Matrix-designed bright near-infrared fluorophores for precision peripheral nerve imaging

The FDA's recent approval of pafolacianine, the first molecular targeted contrast agent for fluorescence-guided surgery (FGS), signifies a remarkable milestone in precision medicine. This advance offers new hope for cancer patients by enabling guided removal of cancerous tissues, where completed surgical removal remains a consistent challenge without real-time intraoperative guidance. For optimal surgical outcomes, delicate nerve tissues must be preserved to maintain patient quality of life. Despite advances in the clinical translation pipeline, the development of clinically viable nerve-specific contrast agents for FGS remains a significant challenge. Herein, a medicinal chemistry-based matrix design strategy was applied to effectively generate a synthetic roadmap permitting management of nerve-specificity within the near-infrared (NIR) oxazine fluorophore family. Many of these newly developed fluorophores demonstrated robust nerve-specificity and superior safety profiles, while also offering spectral profiles that are compatible with the clinical surgical FGS infrastructure. Notably, improving observed brightness in vivo enabled exceptional visibility of buried nerve tissue, a priority during surgical procedures. Critically, the lead probe showed a large dosage safety window capable of generating substantial contrast at doses 100x lower than the maximum tolerated dose. Following clinical translation, such NIR nerve-specific fluorophores stand poised to significantly improve outcomes for surgical patients by improving identification and visualization of surface and buried nerve tissues in real time within the surgical arena.