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Self-Assembling Amphiphilic PROTACs: A Chemical Strategy for Improved EGFR-Targeted Protein Degradation
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DOI：10.1021/acs.jmedchem.6c00971.png)
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Abstract
En 中文
Proteolysis-targeting chimeras (PROTACs) are attractive targeted protein degradation modalities, while their clinical advancement is limited by high molecular weight, suboptimal bioavailability, low cellular permeability, and unsatisfactory in vivo efficacy. Herein, we developed a self-assembled nanoparticle system (PRO NPs) constructed from amphiphilic PROTACs. Owing to their intrinsic amphiphilicity, PRO NPs can spontaneously assemble into stable nanoparticles without external excipients, simplifying fabrication and alleviating carrier-associated toxicity. Compared with the free EGFR-targeting PROTAC, PRO NPs exhibited enhanced aqueous solubility and efficient EGFR degradation in HCC827 cells. In vivo, PRO NPs functionalized with hyaluronic acid (HA) through electrostatic adsorption could actively accumulate at tumor sites via CD44-mediated targeting, exerting potent antitumor efficacy (TGI = 76.8%) with reduced systemic toxicity. Collectively, these findings provide novel insights into nano-PROTAC design and a promising strategy for the development of targeted protein degradation therapies.
Keywords:
Degradation
Peptides and proteins
Thermodynamic properties
Toxicity
Tumors
Journal
IF:
6.8
Papers:
2.7W
Citations:
9.4W
Organization
Cited Papers