Abstract 554: Nanoparticle enabled miR-205 restoration in docetaxel resistant prostate cancer

Background: Prostate cancer (PrCa) is the second most diagnosed malignancy and a leading cause of cancer-related death in men worldwide. Docetaxel (Dtxl)-based chemotherapy remains a cornerstone of treatment for PrCa. However, most patients develop resistance to Dtxl treatment, leaving limited therapeutic options. Although cabazitaxel offers a secondary line of therapy, it is associated with many severe adverse effects. Restoring miR-205, a tumor-suppressor microRNA frequently downregulated in PrCa, has emerged as a promising strategy to reverse Dtxl resistance and achieve tumor regression. Methods: A novel nanoformulation (MNP-miR-205) was developed using iron oxide magnetic nanoparticles (MNPs) layered with polyethylene imine (PEI) polymer to deliver miR-205. The optimized nanoformulation of MNP-miR-205 was characterized by size, surface charge, biochemical properties using DLS, gel retardation, and biochemical analyses. Chemo-sensitizing and anti-cancerous effects of MNP-miR-205 were evaluated in Dtxl-resistant PrCa cell lines and corresponding xenograft mouse models. Biodistribution of the formulation was evaluated by incorporation of indocyanine green (ICG) dye to track tumor accumulation. Results: The MNP-miR-205 nanoformulation demonstrated optimal particle size and zeta potential, ensuring efficient cancer cell delivery. Hemocompatibility studies confirmed its safety profile. The formulation achieved an excellent cellular uptake via endocytosis, by passing endosomal and lysosomal degradation pathways. In Dtxl resistant PrCa cells, MNP-miR-205 enhanced chemosensitivity to Dtxl, as evident by increased apoptosis, Caspase 3/7 activity, and reduced mitochondrial membrane potential. In vivo studies confirmed that MNP-miR-205 exhibited superior tumor accumulation, significantly reducing tumor volume and weight, and prolonging overall mice survival in xenograft mouse models. Conclusion: This innovative MNP-miR-205 nanoformulation offers a groundbreaking theranostic approach to address Dtxl resistance in prostate cancer. By enhancing chemo-sensitization and providing a safer imaging platform, it holds significant potential to improve prostate cancer management. Citation Format: Neeraj Chauhan, Eswara NHK Ghali, Rahul Tiwari, Iris Enriquez, Rajasekhar Baru, Subhash C. Chauhan, Murali M. Yallapu. Nanoparticle enabled miR-205 restoration in docetaxel resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 554.