Nerve-specific Fluorophores for Improved Nerve Sparing during Prostatectomy using the Clinical Fluorescence Guided Surgery Infrastructure

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PROJECT SUMMARY Management of tumors at the skull base has been clinically challenging for over a century. Tumors are typically located deep in the skull and are routinely associated with critical neurovascular structures, where damage leads to high morbidity and mortality. Major advances in exposure techniques, tumor removal, skull base reconstruction and minimally invasive procedures have improved surgical safety, however cranial nerves remain one of most frequently injured nerve structures across all surgical subspecialties. Tumors of the skull base are generally benign, but arise in close proximity to the cranial nerves with the most common pathologies originating from the cranial nerve sheaths (i.e., acoustic schwannomas) or lining of the skull (i.e., meningiomas). Meningiomas account for ~40% of primary brain tumors with ~35,000 diagnoses expected in 2021. Since meningiomas arise from the meninges, they can present in a variety of locations within the skull. In contrast, acoustic schwannomas are far less prevalent, but are always intimately associated with cranial nerves as they arise from the nerve sheath. Complete surgical resection of both tumor types is potentially curative, but must be balanced with nerve preservation, where these critical structures are closely associated with a tumor that distorts normal anatomy. While neuroanatomical knowledge, white light visualization and neurophysiological monitoring are utilized in- concert to preserve cranial nerves, nerve damage and incomplete resection continue to challenge skull base surgeries. This work will directly address this unmet clinical need. To facilitate clinical translation and utility for neurosurgery, the overall goal herein is to generate a nerve-specific fluorophore with spectral properties matched to the clinically approved near infrared (NIR) fluorescence guided surgery (FGS) systems. These novel probes would enable cranial nerve visualization that is spectrally distinct from the visible tumor enhancing contrast commonly used in neurosurgery, while enabling future clinical translation using existing clinical FGS infrastructure. Development of a NIR nerve-specific probe has presented a synthetic challenge as molecules must be small enough to cross the tight blood nerve and/or blood brain barrier(s), but with a sufficient degree of conjugation to reach NIR wavelengths. This is a particular challenge in neurosurgical applications where identification and visualization of structures at the interface between the peripheral and central nervous systems (i.e., PNS and CNS, respectively) are required for successful surgical outcomes. In preliminary work, our group has designed and developed NIR oxazine-based probes where a subset provide both PNS and CNS specificity, however an agent suitable for clinical translation is still required. Additionally, synthetic optimization studies have also provided us with a roadmap to develop water-soluble nerve-specific probes, allowing facile systemic administration. In this supplemental grant to R01EB032226 which is focused entirely on PNS contrast, clinically- relevant, water-soluble, NIR nerve-specific fluorophore(s) for visualization of the cranial nerves will be designed and developed as part of the career development and training program for Mr. Antonio Montaño.