Fluorescence Guided Surgery using Near Infrared Nerve-specific Probes for Cranial Nerve Preservation

使用近红外神经特异性探针进行荧光引导手术以保留脑神经

• 批准号: 10608732
• 负责人: Summer Lynne Gibbs
• 金额: $ 65.05万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608732
• 关键词: Address; Animal Model; Blood; Blood - brain barrier anatomy; Blood Vessels; Central Nervous System; Chronic; Clinical; Clinical Medicine; Cranial Nerves; Development; Excision; FDA approved; Fluorescein; Fluorescent Probes; Fright; Future; Goals; Iatrogenesis; Image; Indocyanine Green; Infrastructure; Injury; Knowledge; Libraries; Light; Methods; Methylene blue; Microscope; Monitor; Morbidity - disease rate; Motor; Nerve; Neurilemmoma; Neuroanatomy; Neuropathy; Operative Surgical Procedures; Patients; Peripheral Nervous System; Property; Quality of life; Risk; Sensory; Skull Base Neoplasms; Source; Specificity; Structure; Surgeon; Surgical Specialties; Surgical complication; System; Technology; Tissues; Visualization; Work; blood-brain barrier crossing; clinical translation; cranium; design; disability; fluorescence-guided surgery; fluorophore; functional improvement; imaging system; improved; meningioma; minimally invasive; mortality; nerve damage; nerve injury; nerve repair; neurophysiology; neurosurgery; neurovascular; novel; preservation; prevent; skull base; small molecule; surgery outcome; tumor

PROJECT SUMMARY Iatrogenic nerve injury presents one of the most feared surgical complications and a major source of morbidity across all surgical specialties. While crucial to maintain their vital functions, preservation of cranial nerves re- mains a major challenge in skull base surgeries. Additionally, with the increased use of minimally invasive sur- gical approaches, difficulty with cranial nerve identification and visualization is amplified. Cranial nerves are often intimately associated with tumors of the skull base, where surgery can be curative, but must be balanced against injury risk. Unlike other critical tissues (e.g., blood vessels), nerve repair produces negligible, unreliable func- tional improvement. Permanent motor or sensory disabilities and chronic neuropathies result, limiting patient quality of life, employability and participation in daily activities. The only known method to avoid nerve injury is to prevent its occurrence. However, no clinically approved technology sufficiently enhances intraoperative nerve visualization, where a combination of neuroanatomical knowledge, white light visualization and neurophysiolog- ical monitoring are currently used. This work will directly address this unmet clinical need. Fluorescence Guided Surgery (FGS) has successfully integrated into clinical medicine with only a few FDA-approved fluorophores (i.e., fluorescein, Aminolevulinic/Protoporphyin IX [ALA/PpIX], methylene blue and indocyanine green [ICG]). While FGS systems for imaging outside the skull operate almost exclusively in the near infrared (NIR, 650-900 nm), imaging system for neurosurgery are commonly equipped with the ability to image in the visible. However, all clinical FGS systems have an “800 nm” channel designed to image ICG, including neurosurgical microscopes and wide-field exoscopes. To facilitate clinical translation and utility for neurosurgery, the overall goal herein is to generate a nerve-specific small molecule fluorophore with spectral properties matched to ICG. This novel probe would enable cranial nerve visualization that is spectrally distinct from the visible fluorescein and ALA/PpIX that are commonly used for tumor enhancement, while enabling future clinical translation using existing neuro- surgical 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) (BNB and/or BBB, respectively), 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 of the peripheral and central nervous system (PNS and CNS, respectively) are required for successful surgical outcomes. In pre- liminary work, our group has designed and developed NIR oxazine-based probes with exquisite PNS specificity and recently discovered that a new library of oxazine probes provide BBB-cross and CNS specificity, however an agent suitable for clinical translation does not yet exist. Herein, we will develop NIR nerve-specific fluoro- phore(s) for identification and visualization of the cranial nerves with and without tumor counterstain (i.e., fluo- rescein or ALA/PpIX) in animal models of meningioma and schwannoma.

项目摘要 医源性神经损伤表现出最令人恐惧的手术并发症之一，也是发病率的主要来源 在所有手术专业中。虽然至关重要地保持其重要功能，但保存颅神经 在颅底手术中引起主要挑战。此外，随着最小侵入性的使用增加 基因方法，颅神经识别和可视化的困难被放大。颅神经通常是 与颅底的肿瘤密切相关，手术可以治愈，但必须平衡 伤害风险。与其他关键组织（例如，血管）不同，神经修复会产生可忽略的，不可靠的功能 改进。永久运动或感觉障碍和慢性神经病，限制患者 生活质量，就业和日常活动。避免神经伤害的唯一已知方法是 为了防止其发生。但是，没有足够的临床认可的技术可以增强术中神经 可视化，其中神经解剖学知识，白光可视化和神经生理学的结合 目前正在使用ICAL监视。这项工作将直接满足这种未满足的临床需求。荧光指南 手术（FGS）已成功整合到临床医学中，只有少数FDA批准的荧光团 （即，荧光素，氨基乙烯/原甲状腺素IX [ALA/PPIX]，亚甲基蓝色和吲哚氰氨基绿[ICG]）。 虽然用于颅骨外部成像的FGS系统几乎完全在近红外工作（NIR，650-900 NM），神经外科的成像系统通常等于可见图像中图像的能力。然而， 所有临床FGS系统都有一个“ 800 nm”通道，该通道旨在成像ICG，包括神经外科显微镜 和宽场外观。为了促进临床翻译和神经外科的实用性，本文的总体目标是 为了产生具有与ICG相匹配的光谱特性的神经特异性小分子荧光团。这本小说 探针将使颅神经可视化与可见的荧光素和ALA/PPIX不同 通常用于增强肿瘤的同时，可以使用现有的神经 - 实现未来的临床翻译 手术FGS基础设施。 NIR神经特异性探针的开发提出了综合挑战 分子必须足够小才能跨越紧密的血神经和/或血脑屏障（S）（BNB和/或BBB， ），但具有足够程度的共轭才能达到NIR波长。这是一个特别的挑战 在神经外科应用中，在周围界面的结构识别和可视化 成功的手术结局需要中枢神经系统（分别为PN和CNS）。在pre- Liminary Work，我们的小组设计和开发了具有独家PNS特异性的基于NIR的恶毒问题 最近发现，奥恶嗪问题的新图书馆提供了BBB-CROSS和CNS特异性，但是 适合临床翻译的药物尚不存在。在此，我们将发展NIR神经特异性的氟 - phore（S）用于鉴定和可视化颅神经，有和没有肿瘤的反染色（即氟） 在脑膜瘤和切氏瘤的动物模型中，溶解或ALA/PPIX）。