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: 10461857
• 负责人: Summer Lynne Gibbs
• 金额: $ 61.49万
• 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/10461857
• 关键词: Address; Autopsy; Biodistribution; Biological; Blood-Nerve Barrier; Canis familiaris; Clinical; Clinical Medicine; Development; Dose; Dose-Limiting; Drug Kinetics; FDA approved; Family suidae; Fireflies; Fluorescence; Formulation; Fright; Future; Goals; Gold; Hour; Human; Iatrogenesis; Image; Impotence; Incontinence; Indocyanine Green; Infrastructure; Intuition; Knowledge; Lead; Light; Local Therapy; Malignant neoplasm of prostate; Methodology; Methylene blue; Modeling; Molecular Weight; Morbidity - disease rate; Nerve; Nerve Tissue; Nerve-Sparing Prostatectomy; No-Observed-Adverse-Effect Level; Operating Rooms; Operating System; Operative Surgical Procedures; Optics; Patients; Pharmacodynamics; Pharmacology and Toxicology; Photoaffinity Labels; Property; Prostate; Prostatectomy; Prostatic; Proteomics; Radical Prostatectomy; Reporting; Robot; Robotics; Rodent; Specificity; Stains; Structure-Activity Relationship; Surgeon; Surgical Specialties; Surgical complication; System; Technology; Testing; Tissues; Toxic effect; Toxicology; Translating; Translations; United States; Validation; Visualization; Work; Zebrafish; base; canine model; chromophore; clinical translation; clinically relevant; design; falls; fluorescence imaging; fluorescence-guided surgery; fluorophore; high resolution imaging; improved; nerve damage; nerve injury; neurotransmission; novel; porcine model; pre-clinical; preservation; robotic system; small molecule; surgery outcome

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.

项目概要 医源性神经损伤是最令人担心的手术并发症之一，并且仍然是主要的发病率 在所有外科专业中，保留神经的根治性前列腺切除术是一个令人信服的临床例子。 据报道，高达 60% 的患者出现神经损伤，导致失禁和阳痿。 令人惊讶的是，通常没有临床批准的技术可以增强术中神经可视化。 仅通过神经解剖学知识和传统的白光可视化进行。 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转化为保留神经的前列腺切除术 达芬奇手术机器人系统（Firefly，Intuitive Surgical, Inc.），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。 引导手术 (FGS) 已成功融入临床医学，仅有两种 FDA 批准的近红外荧光技术 荧光素（即吲哚菁绿 [ICG] 和亚甲蓝）几乎只在 NIR 中运行。 （700-900 nm），组织发色团吸光度、自发荧光和散射降至局部最小值，从而允许 所有临床 FGS 系统都具有“800 nm”深度的高对比度和高分辨率成像。 旨在对 ICG 进行成像的通道 为了促进快速临床转化，本文的总体目标是生成一个 神经特异性小分子荧光团，其光谱特性与 ICG 匹配，可实现神经成像 使用现有的临床 FGS 基础设施进行深度和未来的临床翻译设计和开发。 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 这是一个重大挑战，因为这些探针需要具有足够低的分子量才能穿过紧密的 血神经屏障连接具有足够的接合度以进行近红外激发和发射。 前期工作中，我们的团队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 系统进行成像。在此，这些新型探针将被合成。 通过使用达芬奇转化为猪和犬模型，对临床实用性进行调整和验证 临床前药理学和毒理学（药物/毒理学）研究的完成，使未来的 IND 申请成为可能 向 FDA 申请机器人辅助根治性前列腺切除术 (RARP) 的临床转化。 通过以下具体目标实现： 目标 1：NIR 神经特异性的综合调谐和表征 用于未来临床 FGS 的荧光团 目标 2：证明与达芬奇 Firefly 和临床前的兼容性。 适合临床转化的 pharm/tox 目标 3：为未来选择最佳的 800 nm 神经特异性荧光团。 指导神经保护 RARP 的临床转化 成功完成此 R01 将产生最佳的 NIR。 神经特异性荧光团适用于所有临床 FGS 系统和神经特异性对比验证 使用达芬奇萤火虫进行 RARP。