Targeting parathyroid glands with novel fluorophores for intraoperative imaging

项目摘要/摘要：甲状旁腺(PG)通常很难在术中定位，因为其 在手术灯光下体积小，对比度差。最近，外科医生一直在使用近红外线(NIR) 自体荧光作为一种帮助识别PG的手段，然而，与此有假阳性和假阴性 技术和在敏感性和特异性方面有待改进的空间。有一种尚未得到满足的需求，即开发一种可靠、 明亮的近红外探头，可用于1)在甲状腺手术中识别和保存正常的PG，从而减少 术后低钙血症并发症和2)在甲状旁腺切除术中发现甲状旁腺腺瘤 甲状旁腺功能亢进症患者。因此，一种帮助外科医生发现前列腺癌的术中成像方法 在没有可用的造影剂的情况下，实时保存正常组织代表着一种未得到满足的临床需求。 指导这项研究的假设是，卤化近红外荧光团提供了灵敏、特异和真实的- 时间影像指导，用于改进的治疗干预，包括无创定位和 术中影像引导甲状旁腺切除术。在之前的NIH资金#R01EB011523下，我们有 开发了850多个为内分泌成像量身定做的新型近红外荧光团(内分泌特异性近红外荧光团； ESNF)，并成功靶向甲状腺/甲状旁腺(TG/PG)、垂体腺、胸腺、肾上腺、 胰腺和它们的肿瘤。在结构和化学上与自然产生的激素和 药物，ESNF可以在内分泌腺上提供高对比度，用于图像引导手术 静脉注射小鼠、大鼠和猪(见初步数据)。 在目前的NIH/NIBIB资助下(#R01EB022230；用于神经内分泌的图像引导药物输送 胰腺肿瘤)，我们成功地开发了一系列针对胰腺和胰腺的恶嗪衍生物 胰腺神经内分泌肿瘤。有趣的是，这些药物中的许多在其他内分泌系统中表现出特异性摄取。 包括PG在内的腺体。因此，在这次续期申请中，因此，在这次续期申请中，我们的目标是 研究这些荧光团的靶向机制及其药代动力学/药效学 和安全研究。使用结构-固有定向策略，我们的目标是增加特定的亲和力 在减少甲状腺、淋巴结或脂肪组织的非特异性摄取的同时 颈部，没有明显的偏离目标的不良反应。具体目标集中在三个关键领域：1)系统性 通过制备性放大合成优化最终配方，2)分子靶标识别和 肿瘤小鼠原发性甲状旁腺功能亢进症的术前影像及3)靶向对比剂的评价 术中影像引导肿瘤手术的制剂。我们建议加强临床翻译活动 第二个获奖期，包括放大的化学和两个物种的毒性评估。

Project Summary/Abstract: Parathyroid glands (PGs) are often difficult to locate intraoperatively due to their small size and poor contrast under the surgical light. Recently, surgeons have been using near-infrared (NIR) autofluorescence as a means to help identify PGs, however, there are false positives and negatives with this technology and room for improvement in sensitivity and specificity. There is an unmet need to develop a reliable, bright NIR probe that can be utilized to 1) identify and preserve normal PGs during thyroid surgery, thus reducing postoperative hypocalcemia complications and 2) identify parathyroid adenomas during parathyroidectomy for patients with hyperparathyroidism. Therefore, an intraoperative imaging method to help surgeons find PGs in real-time while preserving normal tissue represents an unmet clinical need, with no available contrast agents. Our hypothesis guiding this study is that halogenated NIR fluorophores provide sensitive, specific, and real- time image-guidance for improved therapeutic interventions, including noninvasive localization and intraoperative image-guided parathyroidectomy. Under the previous NIH funding #R01EB011523, we have developed over 850 novel NIR fluorophores tailored to endocrine imaging (endocrine-specific NIR fluorophores; ESNFs) and successfully targeted thyroid/parathyroid glands (TG/PG), pituitary glands, thymus, adrenal glands, pancreas, and their tumors. Sharing structural and chemical similarities with naturally occurring hormones and drugs, ESNFs could provide high contrast on endocrine glands for image-guided surgery after a single intravenous injection into mice, rats, and pigs (see Preliminary Data). Under the current NIH/NIBIB funding (#R01EB022230; Image-guided drug delivery for neuroendocrine pancreatic tumor), we have successfully developed a series of oxazine derivatives for targeting pancreas and pancreatic neuroendocrine tumors. Interestingly, many of these agents show specific uptake in other endocrine glands including PGs. Therefore, in this renewal application, Therefore, in this renewal application, we aim to investigate the targeting mechanism of these fluorophores along with their pharmacokinetics/pharmacodynamics and safety studies. Using the “Structure-Inherent Targeting” strategy, our goal is to increase the specific affinity of targeted fluorophores while minimizing nonspecific uptake in the thyroid, lymph nodes, or fatty tissues of the neck, with no overt off-target adverse effects. Specific Aims are focused on three key areas: 1) systematic optimization of the final formulation with preparative scale-up synthesis, 2) molecular target identification and pre-operative imaging of primary hyperparathyroidism in tumor mice, and 3) evaluation of the targeted contrast agents for intraoperative image-guided tumor surgery. We propose to intensify clinical translation activities during the second award period, including scale-up chemistry and two species toxicity evaluations.