Nano-Encapsulated Aprepitant Enhances Anticancer Potency in Lung Cancer Cells.

Abstract

Introduction/objective: The repurposing of aprepitant (APR), a clinically approved NK-1R antagonist, represents a promising anticancer strategy; however, its rapid systemic clearance limits its therapeutic efficacy. This study aimed to design and systematically evaluate PLGA- and ERS-based APR nanoparticles, characterizing their physicochemical properties, assessing their anticancer potency, and investigating their specific impact on macrophage-mediated tumor invasion using an in vitro lung cancer model.

Methods: APR-loaded poly(lactic-co-glycolic acid) (PLGA-APR) and Eudragit® RS 100 (ERS-APR) nanoparticles were prepared and characterized for particle size, polydispersity index, zeta potential, and encapsulation efficiency. In vitro drug release profiles were evaluated over 24 h. Antiproliferative activity was assessed in A549 lung cancer cells and THP-1 macrophages. A co-culture model with M2c-polarized THP-1 macrophages was used to investigate the effects on cancer cell invasion. Apoptosisrelated gene expression was analyzed to explore the underlying mechanisms.

Results: Nanoparticles exhibited sizes ranging from 186-244 nm, low polydispersity indices, and high encapsulation efficiencies, with distinct surface charges. Sustained drug release over 24 h was observed, whereas free APR dissolved rapidly. Nanoencapsulation enhanced antiproliferative activity, with PLGA-APR showing a lower IC₅₀ at 48 h compared with free APR, and demonstrated tumor-selective cytotoxicity. Additionally, the nanoparticle formulations reduced M2c macrophage-induced invasion and increased the expression of apoptosis-related genes, including TNF-α, CASP8, and CASP3.

Discussion: These findings suggest that nanoparticle-based delivery enhances the therapeutic potential of APR by improving its antitumor activity and limiting macrophage-mediated pro-tumor interactions.

Conclusion: PLGA- and ERS-based APR nanoparticles demonstrated enhanced anticancer activity and represent a promising nanoparticle-based drug repurposing strategy for lung cancer.