Integrating PET and Fluorescence Imaging with a Novel PSMA-ICG Conjugate for Prostate Cancer Management

Prostate cancer (PCa) is a major global health burden, but current preoperative imaging modalities lack sufficient sensitivity for precise diagnosis. Thus, developing efficient novel imaging probes is urgently needed to improve PCa diagnosis and management. In this study, a novel PET/fluorescence dual-modality probe [⁶⁸Ga]Ga-XY-PSMA-ICG was designed and synthesized, and its affinity, specificity, biodistribution, pharmacokinetics, and radiation dosimetry were evaluated in vitro and in vivo. PSMA-positive xenograft models were established to verify the PSMA-targeting ability of XY-PSMA-ICG and [⁶⁸Ga]Ga-XY-PSMA-ICG via fluorescence and PET imaging, and first-in-human studies were conducted to assess the safety, biodistribution, and PSMA imaging potential of [⁶⁸Ga]Ga-XY-PSMA-ICG. [⁶⁸Ga]Ga-XY-PSMA-ICG was successfully prepared through a 14-step synthesis and ⁶⁸Ga labeling with good yield and stability. In PSMA-positive xenograft models, it showed rapid and specific tumor uptake, long tumor retention (up to 240 min), and favorable tumor-to-background ratios, which were significantly better than those of [⁶⁸Ga]Ga-PSMA-617 at 60 min (P < 0.01). Strong tumor fluorescence persisted up to 96 h, with a 72.8-fold higher intensity than free ICG. In clinical studies, [⁶⁸Ga]Ga-XY-PSMA-ICG mainly accumulated in the kidneys, bladder, spleen, and liver, with moderate uptake in the blood pool, parotid glands, and ureters in healthy volunteers. It exhibited excellent lesion detectability in patients, with intense accumulation in primary lesions (maximum SUV 50.15) and no adverse events. These results demonstrate that [⁶⁸Ga]Ga-XY-PSMA-ICG is a clinically translatable dual-modality probe, offering a promising strategy to enhance the precise diagnosis and management of prostate cancer and supporting its further clinical application.