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.

项目摘要/摘要：甲状旁腺（PGs）在术中往往难以定位