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，但由于其体积小，白光对比度差，手术治疗非常困难。内分泌肿瘤，如卵巢癌，很常见，但同样难以手术治疗，其生存率的提高依赖于完全的细胞减少。同样，正常的内分泌组织，如甲状腺和肾上腺，由于粘连和上覆筋膜，在手术中往往难以定位。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、特异和实时的图像引导。当与合适的术中成像系统配合使用时，700 - 900 nm的近红外荧光可以为外科医生提供正常和病变组织的实时定位，而不会改变手术视野的外观。作为先前资助的生物工程研究伙伴关系（BRP）拨款的一部分，我们开发了FLARE“（荧光辅助切除和探查）图像引导手术系统。FLARE通过两个独立的近红外荧光通道（700 nm和800 nm发射）同时提供手术解剖的实时成像（即彩色视频）。一个近红外通道通常用于待切除组织（如肿瘤），而另一个通道用于需要避开的组织（如神经、血管、正常腺体等）。FLARE已经被应用于临床，用于乳腺癌前哨淋巴结（SLN）定位、肺癌SLN定位和整形手术。切除内分泌腺肿瘤（如胰岛素瘤和卵巢癌）和避开正常内分泌组织（如甲状腺和肾上腺）是一个重要的未满足的临床需求，没有可用的对比剂。我们与佐治亚州立大学的Henary/Strekowski/Patonay实验室（荧光团化学领域公认的领导者）合作，开发了专门用于内分泌成像的新型近红外荧光团（内分泌特异性近红外荧光团；esnf）。esnf与自然产生的激素和药物具有结构和化学相似性，在小鼠、大鼠和猪的单次静脉注射后，为图像引导手术提供了高对比度。这笔拨款的具体目的是集中在三种新的化学类esfs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图像引导手术中esnf的临床测试奠定基础。

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. 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.