Abstract 1851: Development of a smart nanocarrier system for prostate cancer immunotherapy

Abstract Prostate cancer (PCa) is characterized by the overexpression of monoamine oxidase-A (MAO-A), a driver of tumor growth, metastasis, and treatment resistance. Monoamine oxidase inhibitors (MAOIs), such as phenelzine, have shown promise as repurposed agents for PCa therapy. However, systemic administration of phenelzine at effective doses carries significant risks of neuropsychiatric side effects, including aggression, seizures, and suicidal ideation, highlighting the need for a targeted delivery approach. This study aims to develop a smart nanocarrier system for the co-delivery of phenelzine (PHE) and the anti-programmed death ligand 1 (PD-L1) peptide (C7), enhancing therapeutic efficacy while reducing off-target effects. The nanocarrier employs a pH-sensitive hydrazone bond and a matrix metalloproteinase-2 (MMP-2) cleavable linker to achieve site-specific drug release. The system integrates polyethylene glycol-hydrazone-phenelzine (PEG-HZ-PHE) and an MMP-2cleavable linker tethered to the anti-PD-L1 peptide (C7-MMP2), into a lipid nanocarrier platform. Characterization using dynamic light scattering (DLS) revealed a particle size of 190.0 ± 3.9 nm, a polydispersity index (PDI) of 0.17 ± 0.02, and a zeta potential of -33.6 ± 1.3 mV. pH-dependent release studies showed that phenelzine release was highest at pH 5.4 (74.7 ± 0.6%) and lowest at pH 7.4 (11.3 ± 0.1%) after 18 hours, with a 42.3 ± 0.6% release at pH 6.4. Enzyme cleavage studies demonstrated that 73.8 ± 14.5 % of C7 was released within 4 hours of incubation with MMP-2 enzyme, with only 20.3 ± 2.1% of C7-MMP2 remaining after the same period. Cytocompatibility assessment using a red blood cell (RBC) hemolysis assay showed no significant hemolytic activity compared to the negative control (PBS buffer), while the positive control (0.5% Triton X-100) caused significant hemolysis. In conclusion, the developed dual-responsive nanocarrier is stable at physiological pH (7.4) but efficiently releases therapeutic agents in acidic and MMP-2 enzyme-rich environments, offering potential for improved PCa therapy by minimizing off-target effects. Citation Format: Imani Roundtree, Angelo Altenor, Rodney Valdivia, Tovah St. Ignac, Alexandra Esposito, Karelys DiazDavila, Richard Lamptey, John Fetse. Development of a smart nanocarrier system for prostate cancer immunotherapy [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 1851.