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

使用临床荧光引导手术基础设施，神经特异性荧光团可改善前列腺切除术期间的神经保护

• 批准号: 10540590
• 负责人: Summer Lynne Gibbs
• 金额: $ 7.52万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-05 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10540590
• 关键词: Acoustic Neuroma; Address; Anatomy; Benign; Blood; Blood - brain barrier anatomy; Clinical; Contrast Media; Cranial Nerves; Development; Diagnosis; Excision; Future; Goals; Grant; Image; Infrastructure; Knowledge; Light; Location; Meninges; Monitor; Morbidity - disease rate; Nerve; Nerve Sheaths; Neuraxis; Operative Surgical Procedures; Pathology; Patients; Peripheral; Primary Brain Neoplasms; Procedures; Property; Prostatectomy; Safety; Skull Base Neoplasms; Specificity; Structure; Surgeon; System; Techniques; Training Programs; Visualization; Water; Work; base; career development; clinical translation; clinically relevant; contrast enhanced; cranium; design; fluorescence-guided surgery; fluorophore; improved; meningioma; minimally invasive; mortality; nerve damage; nerve injury; neurophysiology; neurosurgery; neurovascular; novel; preservation; reconstruction; skull base; surgery outcome; tumor

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.

项目概要 一个多世纪以来，颅底肿瘤的治疗一直是临床上的挑战。 位于颅骨深处，通常与关键的神经血管结构相关，损伤会导致 暴露技术、肿瘤切除、颅底重建方面的重大进展。 微创手术提高了手术安全性，但脑神经仍然是最重要的手术之一 所有外科亚专科中经常受伤的神经结构通常是颅底肿瘤。 良性，但发生在靠近脑神经的地方，最常见的病变源于脑神经 颅神经鞘（即听神经鞘瘤）或颅骨内层（即脑膜瘤）。 约占原发性脑肿瘤的 40%，预计到 2021 年诊断出约 35,000 例。由于脑膜瘤出现 与脑膜相比，它们可以出现在颅骨内的多个位置。 不太常见，但总是与脑神经密切相关，因为它们起源于神经 两种肿瘤类型的完整手术切除都有可能治愈，但必须与神经相平衡。 保存，其中这些关键结构与扭曲正常解剖结构的肿瘤密切相关。 虽然神经解剖学知识、白光可视化和神经生理学监测被用于： 音乐会保留颅神经，神经损伤和不完全切除继续挑战颅底 这项工作将直接解决这一未满足的临床需求。 神经外科，总体目标是生成具有匹配光谱特性的神经特异性荧光团 临床批准的近红外 (NIR) 荧光引导手术 (FGS) 系统。 将使脑神经可视化与可见肿瘤增强对比度在光谱上不同 常用于神经外科，同时使用现有的临床 FGS 实现未来的临床转化 近红外神经特异性探针的开发对分子提出了综合挑战。 必须足够小以穿过紧密的血神经和/或血脑屏障，但具有足够的程度 共轭以达到近红外波长，这在神经外科应用中是一个特殊的挑战。 周围神经系统和中枢神经系统之间界面结构的识别和可视化 在前期工作中，我们的团队需要（分别是三七总皂苷（PNS）和中枢神经系统（CNS））才能获得成功的手术结果。 设计并开发了基于近红外恶嗪的探针，其中一个子集提供三七总皂甙和中枢神经系统特异性， 然而，仍然需要适合临床转化的试剂，此外，合成优化研究也已完成。 还为我们提供了开发水溶性神经特异性探针的路线图，使系统能够轻松 在这项对 R01EB032226 的补充资助中，完全专注于 PNS 对比，临床上- 将设计用于脑神经可视化的相关、水溶性、近红外神经特异性荧光团 并作为 Antonio Montaño 先生职业发展和培训计划的一部分而制定。