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.

项目摘要 一个多世纪以来，颅底肿瘤的管理一直在临床上具有挑战性。肿瘤通常是 位于头骨深处，通常与关键的神经血管结构相关，损害导致损害 高发病和死亡率。暴露技术，肿瘤清除，颅底重建的重大进展 并且最小的侵入性手术提高了手术安全性，但是颅神经仍然是最多的。 在所有手术亚专科中，经常受伤的神经结构。颅底肿瘤通常是 良性，但与颅神经非常接近，最常见的病理起源于 颅神经鞘（即声学schwannomas）或头骨衬里（即脑膜瘤）。 占2021年预期诊断约35,000次诊断的原发性脑肿瘤的约40％。 从脑膜中，它们可以出现在头骨内的各个位置。相反，声学schwannomas 远不那么普遍，但始终与颅神经紧密相关，因为它们是由神经引起的 鞘。两种肿瘤类型的完全手术切除均可治愈，但必须与神经保持平衡 保存，这些关键结构与扭曲正常解剖结构的肿瘤密切相关。 而神经解剖学知识，白光可视化和神经生理监测的利用是 节省颅神经的音乐会，神经损伤和不完整的切除继续挑战颅底 手术。这项工作将直接满足这种未满足的临床需求。促进临床翻译和实用程序 神经外科手术，本文的总体目标是产生具有匹配光谱特性的神经特异性荧光团 到临床批准的红外线（NIR）荧光指导手术（FGS）系统。这些新颖的问题 可以使颅神经可视化在频谱上与可见的肿瘤增强对比度不同 通常用于神经外科手术，同时使用现有的临床FG实现未来的临床翻译 基础设施。 NIR神经特异性探针的开发提出了合成的挑战 必须足够小才能越过紧密的血神经和/或血脑屏障（S），但有足够的程度 结合到达到NIR波长。这是在神经外科应用中的一个特殊挑战 识别和可视化结构在周围和中枢神经系统之间的界面处 （即PN和CNS分别是成功的手术结果所必需的。在初步工作中，我们的小组 已经设计和开发了基于NIR的奥恶嗪问题，其中一个子集提供PNS和CNS特异性， 但是，仍然需要适合临床翻译的药物。此外，合成优化研究具有 还为我们提供了发展水溶性特定特定问题的路线图 行政。在此补充授予的R01EB032226中，该授予完全集中在PNS对比度上 将设计相关的，水溶性的，NIR神经特异性的荧光团（S）用于可视化颅神经 并作为安东尼奥·蒙塔诺先生的职业发展和培训计划的一部分开发。