Developing SWIR fluorophores for enhanced visualization of buried nerves in head and neck cancer surgery

Iatrogenic nerve injury represents one of the most feared surgical complications and remains a major cause of morbidity across all surgical specialties. Head and neck cancer surgery is a compelling clinical example of sig- nificant patient morbidity, where nerve damage provoked by surgical trauma is reported in up to 30% of patients, resulting in severe pain and increased stress exceeding that seen in many other cancer types due to the potential disfigurement. Surprisingly, no clinically approved technology currently exists to enhance intraoperative nerve identification, where techniques for nerve visualization still rely heavily on neuroanatomical knowledge and tra- ditional white light visualization. Fluorescence Guided Surgery (FGS) has made significant advances using FDA- approved near-infrared (NIR, 650-900 nm) fluorophores and cancer-targeted probes. However, clinical nerve FGS lags behind in the development and translation of cancer-specific contrast agents due to challenges in creating clinically relevant nerve-specific fluorophores. Importantly, although NIR fluorophores offer better tissue penetration and reduced light scattering compared to the visible spectrum, their utility is still limited in imaging depths and resolution for buried fine tissue structures (e.g., facial nerves, cranial nerves). Given the varied sizes and depths at which facial nerves are buried, and the critical need to minimize nerve damage, there is a com- pelling case for exploring beyond the NIR spectrum. The short-wave infrared (SWIR, 900–1700 nm) region emerges as a superior alternative for in vivo fluorescence imaging, with advantages including further reduced light scattering and increased tissue penetration, leading to dramatically improved resolution. These properties are particularly advantageous for the visualization and identification of delicate facial nerve tissues during head and neck cancer surgeries, where precise identification at depth can significantly mitigate the risk of iatrogenic nerve injury. However, the development of a SWIR nerve-specific small molecule has been a significant chal- lenge, because these fluorophores need to have a low enough molecular weight to cross the tight blood-nerve barrier junction, with a sufficient degree of conjugation for SWIR excitation and emission, inherently increasing their molecular weight. Our preliminary work has led to the development of over 400 novel oxazine-based small molecule fluorophores, providing quantitative structure-activity relationship (QSAR) modeling on the oxazine scaffold for nerve specificity management. Building on this foundation, we propose to synthetically develop first- in-class SWIR nerve-specific fluorophores that will push the boundaries of current imaging capabilities. The newly designed SWIR fluorophores will undergo rigorous validation for nerve specificity in rodent models, and the most promising candidates will be validated for their efficacy in buried facial nerve visualization during head and neck cancer surgeries in more complex cancer models. This work is poised to set a new standard for nerve preservation in one of the most challenging areas of oncologic surgery. Project Number: 1R56DE034779-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Lei Wang | Institution: OREGON HEALTH & SCIENCE UNIVERSITY, PORTLAND, OR | Award Amount: $620,592 | Activity Code: R56 | Study Section: Imaging Probes and Contrast Agents Study Section[IPCA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11324402