PSMA-Targeted Dendrimer Delivery of Sorafenib Enhances MAPK Suppression and Anti-Angiogenic Activity in Prostate Cancer

Metastatic castration-resistant prostate cancer remains difficult to treat because conventional small-molecule therapies often lack tumor selectivity and have limited effective exposure. Sorafenib is a multikinase inhibitor that suppresses RAF-MEK-ERK signaling and angiogenesis, but its poor aqueous solubility limits its use. Here, we developed a prostate-specific membrane antigen (PSMA)-targeted poly(amidoamine) dendrimer-sorafenib conjugate, PD-Sora-CTT1298, using sequential CuAAC and SPAAC chemistry. The conjugate showed reproducible composition, high aqueous solubility, nanoscale size, and formulation stability. PD-Sora-CTT1298-Cy5 showed time-dependent PSMA-associated internalization in VCaP and PC3-PIP cells, with limited uptake in PSMA-negative DU145 cells. In VCaP cells, PD-Sora-CTT1298 produced greater in vitro suppression of viability, proliferation, MAPK signaling, VEGF-A secretion, endothelial tube formation, and autophagic vesicle accumulation than did free sorafenib. Combination with olaparib further reduced viability and increased apoptotic signaling. These findings support the further preclinical evaluation of PSMA-targeted dendrimer delivery for sorafenib-based prostate cancer therapy.