Abstract B061: Prostate specific membrane antigen (PSMA) directed small molecule and dendrimer conjugates for targeted therapy in prostate cancer

Abstract Prostate specific membrane antigen (PSMA) has emerged as a clinically validated target for both imaging and radioligand therapy in prostate cancer, yet translation of PSMA based chemotherapy remains limited by poor pharmacokinetics and systemic toxicity of small molecule agents. To address these challenges, our lab has developed a series of PSMA targeted small molecule drug conjugates (SMDCs) that employ the irreversible PSMA ligand CTT1298 to achieve selective delivery of chemotherapeutics such as monomethyl auristatin E (MMAE) and SN-38. These conjugates demonstrated potent and selective antitumor activity in PSMA expressing models, establishing CTT1298 as a robust targeting scaffold for therapeutic payload delivery. Building on this foundation, we expanded to a nanoscale approach by coupling CTT1298 to a generation 4 hydroxyl polyamidoamine (PAMAM-G4-OH) dendrimer, creating a PSMA targeted nanoplatform (PD-CTT1298) for enhanced drug loading, tunable release, and improved pharmacokinetic performance. The neutral dendrimer backbone minimizes nonspecific interactions and systemic accumulation while preserving high surface functionality for modular drug attachment. In-vitro, PD-CTT1298 exhibited nanomolar PSMA affinity and selective internalization in PSMA positive prostate cancer cells, and in-vivo, Cy5 labeled PD-CTT1298 showed preferential tumor accumulation with minimal off target uptake or toxicity. Subsequent work with a Camptothecin loaded conjugate (PD-Campto-CTT1298) revealed potent, dose dependent cytotoxicity in PSMA positive PC3-PIP and C4-2B cells, surpassing the efficacy of free Camptothecin. Mechanistic assays indicated mitochondrial depolarization and caspase-3/7 activation, confirming apoptosis as the primary mode of cell death. Consistent with the known mechanism of topoisomerase I inhibitors, PD-Campto-CTT1298 treatment likely affects DNA replication processes, contributing to apoptotic signaling. Elevated reactive oxygen species, reduced hypoxia marker expression, and suppression of VEGF-A secretion further demonstrated concurrent disruption of survival and angiogenic signaling. Combination treatment with the PARP inhibitor, Olaparib, produced synergistic cytotoxic effects, highlighting the potential of PSMA targeted dendrimer conjugates for combination therapy. Collectively, these findings establish an evolutionary trajectory from small molecule conjugates to dendrimer nanoplatforms, demonstrating how irreversible PSMA targeting and modular linker design can enable future development of combination or dual-payload therapeutics in prostate cancer. Citation Format: Anunay James. Pulukuri, Anubhav Dhull, Anjali Sharma, Clifford E. Berkman. Prostate specific membrane antigen (PSMA) directed small molecule and dendrimer conjugates for targeted therapy in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B061.