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

描述（由申请人提供）：内分泌肿瘤，如胰岛素瘤，是罕见的，但众所周知，由于其体积小，使用白色光对比度差，难以手术治疗。内分泌肿瘤，如卵巢癌，是常见的，但同样难以手术治疗，提高生存依赖于完全细胞减少。同样，正常的内分泌组织，如甲状腺和肾上腺，由于粘连和筋膜覆盖，在手术过程中往往难以定位。我们的假设是，靶向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灵敏、特异和实时的图像引导。 当与适当的术中成像系统一起使用时，700至900 nm的NIR荧光灯可以为外科医生提供正常和病变组织的实时定位，而不会改变手术野的外观。作为先前资助的生物工程研究伙伴关系（BRP）赠款的一部分，我们开发了FLARE”（手术辅助切除和探索）图像引导手术系统。FLARE提供手术解剖结构的实时成像（即，彩色视频），同时具有两个独立通道的NIR荧光（700 nm和800 nm发射）。一个NIR通道通常被保留用于待切除的组织（例如，肿瘤）而另一个保留用于需要避免的组织（例如，神经、血管、正常腺体等）。FLARE已被应用于临床，用于乳腺癌前哨淋巴结（SLN）标测、肺癌SLN标测和整形外科手术。 切除内分泌腺肿瘤（例如，胰岛素瘤和卵巢癌）和避免正常内分泌组织（例如，甲状腺和肾上腺）代表了显著的未满足的临床需求，没有可用的造影剂。我们与格鲁吉亚州立大学的Henary/Strekowski/Patonay实验室合作，开发了适用于内分泌成像的新型NIR荧光团（内分泌特异性NIR荧光团; ESNFs）。与天然存在的激素和药物共享结构和化学相似性，ESNFs在单次静脉注射到小鼠，大鼠和猪后为图像引导手术提供高对比度。 该补助金的具体目标集中在三种新化学类别的ESNFs的合成，从分析到制备生产的规模扩大，以及其光学和化学性质的优化。这些目标的完成将为将来在图像引导手术中进行ESNFs的临床试验奠定基础。

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.