Prostate-Specific Membrane Antigen (PSMA)-Directed Dendrimer–Camptothecin Conjugate for Targeted Treatment of Prostate Cancer

Prostate cancer (PC) remains a major global health challenge, particularly in its advanced, treatment-resistant form. Although Camptothecin (Campto) is a potent topoisomerase I inhibitor with strong antiproliferative and pro-apoptotic activity, its clinical utility is limited by poor aqueous solubility, instability, and systemic toxicity. To address these challenges, we developed a prostate-specific membrane antigen (PSMA)-targeted dendrimer-Camptothecin conjugate (PD-Campto-CTT1298) that improves drug solubility, enables receptor-mediated uptake, and enhances therapeutic effects. This platform was synthesized by conjugating Campto and a high-affinity PSMA ligand (CTT1298) to a generation-4 hydroxyl-terminated PAMAM dendrimer (PD) via copper-catalyzed and strain-promoted azide-alkyne cycloaddition reactions. The resulting conjugate exhibited high aqueous solubility, formulation stability, and efficient drug loading. <i>In vitro</i> drug release studies demonstrated pH- and esterase-responsive Campto release mimicking the tumor microenvironment. PD-Campto-CTT1298 showed selective uptake in PSMA-positive PC cells (PC3-PIP, C4-2B), leading to enhanced cytotoxicity, apoptosis induction, mitochondrial dysfunction, and reactive oxygen species generation. Confocal imaging and flow cytometry confirmed receptor-specific internalization via clathrin-mediated endocytosis. Moreover, PD-Campto-CTT1298 suppressed VEGF-A secretion and disrupted angiogenesis in HUVEC tube formation assays, indicating antiangiogenic activity. Combination therapy with Olaparib demonstrated synergistic effects. Overall, PD-Campto-CTT1298 represents a promising strategy for PSMA-targeted prodrug delivery, offering a multifaceted therapeutic approach through enhanced solubility, intracellular release, and PSMA-positive tumor-specific enhanced cytotoxicity.