PSMA and Integrinαvβ3 Dual-Targeted Radioligandsfor Prostate Cancer Targeted RadionuclideTherapy

Abstract Prostate cancer, particularly its metastatic castration-resistant form, presents major challenges due to tumor heterogeneity and limited treatment efficacy. The inherent limitations of single-target radiopharmaceuticals, such as variable antigen expression, underscore the need for innovative strategies. To address this, we developed a novel dual-targeting radioligand, 177Lu-PSMA-3-RGD, via solid-phase synthesis and click chemistry, designed to simultaneously bind prostate-specific membrane antigen (PSMA) and integrin αvβ3. The ligand demonstrated high radiochemical purity, excellent radiostability, and selective uptake in PSMA-positive cells. In vivo studies using xenograft models revealed rapid tumor accumulation and prolonged retention, with specificity confirmed through competitive receptor-blocking. Furthermore, therapeutic administration of 177Lu-PSMA-3-RGD resulted in significantly greater tumor growth delay compared to single-targeted radioligands, without inducing observable systemic toxicity. Ultimately, this dual-targeted mechanism proves highly effective, identifying the radioligand as a promising theranostic candidate for prostate cancer that merits further preclinical and clinical investigation.