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

项目总结 医源性神经损伤是最令人畏惧的手术并发症之一，也是一种主要的发病率。 横跨所有外科专科。保留神经的前列腺癌根治术是一个引人注目的临床例子 患者发病率，据报道，高达60%的患者神经损伤导致大小便失禁和尿失禁。 坦斯。令人惊讶的是，没有临床批准的技术可以加强术中神经可视化，典型的 仅通过神经解剖学知识和传统的白光可视化进行。发展 一种专门突出手术室神经组织的近红外(NIR)荧光团 通过FDA批准的荧光通道直接临床移植到保留神经的前列腺切除术 达芬奇手术机器人系统(Firefly，Intusitive Surgical，Inc.)，用于80%的前列腺切除术。 形成于今天的美国。拟议的工作将直接解决这一未得到满足的临床需求。荧光 引导手术(FGS)已经成功地整合到临床医学中，只有两种FDA批准的近红外荧光- 载体(即吲哚青绿[ICG]和亚甲基蓝)。FGS系统几乎只在近红外区域运行 (700-900 nm)，其中组织发色团吸光度、自体荧光和散射降至局部最小值，允许 高对比度和高分辨率成像，深度可达厘米。所有的临床FGS系统都有“800 nm” 为形象ICG而设计的频道。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体，使神经成像 利用现有的临床FGS基础设施进行深度和未来的临床翻译。一种可编程逻辑控制器的设计与开发 可以使用针对ICG优化的FGS系统进行成像的小分子神经特异性荧光团已经被 这是一个巨大的挑战，因为这些探针需要具有足够低的分子质量才能穿过紧密的 具有足够共轭程度的血神经屏障连接，可用于近红外激发和发射。在激动人心的 前期工作，我们团队合成了一流的近红外神经特异性小分子荧光团， 可使用针对ICG优化的标准FGS系统进行成像。在这里，这些新颖的探针将被合成 通过使用达芬奇模型转换为猪和犬模型，调整和验证了临床实用性 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申请临床转化为机器人辅助前列腺癌根治术(RARP)。这一目标将伴随着- 实现了以下具体目标：目标1：近红外神经特异性的合成调谐和表征 未来临床FGS的荧光载体。目标2：展示与达芬奇萤火虫和临床前的兼容性 适用于临床翻译的药物/毒物。目标3：为未来选择最佳的800 nm、神经特异性荧光团 指导保留神经的RARP的临床翻译。成功完成此R01将产生最佳的近红外 适用于所有临床FGS系统的神经特异性荧光体和神经特异性造影剂的验证 使用达芬奇萤火虫的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.