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

多通道荧光引导手术工具可在前列腺切除术中同时实现癌症边缘和神经可视化

• 批准号: 10619640
• 负责人: Summer Lynne Gibbs
• 金额: $ 61.13万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-10 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619640
• 关键词: Adverse effects; Affect; Affinity; Antigen Targeting; Biodistribution; Cancer Control; Cancer Etiology; Cancer Patient; Cessation of life; Clinical; Clinical Medicine; Collaborations; Color; Contrast Media; Development; Dose; Dose Limiting; Drug Kinetics; FDA approved; FOLH1 gene; Face; Fluorescence; Future; Goals; Image; Impotence; Incontinence; Intuition; Label; Lead; Light; Malignant Neoplasms; Malignant neoplasm of prostate; Methods; Morbidity - disease rate; Nerve; Nerve Plexus; Nerve Tissue; Nerve-Sparing Prostatectomy; Nude Rats; Operating Rooms; Operative Surgical Procedures; Outcome; Patient-Focused Outcomes; Patients; Pharmacodynamics; Pharmacology and Toxicology; Phase I Clinical Trials; Postoperative Period; Prostate; Prostate Cancer therapy; Prostatectomy; Prostatic; Quality of life; Robot; Rodent; Safety; Specificity; Surgeon; Surgical margins; System; Technology; Time; Tissues; Toxic effect; Toxicology; Translations; Tumor Tissue; Visual Acuity; Visualization; Water; Work; Xenograft procedure; cancer imaging; chromophore; clinical translation; clinically relevant; comorbidity; contrast imaging; experience; falls; fluorescence imaging; fluorescence-guided surgery; fluorophore; improved; men; mortality; nerve damage; novel; overexpression; pre-clinical; preclinical safety; preservation; prototype; robot assistance; small molecule; spared nerve; surgery outcome; tool; tumor

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.

项目总结 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。前列腺素- TOMY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： 前列腺癌的治疗和神经保护。然而，对于神经丛识别和识别的视觉敏锐度很低 确凿的癌症描述，患者的理想结果继续挑战着即使是有经验的外科医生。 高达21%的患者手术切缘呈阳性，60%的患者神经受损，导致 癌症控制不佳以及大小便失禁和阳萎严重影响术后生活质量。不是 临床认可的方法可以在术中增强直肠癌或神经丛的可视化。因此， 能够同时实时地直接可视化癌症组织和神经的技术将大大 减少相关的合并症，显著改善前列腺切除术的结果。荧光导引苏尔波 Gery(FGS)已经成功地整合到临床医学中，只有两个FDA批准的荧光团，提供 外科医生的实时可视化。FGS系统主要工作在近红外(NIR，700-900 nm)波长， 当组织发色团的吸光度、自体荧光和散射降至局部极小值时，允许高对比度 成像深度可达厘米。一些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结合在一起将为前列腺切除术提供一个集成的FGS工具。在 美国80%的前列腺切除术是使用机器人辅助进行的，其中达芬奇手术机器人(直观 外科)是最常见的，并且标准配备了能够 实时可视化。在这里，我们将与乔纳森·索格博士(直觉外科)和斯科特·戴维斯合作 (达特茅斯)开发一种用于前列腺切除术的多色FGS解决方案，既能突出癌症，又能突出神经组织 以改善患者的预后。前列腺特异性膜抗原(PSMA)在大多数前列腺癌中过度表达 前列腺癌使其成为前列腺癌成像的有希望的靶点。一些分子已经显示出 在标记后对PSMA具有高亲和力，这已经被广泛研究，其中800 nm PSMA焦油- Geted IS-002已成功完成直觉外科赞助的I期临床试验。在这里，我们将 开发一种近红外、光谱清晰、神经特异的荧光团，用于与PSMA靶向IS-002共同给药 将这一新的FGS范例带给前列腺癌患者。在激动人心的前期工作中，我们的团队已经合成了 可用临床FGS系统成像的近红外神经特定荧光团。在此，700 nm近红外光谱分析 针对PSMA特定的800 nm IS-002的联合给药，将对CICC探测器进行综合调整，并对其进行验证 未来移植到引导下的前列腺切除术。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FGS探针。目标2：量化临床前药理和毒性 与IS-002联合给药的近红外神经特异性探针的病理学。目标3：选择一种神经特异性的先导探针 通过展示神经和前列腺癌特异性对比，与IS-002联合给药。