Targeting parathyroid glands with novel fluorophores for intraoperative imaging

使用新型荧光团靶向甲状旁腺进行术中成像

• 批准号: 10657160
• 负责人: Michael Bouvet
• 金额: $ 73.33万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-16 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657160
• 关键词: Acute; Address; Adipose tissue; Adrenal Glands; Adverse effects; Affinity; Animal Model; Animals; Area; Award; Binding; Biological Availability; Blood Tests; Carcinoma; Cells; Chemicals; Chemistry; Clinical; Clinical Research; Contrast Media; Data; Detection; Development; Dose; Down-Regulation; Drug or chemical Tissue Distribution; Endocrine; Endocrine Glands; Evaluation; Excretory function; Family suidae; Feces; Fluorescence; Formulation; Funding; Future; Goals; Grant; Halogens; Histologic; Hormones; Human; Hyperparathyroidism; Hyperplasia; Hypocalcemia; Image; Image-Guided Surgery; Imaging Techniques; Injections; Islet Cell Tumor; Kinetics; Lead; Light; Location; Mediating; Medicine; Mitochondria; Molecular Target; Morbidity - disease rate; Multi-Drug Resistance; Mus; National Institute of Biomedical Imaging and Bioengineering; Nature; Neck; Normal tissue morphology; Operative Surgical Procedures; Pancreas; Parathyroid Adenoma; Parathyroid gland; Parathyroidectomy; Patients; Performance; Pharmaceutical Preparations; Pituitary Gland; Postoperative Period; Procedures; Rattus; Safety; Sensitivity and Specificity; Series; Structure; Surgeon; Technology; Testing; Therapeutic Intervention; Thymus Gland; Thyroid Gland; Thyroidectomy; Time; Tissues; Toxic effect; United States National Institutes of Health; Urine; Validation; Visualization; absorption; adenoma; cellular targeting; clinical translation; curative treatments; fluorophore; halogenation; image guided; image-guided drug delivery; imaging modality; imaging system; improved; intravenous injection; lymph nodes; molecular imaging; novel; pancreatic neoplasm; pharmacokinetics and pharmacodynamics; phenoxazine; preservation; real-time images; resistance gene; safety study; scale up; single photon emission computed tomography; subcellular targeting; tumor; uptake; whole body imaging

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.

项目总结/摘要：甲状旁腺（PG）通常难以在术中定位，因为其 体积小，手术光下对比度差。最近，外科医生一直在使用近红外（NIR） 自体荧光作为一种手段，以帮助识别PG，然而，有假阳性和阴性与此 技术和灵敏度和特异性的改进空间。有一个未满足的需要， 明亮的近红外探头，可用于1）在甲状腺手术期间识别和保存正常PG， 术后低钙血症并发症和2）在甲状旁腺切除术中识别甲状旁腺腺瘤， 甲状旁腺功能亢进患者。因此，术中成像方法，以帮助外科医生发现PG在 在没有可用造影剂的情况下，实时同时保留正常组织代表了未满足的临床需求。 我们的假设指导这项研究是卤化近红外荧光团提供灵敏，特异性和真实的- 用于改善治疗干预的时间图像引导，包括无创定位， 术中影像引导甲状旁腺切除术。根据之前的NIH资助#R01EB011523，我们有 开发了超过850种适合内分泌成像的新型NIR荧光团（内分泌特异性NIR荧光团; ESNFs），并成功靶向甲状腺/甲状旁腺（TG/PG），脑垂体，胸腺，肾上腺， 胰腺和肿瘤与自然产生的激素在结构和化学上相似， 药物，ESNFs可以提供高对比度的内分泌腺的图像引导手术后，单 小鼠、大鼠和猪静脉注射（见初步数据）。 在目前的NIH/NIBIB资助下（#R01EB022230;神经内分泌的图像引导药物递送 胰腺肿瘤），我们已经成功地开发了一系列用于靶向胰腺的恶嗪衍生物， 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显示出特异性摄取。 包括PG在内的腺体。因此，在这份更新申请中，我们的目标是 研究这些荧光团的靶向机制沿着药代动力学/药效学 和安全性研究。采用“结构-固有靶向”策略，我们的目标是增加特异性亲和力 同时最大限度地减少甲状腺，淋巴结或脂肪组织中的非特异性摄取， 颈部，没有明显的脱靶不良反应。具体目标集中在三个关键领域：1）系统 用制备性放大合成优化最终制剂，2）分子靶标鉴定， 肿瘤小鼠中原发性甲状旁腺功能亢进的术前成像，以及3）靶向造影剂的评价 用于术中图像引导肿瘤手术的药剂。我们建议加强临床翻译活动， 第二个授予期，包括扩大化学和两个物种的毒性评价。