor Effects

Author:

Liu Hai‐Jun12,Chen Wei1,Wu Gongwei3,Zhou Jun1,Liu Chuang1,Tang Zhongmin1,Huang Xiangang1,Gao Jingjing1,Xiao Yufen1,Kong Na1,Joshi Nitin1,Cao Yihai4,Abdi Reza2,Tao Wei1ORCID

Affiliation:

1. Center for Nanomedicine and Department of Anesthesiology Brigham and Women's Hospital Harvard Medical School Boston MA 02115 USA

2. Transplantation Research Center Renal Division Brigham and Women's Hospital Harvard Medical School Boston MA 02115 USA

3. Department of Medical Oncology Dana‐Farber Cancer Institute Harvard Medical School Boston MA 02215 USA

4. Department of Microbiology Tumor and Cell Biology Karolinska Institute Stockholm 171 77 Sweden

Abstract

AbstractPROteolysis TArgeting Chimeras (PROTACs) are an emerging class of promising therapeutic modalities that selectively degrade intracellular proteins of interest by hijacking the ubiquitin‐proteasome system. However, the lack of techniques to efficiently transport these degraders to targeted cells and consequently the potential toxicity of PROTACs limit their clinical applications. Here, a strategy of nanoengineered PROTACs, that is, Nano‐PROTACs, is reported, which improves the bioavailability of PROTACs and maximizes their capacity to therapeutically degrade intracellular oncogenic proteins for tumor therapy. The Nano‐PROTACs are developed by encapsulating PROTACs in glutathione (GSH)‐responsive poly(disulfide amide) polymeric (PDSA) nanoparticles and show that ARV@PDSA Nano‐PROTAC, nanoengineered BRD4 degrader ARV‐771, improves BRD4 protein degradation and decreases the downstream oncogene c‐Myc expression. Benefiting from the GSH‐scavenging ability to amply the c‐Myc‐related ferroptosis and cell cycle arrest, this ARV@PDSA Nano‐PROTACs strategy shows superior anti‐tumor efficacy with a low dose administration and good biocompatibility in vivo. The findings reveal the potential of the Nano‐PROTACs strategy to treat a broad range of diseases by dismantling associated pathogenic proteins.

Funder

American Heart Association

Publisher

Wiley

Subject

General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)

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