Vitamin-Integrated PROTAC Nanoparticle for Combined Therapy of NSCLC

Abstract

Proteolysis-targeting chimeric (PROTAC) technology represents a groundbreaking approach with immense potential for treating a wide range of diseases. However, its clinical application is often limited by challenges in solubility and permeability. Herein, we have developed an innovative three-in-one nanoparticulate therapeutic agent tailored for non-small-cell lung cancer (NSCLC). This agent features a PROTAC molecule derived from ceritinib, designated as 27B, serving as a targeted degrader of anaplastic lymphoma kinase (ALK). 27B is self-assembled with vitamin A palmitate (VAP) and vitamin E poly(ethylene glycol) succinate (TPGS) to form stable nanoparticles (BVT-NPs) that exhibit a uniform spherical morphology, excellent storage stability, and robust plasma stability. With an average particle size of approximately 130 nm and a loading capacity of 27B of 20%, BVT-NPs demonstrate a pH-responsive drug release profile. In vitro studies reveal that BVT-NPs significantly inhibit the proliferation of H3122 cells more effectively than free 27B, indicating a synergistic antitumor effect. Western blot analysis further confirms the superior efficacy of BVT-NPs in downregulating ALK and P-glycoprotein and upregulating Caspase-3. BVT-NPs markedly suppress tumor growth without inducing significant tissue toxicity. This carrier-free, multifunctional nanoparticulate system integrates PROTAC-mediated protein degradation with chemotherapy, thereby improving the PROTAC absorption and generating a synergistic therapeutic effect against NSCLC.