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

项目摘要 医源性神经损伤是外科手术中最令人恐惧的并发症之一，并且仍然是主要的发病率 所有外科专科的医生保留神经的根治性直肠癌切除术是一个引人注目的临床例子， 患者发病率，其中高达60%的患者报告神经损伤，导致失禁和严重并发症， tence.令人惊讶的是，没有临床批准的技术可以提高术中神经可视化，通常 仅通过神经解剖学知识和传统的白色光可视化进行。发展 一种近红外（NIR）荧光团，专门突出神经组织在手术室将有 通过FDA批准的荧光通道，直接临床转化为神经保留切除术， da芬奇手术机器人系统（Firefly，Intuitive Surgical，Inc.），它用于>80%的前列腺切除术， 今天在美国成立。拟议的工作将直接解决这一未满足的临床需求。荧光 引导手术（FGS）已经成功地融入临床医学，只有两个FDA批准的近红外荧光， 载体（即，吲哚菁绿色[ICG]和亚甲蓝）。FGS系统几乎完全在NIR中运行 （700-900 nm），其中组织发色团吸光度、自发荧光和散射降至局部最小值， 高对比度和高分辨率成像。所有临床FGS系统均具有“800 nm” 设计用于成像ICG的通道。为了促进快速临床翻译，本文的总体目标是生成 具有与ICG匹配的光谱特性的神经特异性小分子荧光团， 在深度和未来的临床翻译使用现有的临床FGS基础设施。的设计与开发 可以使用针对ICG优化的FGS系统成像的小分子神经特异性荧光团已经被 这是一个重大的挑战，因为这些探针需要具有足够低的分子量以穿过紧密的 血神经屏障连接处具有足够的共轭度，用于NIR激发和发射。以令人兴奋 初步工作，我们的团队已经合成了一流的近红外神经特异性小分子荧光团， 可以使用针对ICG优化的标准FGS系统成像。在此，这些新的探针将被合成。 通过使用da芬奇将其转化为猪和犬模型，调整并验证其临床实用性 完成临床前药理学和毒理学（pharm/tox）研究，使未来的IND申请成为可能 向FDA申请机器人辅助根治性乳腺癌切除术（RARP）的临床转化。这一目标将在... 目标1：合成调谐和表征NIR神经特异性 用于未来临床FGS的荧光团。目的2：证明与da芬奇Firefly和临床前的兼容性 pharm/tox适合临床翻译。目的3：选择最佳的800 nm，神经特异性荧光团的未来 临床翻译以指导神经保留RARP。成功完成此R 01将产生最佳NIR 适用于所有临床FGS系统的神经特异性荧光团和神经特异性对比度的验证 用达芬奇萤火虫进行RARP。

PROJECT SUMMARY Iatrogenic nerve injury represents one of the most feared surgical complications and remains a major morbidity across all surgical specialties. Nerve-sparing radical prostatectomy is a compelling clinical example of significant patient morbidity, where nerve damage is reported in up to 60% of patients resulting in incontinence and impo- tence. Surprisingly, no clinically approved technology can enhance intraoperative nerve visualization, typically performed through neuroanatomical knowledge and conventional white light visualization alone. Development of a near infrared (NIR) fluorophore that specifically highlights nerve tissue in the operating room would have direct clinical translation to nerve sparing prostatectomy through the FDA approved fluorescence channel in the da Vinci surgical robotic system (Firefly, Intuitive Surgical, Inc.), which is used in >80% of prostatectomies per- formed in the United States today. The proposed work will directly address this unmet clinical need. Fluorescence Guided Surgery (FGS) has successfully integrated into clinical medicine with only two FDA-approved NIR fluor- ophores (i.e., indocyanine green [ICG] and methylene blue). FGS systems operate almost exclusively in the NIR (700-900 nm), where tissue chromophore absorbance, autofluorescence and scatter fall to local minima, allowing high contrast and high resolution imaging at up to centimeter depths. All clinical FGS systems have an “800 nm” channel designed to image ICG. To facilitate rapid clinical translation, the overall goal herein is to generate a nerve-specific small molecule fluorophore with spectral properties matched to ICG, enabling both nerve imaging at depth and future clinical translation using existing clinical FGS infrastructure. Design and development of a small molecule nerve-specific fluorophore that can be imaged using FGS systems optimized for ICG has been a significant challenge because these probes need to have a low enough molecular weight to cross the tight blood nerve barrier junction with a sufficient degree of conjugation for NIR excitation and emission. In exciting preliminary work, our team has synthesized first-in-class NIR nerve-specific small molecule fluorophores that can be imaged with standard FGS systems optimized for ICG. Herein, these novel probes will be synthetically tuned and validated for clinical utility through translation to swine and canine models using the da Vinci as well as completion of preclinical pharmacology and toxicology (pharm/tox) studies, enabling a future IND application to the FDA for clinical translation to robotic assisted radical prostatectomies (RARP). This goal will be accom- plished through the following specific aims: Aim 1: Synthetic tuning and characterization of NIR nerve-specific fluorophores for future clinical FGS. Aim 2: Demonstrate compatibility with the da Vinci Firefly and preclinical pharm/tox suitable for clinical translation. Aim 3: Select the optimal 800 nm, nerve-specific fluorophore for future clinical translation to guide nerve-sparing RARP. Successful completion of this R01 will result in an optimal NIR nerve-specific fluorophore suitable for use with all clinical FGS systems and validation of nerve-specific contrast for RARP using the da Vinci Firefly.