Augmenting Protein Degradation Capacity of PROTAC through Energy Metabolism Regulation and Targeted Drug Delivery

Augmenting Protein Degradation Capacity of PROTAC through Energy Metabolism Regulation and Targeted Drug Delivery

© 2024 Wiley‐VCH GmbH.

Bibliographische Detailangaben
Veröffentlicht in:Advanced materials (Deerfield Beach, Fla.). - 1998. - (2024) vom: 03. Nov., Seite e2412837
1. Verfasser: Tan, Mixiao (VerfasserIn)
Weitere Verfasser: Li, Xiaoyang, Cheng, Long, Long, Xianli, Cao, Guoliang, Yu, Shengji, Ran, Haitao, Feng, Helin, Wang, Hai
Format: Online-Aufsatz
Sprache:English
Veröffentlicht: 2024
Zugriff auf das übergeordnete Werk:Advanced materials (Deerfield Beach, Fla.)
Schlagworte:Journal Article autophagy energy metabolic reprogramming fasting‐mimicking diet proteolysis targeting chimera ubiquitination
Beschreibung
Zusammenfassung:© 2024 Wiley‐VCH GmbH.
The ubiquitin-proteasome system (UPS) is responsible for degrading over 70-80% of cellular proteins. Consequently, proteolysis-targeting chimeras (PROTACs) are developed to induce the ubiquitination and subsequent degradation of proteins of interest (POIs) by the UPS. To amplify the therapeutic efficacy of PROTACs, energy metabolism regulation is first harnessed to boost UPS function in tumor cells. Proteomic and ubiquitinome analyzes reveal that total ubiquitinated proteins and proteasome activity are significantly increased in 143B and MDA-MB-231 tumor cells following fasting-mimicking diet (FMD) treatment. As a result, the degradation efficiency of PROTACs targeting focal adhesion kinase (FAK-P) or bromodomain-containing protein 4 (BRD4-P) is significantly enhanced in FMD-treated 143B and MDA-MB-231 tumor cells. Then, silica-coated iron oxide nanoparticles are developed modified with tumor cell membranes for targeted delivery of PROTACs. Magnetic resonance imaging (MRI) and fluorescence imaging confirm that nanocarriers significantly improve the delivery efficiency of PROTACs in FMD-treated 143B or MDA-MB-231 tumors. In vivo studies demonstrate that the antitumor efficacy of FAK-P and BRD4-P is greatly augmented when combined with targeted delivery and FMD treatment. Overall, this study presents a strategy to enhance the efficacy of PROTACs in cancer therapy
Beschreibung:Date Revised 04.11.2024
published: Print-Electronic
Citation Status Publisher
ISSN:1521-4095
DOI:10.1002/adma.202412837