PSMA-Targeted\n2‑Deoxyglucose-Based Dendrimer\nNanomedicine for the Treatment of Prostate Cancer

Prostate cancer (PC) is the fifth\nleading cause of cancer-related\ndeaths among men worldwide. Prostate-specific membrane antigen (PSMA),\na molecular target of PC, is clinically used for the treatment and\ndiagnosis of PC using radioligand approaches. However, no PSMA-based\nchemotherapies have yet been approved by the FDA. Here, we present\na novel therapeutic approach using PSMA-targeted 2-deoxyglucose-dendrimer\n(PSMA-2DG-D) for targeted delivery of a potent tyrosine kinase inhibitor,\ncabozantinib (Cabo), selectively to PC cells. PSMA-2DG-D demonstrates\nintracellular localization in PSMA (+) PC cells through PSMA-mediated\ninternalization. This PSMA-specific targeting translates to enhanced\nefficacy of Cabo compared to the free drug when conjugated to PSMA-2DG-D.\nFurthermore, systemically administered fluorescently labeled PSMA-2DG-D-Cy5\nspecifically targets PSMA (+) tumors with minimal off-target accumulation\nin the PC3-PIP tumor xenograft mouse model. This demonstrates that\nthe PSMA-2DG-D platform is a promising new delivery system for potent\nchemotherapeutics, where systemic side effects are a significant concern.