Synthesis, Preclinical Evaluation, and First-in-Human Assessment of ICG-PSMA-D5: A PSMA-Targeted Probe for Fluorescence-Guided Surgery of Prostate Cancer.

Precise surgical resection of prostate cancer (PCa) is a significant clinical challenge due to the impact of positive surgical margins on postoperative outcomes. Fluorescence-guided surgery (FGS) enables real-time tumor visualization using fluorescent probes. In this study, we synthesized and evaluated an indocyanine green (ICG)-based PSMA-targeted near-infrared probe, , for intraoperative imaging of PCa lesions. Spectroscopic analysis revealed that retained the optical properties of while improving solubility in PBS due to additional carboxyl groups. assays demonstrated high binding affinity ( = 0.39 nM) and minimal cytotoxicity. studies in tumor-bearing mice showed strong tumor targeting, extended retention at tumor site, and favorable biodistribution, with significant tumor-to-background ratios. The first-in-human study in a patient with localized PCa indicated the probe's potential for real-time, radiation-free surgical guidance. Overall, displayed excellent performance in tumor detection and margin delineation, making it a promising candidate for intraoperative FGS in PCa.