Developing a pretargeting strategy to detect Fe(II) for nuclear medicine applications

开发用于核医学应用检测 Fe(II) 的预靶向策略

• 批准号: 10294866
• 负责人: Michael John Evans
• 金额: $ 67.51万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10294866
• 关键词: Abdomen; Acute; Animal Model; Animals; Antimalarials; Artemisinins; Benchmarking; Biodistribution; Biological; Cardiovascular Diseases; Cell Line; Cells; Chemicals; Child; Chloroquine; Clinical; Clinical Trials; Coupling; Data; Desmoplastic; Development; Discipline of Nuclear Medicine; Disease; Dose; Dose-Limiting; Drug Kinetics; Exhibits; Generations; Genetic; Glioma; Goals; Half-Life; Hepatobiliary; Human; Image; ImmunoPET; In Vitro; Inductively Coupled Plasma Mass Spectrometry; Injections; Iron; KRASG12D; Knowledge; Libraries; Liver; Lysosomes; Malignant Neoplasms; Measurement; Measures; Modeling; Multifocal Lesion; Mus; Neurodegenerative Disorders; Normal Cell; Normal tissue morphology; Nutrient; PET/CT scan; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathology; Pharmaceutical Preparations; Pharmacology; Physiology; Positron-Emission Tomography; Primary carcinoma of the liver cells; Prodrugs; Radioisotopes; Reagent; Refractory; Regulation; Role; Series; Serum; Signal Transduction; Starvation; Techniques; Testing; Therapeutic; Tissues; Toxic effect; Tracer; U251; analog; antimicrobial; base; cancer type; catalyst; clinically relevant; cohort; design; imaging modality; imaging study; improved; in vivo; inhibitor/antagonist; innovation; insight; iron metabolism; mouse model; optical imaging; optical sensor; pancreatic cancer model; protein crosslink; prototype; radioligand; radiotracer; response; small molecule; subcutaneous; success; targeted treatment; tumor; uptake; virtual

Project Abstract While it has been recognized for decades that diseased cells arising from numerous disorders exhibit altered iron metabolism compared to normal cells, only recently has it become apparent that increased concentration of cytosolic free ferrous iron (Fe2+) - the labile iron pool (LIP) – is most associated with these pathologies. Meanwhile, the overwhelming clinical success of the antimalarial artemisinin has established that LIP can be safely exploited to treat diseases in humans (including children), a milestone that has inspired us and others to develop 1,2,4-trioxolane (TRX)-based prodrugs that are activated by LIP and release drug payloads within diseased cells. Although our knowledge of the role of LIP in normal physiology and disease has increased substantially over the past 10 years, virtually all of our insights about LIP are founded on observations from cell lines. Studying LIP in vivo is a major knowledge gap that is currently impeding efforts to apply experimental LIP targeted therapies clinically. We hypothesized based on the well-studied mechanisms of TRX reactivity with LIP that a PET strategy could enable LIP measurements in vivo by sequestering a radioisotope within cells via Fe(II)-dependent protein crosslinking. We designed a prototype, 18F-TRX, and showed that its biodistribution in vivo is Fe2+-dependent, it detects diverse cancer types with an expanded LIP, and tumor uptake of 18F-TRX is directly proportional to tumor response to LIP targeting therapies. However, the tracer's rapid serum clearance (t1/2 ~28 sec) and slow hepatobiliary clearance combine to limit the overall image quality. Thus, the goal of this project is to test if a pre-targeting strategy involving macrodosing of a cold TRX reagent, followed later by a microdose of a cognate 18F-click coupling partner may improve measurements of LIP by eliminating the background signal from unreacted TRX and/or achieving better TRX exposure in tissues with LIP expansion. During Aim 1, we will synthesize and study the in vivo pharmacology of TRX- transcyclooctene (TCO) conjugates and fluoro-tetrazines to identify optimal biorthogonal click partners. During Aim 2, the optimal pre-targeting conditions will be established in tumor bearing mice using immunoPET. Imaging findings (e.g. tumor uptake, tumor to normal ratios) will be benchmarked against 18F-TRX and the 18F- tetrazine alone. During Aim 3, we will perform cohort expansion studies to acquire additional biological replicates while also studying spontaneous and orthotopic tumor models arising in abdominal tissues (e.g. liver, pancreas) that we expect to be occult on 18F-TRX imaging. If successful, defining which disease types harbor high LIP with PET provides a natural segue to clinical trials implementing the myriad experimental LIP targeted therapies currently waiting in the queue. Solving this challenge with pre-targeting would also add a new application for a venerable dosing strategy that could be broadly applied to improve the image quality of other rapidly clearing small molecule radiotracers, or perhaps even the antitumor efficacy of radioligand therapies.

项目摘要 虽然已经被识别出数十年，但由于众多疾病而引起的病态细胞表现出来 与正常细胞相比，铁代谢，直到最近才变得明显增加了浓度分解 胞质游离亚铁（Fe2+） - 不稳定铁池（唇） - 与这些病理最相关。 同时，抗疟清氨基氨酸氨酸氨酸宁宁宁宁宁宁宁宁宁宁素素的压倒性临床成功 安全地利用治疗人类（包括儿童）的疾病，这是一个启发我们和水獭的里程碑 开发1,2,4-三氧醇（TRX）基于唇部的前药，并在内部激活药物有效载荷 病细胞。 在过去的10年中，Virtualy基本上所有关于唇的见解都是基于细胞观察的 线在体内研究唇部是一个主要的知识差距，目前阻碍了实验 临床上的嘴唇疗法。 使用嘴唇，PET策略可以通过隔离在体内实现唇部测量 通过Fe（II）依赖性蛋白质交联的细胞。 体内的生物膜是Fe2+依赖性的，它检测到唇部扩张和肿瘤的多种癌症类型 18F-TRX的吸收与嘴唇靶向疗法成正比 快速血清清除率（T1/2-28秒）和缓慢的肝胆管间隙合并以限制整体图像 质量。 试剂，后来是同源18F点击耦合伴侣的微剂量可能会改善测量值 通过消除无效TRX的背景信号和/或在组织中获得更好的TRX暴露来唇部 在AIM 1期间的唇部扩张。 跨环烯（TCO）结合量和氟心嗪，以识别最佳的生物性点击伙伴。 AIM 2，将使用免疫集在肿瘤轴承小鼠中建立最佳的预靶条件。 成像发现（例如肿瘤摄取，肿瘤与正常比率）将针对18F-TRX和18F-进行基准测试 单独的四嗪。 在腹部组织中出现的自发性和原位肿瘤模型同时进行了复制（例如， 肝脏，pal骨），我们期望在18F-TRX成像上被隐秘。 Harbor High High Lip with Pet为实施无数实验性唇部的临床提供了自然的选择 目前在队列中等待的有针对性疗法。 新的应用于一种可观的给药策略的新应用，该策略可以广泛应用于 其他快速清除小分子放射性示例，甚至是放射性的抗肿瘤功效 疗法。