STTR Phase I: Near Infrared Nerve-Specific Fluorophores for Fluorescence-Guided Surgery

这个小企业创新研究（SBIR）第一阶段项目的更广泛影响是开发一种技术，该技术将使用荧光成像减少术中神经损伤，使外科医生能够看到看不见的东西。术中神经损伤是外科手术的主要并发症，影响所有专业，往往造成无法弥补的损害。神经损伤发生在约17%的手术中，术中神经损伤每年影响全球5000万患者，导致过度疼痛，功能丧失和医疗保健系统的高成本。目前，没有临床批准的技术存在，以提高术中神经识别-外科医生完全依赖于解剖知识和可视化。拟议的项目将完成第一种神经靶向物质的开发，使外科医生能够“按颜色切割”-更有效地识别和保留神经，以减少这些并发症和相关成本，预计每年将耗资125亿美元。拟议项目的重点是开发用于荧光引导手术（FGS）的近红外神经特异性荧光团在临床上可以转化为人类研究。最近的工作已经允许修改荧光团的基本结构，以显着提高亮度，溶解度和毒性，同时保持高神经特异性。本文提出的工作的直接里程碑包括（1）表征具有化学调节的水溶性和量化的神经特异性的苯并[c]吩恶嗪小分子衍生物的库，（2）阐明生物靶标和对荧光团的神经特异性的机理理解，（3）啮齿动物中的初步单剂量毒理学分析，（4）量化的药代动力学、药效学、和生物分布以确定最佳成像剂量和时间窗，以及（5）鉴定用于临床转化的先导化合物。成功完成拟议的工作将能够选择一个领先的候选人，具有经过验证的安全性和明亮，持久（约1小时）的神经特异性荧光，用于识别埋藏在1厘米深的神经结构。该奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

The broader impact of this Small Business Innovation Research (SBIR) Phase I project is the development of a technology that will reduce intraoperative nerve damage using fluorescence imaging to enable surgeons to see the unseen. Intraoperative nerve injury is a major complication of surgery, affecting all specialties and often causing irreparable damage. Nerve damage occurs in ~17% of all surgeries and intraoperative nerve injuries affect 50 million patients annually worldwide, incurring undue pain, loss of function, and high costs to the healthcare system. Currently, no clinically approved technology exists to enhance intraoperative nerve recognition - surgeons rely solely on anatomical knowledge and visualization. The proposed project will finalize development of first-in-kind nerve targeted substance allowing surgeons to “cut by color” – identifying and sparing nerves more effectively to reduce these complications and the associated costs, estimated at $12.5 billion annually.The proposed project is focused on the development of near-infrared nerve-specific fluorophores for fluorescence-guided surgery (FGS) that are clinically viable for translation to human studies. Recent work has allowed modification of the base structures of the fluorophores to significantly improve brightness, solubility, and toxicity while maintaining high nerve specificity. The immediate milestones of the work proposed herein include (1) characterization of a library of benzo[c]phenoxazine small molecule derivatives with chemically tuned water solubility and quantified nerve specificity, (2) elucidation of the biological target and mechanistic understanding of nerve-specificity for the fluorophores, (3) preliminary single-dose toxicology analysis in rodents, (4) quantified pharmacokinetics, pharmacodynamics, and biodistribution to determine the optimal imaging dose and time window, and (5) identification of a lead compound for clinical translation. Successful completion of the proposed work will enable selection of a lead candidate with a proven safety profile and bright, long-lasting (~1 hour) nerve-specific fluorescence for identification of buried nerve structures at up to 1 cm depths.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.