Targeted Protein Degradation in Cancer Therapy via Hydrophobic Polymer-Tagged Nanoparticles

Abstract

Targeted protein degradation (TPD) strategies offer a significant advantage over traditional small molecule inhibitors by selectively degrading disease-causing proteins. While small molecules can lead to recurrence and resistance due to compensatory pathway activation, TPD addresses this limitation by promoting protein degradation, thereby reducing the likelihood of recurrence and resistance over the long-term. Despite these benefits, bifunctional TPD molecules face challenges such as low solubility, poor bioavailability, and limited tumor specificity. In this study, we developed polymer-based nanoparticles that combine TPD strategies with nanotechnology through a hydrophobic tagging method. Hydrophobic polymer-tagged nanoparticles facilitate targeted protein degradation by incorporating hydrophobic polymers that mimic hydrophobic residues in misfolded proteins. This system combines degradation and delivery capabilities within a polymer-based platform, inducing protein degradation while improving solubility, stability, and tumor targeting. These nanoparticles consist of a block copolymer composed of an androgen receptor ligand (ARL)-conjugated hydrophobic polylactic acid (PLA) and a hydrophilic polyethylene glycol (PEG), connected by a GSH-cleavable disulfide bond. In aqueous solutions, this block copolymer (ARL-PLA-SS-PEG) forms micelles that degrade in reducible cellular environments. The micelles demonstrated significant in vitro degradation of the target androgen receptor (AR). Furthermore, they achieved substantial tumor accumulation and significantly inhibited tumor growth in a tumor-bearing mouse model. A mechanistic study revealed that the micelle-mediated TPD follows a dual pathway involving both proteasome and autophagosome. This approach has the potential to serve as a universal platform for protein degradation, eliminating the need to develop disease-specific TPD molecules.