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, ICG-PSMA-D5, for intraoperative
imaging of PCa lesions. Spectroscopic analysis revealed that ICG-PSMA-D5 retained the optical properties of ICG while improving solubility in PBS due to additional carboxyl groups. In vitro assays demonstrated high binding affinity (Ki = 0.39 nM) and minimal cytotoxicity. In vivo 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, ICG-PSMA-D5 displayed excellent performance in tumor detection and margin delineation,
making it a promising candidate for intraoperative FGS in PCa.