Two-Color Near-Infrared Fluorescence Guided Surgery Tools Enabling Simultaneous Cancer Margin and Nerve Visualization during Head and Neck Squamous Cell Carcinoma Resection

项目总结 头颈部鳞状细胞癌(HNSCC)是世界上发病率第六高的癌症， &gt；每年65万起。手术是HNSCC的主要治疗选择，在此期间外科医生面临两个 主要目标：1)彻底切除肿瘤；2)保留肌肉、血液等正常组织结构 血管和神经，以确保术后生活质量。不幸的是，这些目标不是协同的， 完整的癌症切除往往受到保护正常组织和减少生活改变的努力的限制 合并症。事实上，20%-30%的患者手术切缘呈阳性，神经损伤代表 一种主要的外科合并症，5%-30%的患者经历持续疼痛或功能丧失。目前，没有 有技术可以加强术中癌症和神经识别。因此，技术提供了 实时、直接地显示肿瘤边缘和神经将极大地改进外科手术 减少HNSCC患者的预后和并发症。荧光引导手术(FGS)已经成功 集成到临床医学中，为外科医生提供重要组织和复杂情况的实时可视化 解剖学。使用紧凑和高分辨率的FGS成像系统，这些系统几乎只在 近红外(NIR，700-900 nm)，外科医生可以成像高对比度的目标荧光探针，最高可达 厘米深。正在开发的近红外神经特异性和HNSCC靶向探针将共同提供 喉癌切除的综合FGS工具。几种基于多肽的FGS成像探针已经证明 识别肿瘤边缘的有效性，目前处于第二和第三阶段临床试验，包括靶向试验 表皮生长因子受体(EGFR)、基质金属蛋白酶(MMP)和整合素。我们已经开发出 一流的近红外神经特异性荧光小分子探针，向所有人展示高神经信号 背景组织(如肌肉、脂肪、血管、筋膜等)在静脉给药后 啮齿动物和猪。重要的是，以肿瘤为靶点的FGS探针使用以800 nm为中心的荧光报告 波长，而我们的神经特异性探针在700 nm波长发出荧光，提供不同的光谱 组织检测以及与现有双色FGS系统的兼容性。这两者的结合 前景看好的技术将提供一个全面、创新的解决方案来加强癌症控制 HNSCC切除术中神经保护。这项研究的近期里程碑将包括(1) 我们用于头颈部手术的铅近红外神经特异性荧光团的表征，(2)定量 肿瘤和神经特异的FGS探针联合给药性能，包括串扰，和(3)评估 这项技术采用了临床上的双色FGS系统。这项工作将产生第一个全面的FGS工具 用于头颈部手术中的癌症切除和神经保护。建议的发展项目将会 为进一步发展和伙伴关系提供重要的概念验证。在第二期，第一个双色肿瘤 神经靶向FGS研究将在接受HNSCC切除的患者中完成。

PROJECT SUMMARY Head and neck squamous cell carcinoma (HNSCC) is the sixth highest incidence cancer worldwide, with >650,000 cases annually. Surgery is a primary treatment option for HNSCC, during which surgeons face two main goals: 1) complete cancer resection and 2) preservation of normal tissue structures such as muscle, blood vessels, and nerves to ensure post-surgical quality of life. Unfortunately, these goals are not synergistic, where complete cancer resection is often limited by efforts to preserve normal tissue and reduce life altering comorbidities. In fact, positive surgical margins are found in 20-30% of patients, and nerve damage represents a major surgical comorbidity, with 5-30% of patients experiencing lasting pain or loss of function. Currently, no technology exists to enhance intraoperative cancer and nerve recognition. Thus, technology to provide direct visualization of cancer margins and nerves simultaneously in real time would greatly improve surgical outcomes and reduce comorbidities for HNSCC patients. Fluorescence Guided Surgery (FGS) has successfully integrated into clinical medicine, providing surgeons real-time visualization of important tissues and complex anatomy. Using compact and high-resolution FGS imaging systems, which operate almost exclusively in the near-infrared (NIR, 700-900 nm), surgeons can image targeted fluorescent probes with high contrast at up to centimeter depths. NIR Nerve-specific and HNSCC-targeted probes under development would together provide an integrated FGS tool for HNSCC resection. Several peptide-based FGS imaging probes have demonstrated efficacy in identifying tumor margins and are currently in phase II and III clinical trials, including those targeting epidermal growth factor receptor (EGFR), matrix metalloprotease (MMP), and integrins. We have developed first-in-class NIR nerve-specific fluorescent small-molecule probes that demonstrate high nerve signal to all background tissues (e.g., muscle, adipose, vasculature, fascia, etc.) following intravenous administration in rodents and swine. Importantly, the tumor-targeting FGS probes utilize fluorescent reporters centered at 800-nm wavelengths, while our nerve-specific probes fluoresce at 700-nm wavelengths, providing spectrally distinct tissue detection and compatibility with existing two-color FGS systems. The combination of these two promising technologies would provide a comprehensive, innovative solution to enhance cancer control and nerve sparing during HNSCC resection. This study’s immediate milestones will include (1) characterization of our lead NIR nerve-specific fluorophore for head and neck procedures, (2) quantification of tumor- and nerve-specific FGS probe co-administration performance including cross-talk, and (3) assessment of this technology using a clinical two-color FGS system. This work will result in the first comprehensive FGS tool for cancer resection and nerve sparing during head and neck procedures. The proposed development will provide important proof-of-concept for further development and partnership. In Phase II, the first two-color tumor and nerve targeted FGS studies will be completed in patients undergoing HNSCC resection.