Image-Guided Surgery of Endocrine Glands and Their Tumors using Near-Infrared Flu

使用近红外流感图像引导内分泌腺及其肿瘤手术

• 批准号: 8117244
• 负责人: Hak Soo Choi
• 金额: $ 48.93万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8117244
• 关键词: Adhesions; Adrenal Cortex; Adrenal Glands; Amines; Anatomy; Aniline; Animal Model; Applications Grants; Aromatase; Biodistribution; Biomedical Engineering; Blood Vessels; Breast; Carbon; Catecholamines; Cell membrane; Cells; Chemical Structure; Chemicals; Chemistry; Clinic; Clinical; Clinical Trials; Collaborations; Color; Contrast Media; Data; Development; Dose; Endocrine; Endocrine Gland Neoplasms; Endocrine Glands; Estrone; Excision; Exhibits; Family; Family suidae; Fascia; Fluorescence; Foundations; Funding; Future; Gland; Goals; Grant; Hormones; Human; Image; Image-Guided Surgery; Injection of therapeutic agent; Iodine; Kidney; Laboratories; Light; Malignant neoplasm of lung; Malignant neoplasm of ovary; Manuscripts; Mesentery; Modeling; Mus; Nerve; Operative Surgical Procedures; Optics; Ovary; Pancreas; Performance; Pharmaceutical Preparations; Plastic Surgical Procedures; Preparation; Production; Property; Quantitative Structure-Activity Relationship; Rattus; Relative (related person); Research; Resected; Sentinel Lymph Node Mapping; Shapes; Signal Transduction; Simulate; Specificity; Sprague-Dawley Rats; Steroids; Structure; Surgeon; Surgical Oncologist; System; Testing; Thyroid Gland; Time; Tissues; Transgenic Mice; Translating; Tumor Tissue; Universities; Uterus; Variant; Vertebral column; base; chemical property; cyanine; cyanine dye; falls; flu; fluorophore; improved; in vivo; insulinoma; intraoperative imaging; intravenous injection; malignant breast neoplasm; novel; optical imaging; pharmacophore; public health relevance; research clinical testing; scale up; tumor; uptake

DESCRIPTION (provided by applicant): Endocrine tumors, such as insulinoma, are rare but notoriously difficult to treat surgically due to their small size and poor contrast using white light. Endocrine tumors, such as ovarian cancer, are common but equally difficult to treat surgically, with improved survival dependent on complete cytoreduction. Similarly, normal endocrine tissues, such as the thyroid gland and adrenal gland, can often be difficult to locate during surgery due to adhesions and overlying fascia. Our hypothesis is that near-infrared (NIR) fluorophores targeted to endocrine glands and their tumors will provide surgeons with sensitive, specific, and real-time image- guidance after a single, pre-operative, intravenous injection. When used with an appropriate intraoperative imaging system, NIR fluorescent light from 700 to 900 nm can provide surgeons with real-time localization of normal and diseased tissue, without changing the look of the surgical field. As part of a previously funded Bioengineering Research Partnership (BRP) grant, we have developed the FLARE" (Fluorescence-Assisted Resection and Exploration) image-guided surgery system. FLARE provides real-time imaging of surgical anatomy (i.e., color video) simultaneously with two independent channels of NIR fluorescent light (700 nm and 800 nm emission). One NIR channel is typically reserved for the tissue to be resected (e.g., tumor) while the other is reserved for tissue that needs to be avoided (e.g., nerves, blood vessels, normal glands, etc.). FLARE has already been translated to the clinic where it is being used in breast cancer sentinel lymph node (SLN) mapping, lung cancer SLN mapping, and plastic surgery. The resection of endocrine gland tumors (e.g., insulinoma and ovarian cancer) and the avoidance of normal endocrine tissue (e.g., thyroid and adrenal glands) represent a significant unmet clinical need, with no available contrast agents. In collaboration with the Henary/Strekowski/Patonay laboratory at Georgia State University, recognized leaders in the field of fluorophore chemistry, we have developed novel NIR fluorophores tailored to endocrine imaging (endocrine-specific NIR fluorophores; ESNFs). Sharing structural and chemical similarities with naturally occurring hormones and drugs, ESNFs provide high contrast for image-guided surgery after a single intravenous injection into mice, rats, and pigs. The specific aims of this grant are focused on the synthesis of three new chemical classes of ESNFs, scale-up from analytical to preparative production, and optimization of their optical and chemical properties. Completion of these aims will lay the foundation for future clinical testing of ESNFs during image-guided surgery. PUBLIC HEALTH RELEVANCE: Invisible near-infrared fluorescent light can provide sensitive and specific guidance during surgery, but only if optimal contrast agents are available. Endocrine tissues and their tumors are particularly difficult to find during surgery, yet no endocrine-specific near-infrared fluorescent contrast agents presently exist. We have discovered endocrine-specific uptake by certain cyanine and basic aniline near- infrared fluorophores, and in this grant application, describe optimization of these agents and the development of three new families of near-infrared fluorophores for image-guided surgery.

描述（由申请人提供）：内分泌肿瘤（例如胰岛素瘤）很少见，但由于其体积小且白光对比度差而难以通过手术治疗。内分泌肿瘤，如卵巢癌，很常见，但同样难以通过手术治疗，生存率的提高依赖于完全细胞减灭术。同样，由于粘连和覆盖的筋膜，正常的内分泌组织（例如甲状腺和肾上腺）在手术过程中通常很难定位。我们的假设是，针对内分泌腺及其肿瘤的近红外（NIR）荧光团将在单次术前静脉注射后为外科医生提供敏感、特异性和实时的图像引导。 当与适当的术中成像系统一起使用时，700 至 900 nm 的 NIR 荧光可以为外科医生提供正常组织和患病组织的实时定位，而无需改变手术区域的外观。作为先前资助的生物工程研究合作伙伴 (BRP) 拨款的一部分，我们开发了 FLARE”（荧光辅助切除和探索）图像引导手术系统。FLARE 通过两个独立的 NIR 荧光通道（700 nm 和 800 nm 发射）同时提供手术解剖结构的实时成像（即彩色视频）。一个 NIR 通道通常保留用于待切除的组织。 一个被切除（例如肿瘤），另一个则保留给需要避免的组织（例如神经、血管、正常腺体等）。 FLARE 已应用于临床，用于乳腺癌前哨淋巴结 (SLN) 定位、肺癌 SLN 定位和整形外科。 内分泌腺肿瘤（例如胰岛素瘤和卵巢肿瘤）的切除 癌症）和避免正常内分泌组织（例如甲状腺和肾上腺）代表了显着的未满足的临床需求，因为没有可用的造影剂。我们与荧光团化学领域公认的领导者佐治亚州立大学 Henary/Strekowski/Patonay 实验室合作，开发了专为内分泌成像（内分泌特异性 NIR）定制的新型 NIR 荧光团 荧光团； ESNF）。 ESNF 与天然激素和药物具有结构和化学相似性，在对小鼠、大鼠和猪进行单次静脉注射后，可为图像引导手术提供高对比度。 这笔赠款的具体目标集中在 ESNF 的三种新化学类别的合成、从分析型生产到制备型生产的扩大以及其光学和化学性质的优化。完成这些 目标将为未来图像引导手术期间 ESNF 的临床测试奠定基础。 公共健康相关性：不可见的近红外荧光可以在手术过程中提供敏感和具体的指导，但前提是有最佳的造影剂。内分泌组织及其肿瘤在手术中特别难以发现，但目前尚不存在内分泌特异性近红外荧光造影剂。我们发现了某些花青和碱性苯胺近红外荧光团的内分泌特异性摄取，并在本次拨款申请中描述了这些药物的优化以及用于图像引导手术的三个新近红外荧光团家族的开发。