Abstract 6700: Ligand-directed delivery of chemically modified miR-34a to prostate cancer: enhanced targeting and extended pharmacokinetics

Abstract Prostate cancer is a leading cause of cancer-related mortality in men. Current therapeutic options include surgical intervention, chemotherapy, immunotherapy, and localized or systemic radiation therapy. However, advanced metastatic prostate cancers are challenging to treat, underscoring the critical need for more effective strategies. Prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein, is overexpressed up to 1000-fold in ∼90% of prostate cancers. The high expression level of PSMA, coupled with highly specific targeting ligands, makes it a promising target for diagnostic and therapeutic applications. While various modalities can be delivered via PSMA, delivery of microRNAs has many advantages including the ability to overcome resistance often observed with single-agent treatments due to the ability of miRNAs to downregulate multiple genes simultaneously. Among the miRNAs with anti-cancer properties, miR-34a is among the most promising. Our work and that of others has determined that restoring miR-34a leads to tumor regression. Unfortunately, in vivo delivery challenges remain a bottleneck in advancing miR-34a to the clinic. These challenges can be subclassified into three key issues: 1. achieving specific delivery, 2. avoiding nuclease-mediated degradation, and 3. overcoming poor circulation half-life of the miRNA conjugates. Our lab is dedicated to overcoming these challenges. To address these issues, we developed a miRNA-34a vehicle-free strategy that delivers miR-34a to prostate cancer that comprises three critical attributes. Firstly, a peptidomimetic ligand (PSMA-617) was selected based on its selective specificity for PSMA binding, reducing delivery to non-tumorigenic cells. Secondly, the miR-34a is fully modified (FM-miR34a), containing an alternating pattern of 2′-O-methyl and 2′-fluoro modified sugars and phosphorothioate linkages at the 3′ and 5′ ends of each strand to reduce immunogenicity and to provide exonucleases resistance in-vivo. Thirdly, 4-(p-iodophenyl)butyric acid, a small molecule that exhibits high affinity for serum albumin, was added to the conjugate, enhancing the pharmacokinetic properties. Through binding to serum albumin, systemic circulation of the PSMA-617-miRNA-34a conjugate is prolonged, providing additional time to achieve receptor saturation, leading to increased bioavailability and therapeutic efficacy. Overall, our data indicates that bringing all three of these components together into a holist vehicle can enhance the clinical utility of miR-34a for treating prostate cancer. Citation Format: Digambar Kumar Waiker, Ahmed M. Abdelaal, Shreyas G. Iyer, Ikjot Singh Sohal, Esteban A. Orellana, Kasireddy Sudarshan, Kenan E. Ozcan, Andrea P. dos Santos, Philip S. Low, Andrea L. Kasinski. Ligand-directed delivery of chemically modified miR-34a to prostate cancer: enhanced targeting and extended pharmacokinetics [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 6700.