Clinical fluorescent contrast agents for image-guided surgery

Fluorescence image-guided surgery (FIGS) has become an essential modality to improve intraoperative decision-making by enhancing real-time visualization of anatomical structures and pathological lesions. The increasing demand for surgical precision has driven the clinical adoption of contrast agents with improved specificity, safety, and efficacy. In recent years, several drugs have been approved by regulatory agencies such as the U.S. Food and Drug Administration (FDA) for clinical use or clinical trials, marking significant progress in this field. This review provides a comprehensive overview of seven FDA-approved intraoperative fluorescence contrast agents—Indocyanine Green (ICG), Fluorescein Sodium, 5-Aminolevulinic Acid (5-ALA), Methylene Blue (MB), Cysview (Hexaminolevulinate), Cytalux (OTL38), and Akalux—highlighting their molecular characteristics, approved indications, and clinical performance. In addition, we summarize emerging agents currently undergoing clinical evaluation, underscoring the shift from nonspecific dyes to targeted molecular probes. Through comparative analysis, we illustrate how targeted agents have enhanced tumor visualization, improved margin delineation, and facilitated detection of occult lesions, thereby contributing to more complete resections and better patient outcomes. The evolution of contrast agents reflects a broader trend toward precision medicine in surgery, where imaging tools are tailored to disease-specific biomarkers and patient-specific needs. Finally, we discuss key considerations for selecting appropriate agents in clinical practice, including tissue specificity, administration route, imaging depth, and regulatory status. Looking forward, the continued integration of molecular diagnostics and imaging is expected to enable more accurate, individualized surgical interventions and support the future development of theranostic strategies.