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.

项目概要 医源性神经损伤是最令人担心的手术并发症之一，也是发病率的主要来源 在所有外科专业中，虽然保留脑神经对于维持其重要功能至关重要。 此外，随着微创手术的使用增加，颅底手术也面临着重大挑战。 脑神经经常 与颅底肿瘤密切相关，手术可以治愈，但必须权衡 与其他关键组织（例如血管）不同，神经修复产生的功能可以忽略不计，不可靠。 结果导致永久性运动或感觉障碍和慢性神经病变，限制了患者的治疗。 生活质量、就业能力和参与日常活动的唯一已知方法是避免神经损伤。 然而，尚无临床认可的技术能够充分增强术中神经。 可视化，结合了神经解剖学知识、白光可视化和神经生理学 目前使用的技术监测将直接解决这一未满足的临床需求。 外科 (FGS) 已成功融入临床医学，仅使用少数 FDA 批准的荧光团 （即荧光素、氨基乙酰丙酸/原卟啉 IX [ALA/PpIX]、亚甲基蓝和吲哚菁绿 [ICG]）。 虽然用于颅骨外成像的 FGS 系统几乎完全在近红外（NIR，650-900 nm），神经外科成像系统通常具备可见光成像的能力。 所有临床 FGS 系统都有一个“800 nm”通道，旨在对 ICG 进行成像，包括神经外科显微镜 为了促进神经外科的临床转化和实用性，本文的总体目标是 产生具有与 ICG 匹配的光谱特性的神经特异性小分子荧光团。 探头将使脑神经可视化，其光谱与可见荧光素和 ALA/PpIX 不同 通常用于肿瘤增强，同时利用现有的神经元技术实现未来的临床转化 外科 FGS 基础设施的开发提出了一项综合挑战： 分子必须足够小以穿过紧密的血神经和/或血脑屏障（BNB 和/或 BBB， 分别），但具有足够的共轭度以达到近红外波长，这是一个特殊的挑战。 在神经外科应用中，外周界面结构的识别和可视化 成功的手术结果需要中枢神经系统（分别是PNS和CNS）。 经过前期工作，我们课题组设计开发了具有精细PNS特异性的近红外恶嗪探针 最近发现一个新的恶嗪探针库提供了 BBB 交叉和 CNS 特异性，然而 目前尚不存在适合临床转化的试剂。在此，我们将开发 NIR 神经特异性荧光素。 用于识别和可视化脑神经的荧光，有或没有肿瘤复染（即荧光染色） rescein 或 ALA/PpIX) 在脑膜瘤和神经鞘瘤动物模型中的应用。