Intratumoral imaging of hypoxia using 1H- and 19F-MRI with redox-responsive Eu-based contrast agents

使用 1H 和 19F-MRI 以及氧化还原响应铕对比剂进行肿瘤内缺氧成像

• 批准号: 10239104
• 负责人: MATTHEW J ALLEN
• 金额: $ 65.61万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10239104
• 关键词: Address; Area; Biodistribution; Blinded; Cancer Patient; Caring; Cell Nucleus; Chemicals; Complex; Contrast Media; Coupling; Data; Dependence; Detection; Development; Diagnostic; Disease; Effectiveness; Environment; Europium; Fluorine; Foundations; Future; Glutathione Disulfide; Goals; Health; Human; Hypoxia; Image; In Vitro; Investments; Kinetics; Knowledge; Label; Ligands; Magnetic Resonance Imaging; Medicine; Metals; Mission; Monitor; Mus; Necrosis; Outcome; Output; Oxidation-Reduction; Oxides; Positioning Attribute; Property; Public Health; Reporting; Research; Series; Signal Transduction; Solid Neoplasm; Solubility; Structure; Structure-Activity Relationship; Temperature; Testing; Translating; Translations; Transplantation; Treatment Efficacy; Tumor Tissue; United States National Institutes of Health; Water; base; cancer therapy; clinical application; contrast enhanced; design; disease diagnosis; experimental study; human disease; improved; in vivo; in vivo imaging; indexing; innovation; mouse model; multimodality; novel therapeutics; osteosarcoma; outcome prediction; oxidation; patient derived xenograft model; prognostic; ratiometric; response; sarcoma; side effect; small molecule; therapy outcome; tool; tumor

There is a great need for positive contrast agents for magnetic resonance imaging (MRI) that respond to levels of hypoxia in heterogeneous environments like those found in many tumors for the purpose of predicting therapeutic outcomes, developing new therapies, and enabling the testing of hypotheses relevant to our collective fundamental understanding between hypoxia and human health. Our long-term goal is to develop positive contrast agents for MRI to fill this void in diagnostic medicine by focusing on EuII-containing complexes that are among the most promising areas of study. The overall objective of this application is to establish the groundwork necessary for translation of our new 19F-EuII-based complexes into useful hypoxia-responsive contrast agents by studying the influence of the position of fluorine on ligands for europium and characterizing in vitro and in vivo indices of hypoxia. The rationale that underpins the proposed research is that EuII- containing complexes labeled with fluorine differentially (T1 or 19F) influence MRI as a function of the oxidation state of europium as we have recently demonstrated both in vitro and in vivo. The expected outcome of this proposal is the establishment of 19F-EuII-based contrast agents with defined hypoxia indices. This outcome is expected to have a positive impact by contributing to the NIH's mission in the understanding of human diseases. We plan to achieve the objective of the proposal by pursuing three specific aims: (1) to synthesize a series of redox-active Eu-based multimodal contrast agents designed rationally from our initial successful agent; (2) to characterize temperature-dependence of relaxivity and in vitro hypoxia indices for multimodal redox-active 19F-Eu-based probes for MRI; and (3) To define in vivo hypoxia indices in healthy mice, hypoxic mice, and mouse models of osteosarcoma. The new 19F-EuII-based probes will be significant because they are expected to enable changes in hypoxia resulting from therapies to be imaged, consequently aiding in assessing therapeutic efficacy and influencing the care and management of cancer patients. Furthermore, because hypoxia is relevant to a wide-range of diseases, this proposal is expected to maximize returns in many other investments of the NIH.

磁共振成像（MRI）非常需要响应水平的阳性对比剂。 在许多肿瘤中发现的异质环境中缺氧的缺氧是为了预测 治疗结果，开发新疗法并实现与我们有关的假设的检验 缺氧与人类健康之间的集体基本理解。我们的长期目标是发展 MRI的阳性对比剂通过关注含EUII的复合物来填充诊断医学中的空隙 这是最有希望的研究领域之一。该应用程序的总体目的是建立 将我们新的19F-EUII复合物转化为有用的缺氧响应性所需的基础。 通过研究氟的位置对欧洲的配体的影响和表征的对比剂 缺氧的体外和体内指数。拟议的研究的基础是Euii- 包含标记为氟差异（T1或19F）的复合物影响MRI作为氧化的函数 我们最近在体外和体内都证明了Europium的状态。预期的结果 提案是建立具有定义缺氧指数的19F基于EUII的对比剂。这个结果是 预计通过促进NIH的使命对人类的使命产生积极影响 疾病。我们计划通过追求三个具体目标来实现提案的目标：（1）合成一个 一系列基于氧化还原欧盟的多模式对比剂从我们最初的成功中理性设计 代理人; （2）表征多模式的宽松和体外缺氧指数的温度依赖性 MRI的氧化还原活性19f-eu探针； （3）在健康小鼠中定义体内缺氧指数，低氧 小鼠和骨肉瘤的小鼠模型。新的基于19f-EUII的探针将很重要，因为它们是 预计可以成像因疗法而导致的缺氧变化，因此 评估治疗功效并影响癌症患者的护理和管理。此外， 由于缺氧与广泛疾病有关，因此该建议有望最大化回报 NIH的许多其他投资。