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

项目总结 一个多世纪以来，颅底肿瘤的治疗一直是临床上的挑战。肿瘤通常是 位于颅骨深处，通常与关键的神经血管结构有关，在那里损伤导致 高发病率和高死亡率。暴露技术、肿瘤切除、颅底重建的主要进展 微创手术提高了手术的安全性，但脑神经仍是最重要的手术之一。 经常损伤所有外科专科的神经结构。颅底的肿瘤通常是 良性的，但发生在靠近脑神经的地方，最常见的病理起源于 脑神经鞘(即听神经鞘瘤)或颅骨衬里(即脑膜瘤)。脑膜瘤 占原发脑肿瘤的40%，预计2021年将诊断出约35,000例脑肿瘤。由于脑膜瘤的出现 在脑膜中，它们可以出现在头骨内的不同位置。相比之下，听神经鞘瘤 发病率要低得多，但总是与脑神经密切相关，因为它们来自神经。 护套。完全手术切除这两种类型的肿瘤是有可能治愈的，但必须与神经平衡。 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则被用于- 保留颅神经、神经损伤和不完全切除的协奏会继续挑战颅底 手术。这项工作将直接解决这一未得到满足的临床需求。以促进临床翻译和实用 神经外科，这里的总体目标是产生与光谱特性匹配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。这些新颖的探头 将使脑神经可视化与可见的肿瘤增强对比在光谱上截然不同 通常用于神经外科，同时使用现有的临床FGS实现未来的临床翻译 基础设施。近红外神经特异性探针的发展对作为分子的合成提出了挑战 必须小到足以穿过紧密的血神经和/或血脑屏障(S)，但具有足够的 共轭，以达到近红外波长。这在神经外科的应用中是一个特别的挑战 周围神经系统和中枢神经系统交界处结构的识别和可视化 (分别为三叉神经核和中枢神经系统)是手术成功的必要条件。在前期工作中，我们小组 设计和开发了基于恶嗪的近红外探针，其中一个子集提供PNS和CNS特异性， 然而，仍然需要一种适合临床翻译的试剂。此外，综合优化研究已经 也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 行政管理。在R01EB032226的这项补充拨款中，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的、水溶性的、近红外神经特异性荧光团(S) 作为安东尼奥·蒙塔尼奥先生职业发展和培训方案的一部分。

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.