Multichannel Fluorescence Guided Surgery Tools Enabling Simultaneous Cancer Margin and Nerve Visualization in Prostatectomy

项目摘要 前列腺癌是男性中最常见的癌症，也是癌症死亡的第二大原因。前列腺- 切除术是前列腺癌最常见的主要治疗方法之一，外科医生面临两个主要目标： 前列腺癌治疗和神经保护。然而，由于神经丛识别的视力很低， 结论性的癌症描绘，患者的理想结果继续挑战甚至有经验的外科医生。 手术切缘阳性和神经损伤分别发生在21%和60%的患者中，导致 癌症控制差以及失禁和阳痿严重影响术后生活质量。没有 存在临床认可的方法来增强手术中的直接癌症或神经丛可视化。因此，在本发明中， 能够真实的同时直接可视化癌组织和神经的技术将大大 减少相关合并症并显著改善直肠癌切除术的结果。荧光引导表面活性剂 gery（FGS）成功地融入临床医学，只有两个FDA批准的荧光团，提供 外科医生实时可视化。FGS系统主要在近红外（NIR，700-900 nm）波长下工作， 其中组织发色团吸收、自发荧光和散射降至局部最小值，从而允许高对比度 成像深度可达厘米许多靶向近红外造影剂正在开发中，包括 神经和前列腺特异性探针，共同为前列腺切除术提供集成的FGS工具。在 在美国，>80%的阑尾切除术是使用机器人辅助进行的，其中da芬奇手术机器人（直观 手术）是最常见的，并且标准配备有能够 实时可视化。在此，我们将与Jonathan Sorger博士（Intuitive Surgical）和Scott Davis博士合作 （达特茅斯）开发一种用于椎间盘切除术的神经FGS解决方案，该解决方案突出了癌症和神经组织 来改善病人的治疗效果前列腺特异性膜抗原（PSMA）在大多数前列腺癌中过表达。 前列腺癌使其成为前列腺癌成像的有希望的靶点。一些分子已经证明 标记后对PSMA的高亲和力，这已被广泛研究，其中800 nm PSMA焦油- Geted IS-002已成功完成由Intuitive Surgical赞助的I期临床试验。在此，我们将 开发NIR、光谱不同的神经特异性荧光团，用于与PSMA靶向IS-002共同给药， 将这种新的FGS模式带给前列腺癌患者。在激动人心的前期工作中，我们的团队合成了 可以用临床FGS系统成像的NIR神经特异性荧光团。在此，700 nm NIR神经特异性- 将对特异性探针进行合成调整，以与PSMA特异性800 nm IS-002共同施用，并验证其生物学活性。 未来将转化为引导性子宫切除术。这些目标将通过以下具体目标实现： 目的1：合成700 nm近红外神经特异性荧光探针。目的2：量化临床前药理学和毒理学 与IS-002共同施用的NIR神经特异性探针的生物学。目标3：选择电极导线神经特异性探头， 与IS-002共同给药，通过显示神经和前列腺癌特异性对比。

PROJECT SUMMARY Prostate cancer is the most prevalent cancer in men and the second leading cause of cancer death. Prostatec- tomy is one of the most common primary treatments for prostate cancer, where surgeons face two main goals: prostate cancer cure and nerve preservation. However, with little visual acuity for nerve plexus recognition and conclusive cancer delineation, ideal outcomes for patients continue to challenge even experienced surgeons. Positive surgical margins and nerve damage occur in up to 21 and 60% of patients, respectively, resulting in poor cancer control as well as incontinence and impotence severely affecting post-operative quality of life. No clinically approved methods exist to enhance direct cancer or nerve plexus visualization intraoperatively. Thus, technology to enable the direct visualization of cancer tissue and nerves simultaneously in real time would greatly reduce associated comorbidities and significantly improve prostatectomy outcomes. Fluorescence Guided Sur- gery (FGS) has successfully integrated into clinical medicine with only two FDA-approved fluorophores, providing surgeons real-time visualization. FGS systems operate mainly at near infrared (NIR, 700-900 nm) wavelengths, where tissue chromophore absorbance, autofluorescence and scatter fall to local minima, allowing high contrast imaging at up to centimeter depths. A number of targeted NIR contrast agents are under development, including nerve- and prostate-specific probes that together would provide an integrated FGS tool for prostatectomy. In the US, >80% of prostatectomies are performed using robotic-assistance, where the da Vinci surgical robot (Intuitive Surgical) is the most common and is equipped standard with a NIR fluorescence-imaging channel capable of real-time visualization. Herein, we will collaborate with Drs. Jonathan Sorger (Intuitive Surgical) and Scott Davis (Dartmouth) to develop a multicolor FGS solution for prostatectomy that highlights both cancer and nerve tissues to improve patient outcomes. Prostate specific membrane antigen (PSMA) is overexpressed in the majority of prostate cancers making it a promising target for prostate cancer imaging. A handful of molecules have shown high affinity for PSMA following labeling, which have been extensively investigated, where 800 nm PSMA tar- geted IS-002 has successfully completed Phase I clinical trials sponsored by Intuitive Surgical. Herein, we will develop a NIR, spectrally-distinct, nerve-specific fluorophore for co-administration with PSMA-targeted IS-002 to bring this new FGS paradigm to prostate cancer patients. In exciting preliminary work, our team has synthesized NIR nerve-specific fluorophores that can be imaged with clinical FGS systems. Herein, 700 nm NIR nerve-spe- cific probes will be synthetically tuned for co-administration with PSMA-specific 800 nm IS-002 and validated for future translation to guided prostatectomy. These goals will be accomplished through the following specific aims: Aim 1: Synthesize 700 nm NIR nerve-specific FGS probes. Aim 2: Quantify preclinical pharmacology and toxi- cology of NIR nerve-specific probes co-administered with IS-002. Aim 3: Select a lead nerve-specific probe for co-administration with IS-002 through demonstration of nerve- and prostate cancer-specific contrast.