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) 非常需要对水平有反应的阳性造影剂 异质环境中的缺氧，例如在许多肿瘤中发现的情况，目的是预测 治疗结果，开发新疗法，并能够测试与我们相关的假设 缺氧与人类健康之间的集体基本认识。我们的长期目标是发展 MRI 阳性造影剂通过关注含 EuII 的复合物来填补诊断医学领域的空白 这些都是最有前途的研究领域之一。该应用程序的总体目标是建立 将我们的新型 19F-EuII 复合物转化为有用的缺氧响应所需的基础工作 通过研究氟位置对铕配体的影响并表征来制备造影剂 体外和体内缺氧指数。支持拟议研究的基本原理是 EuII- 含有氟标记复合物（T1 或 19F）的氧化作用会影响 MRI 我们最近在体外和体内证明了铕的状态。本次活动的预期结果 提案是建立具有明确缺氧指数的基于 19F-EuII 的造影剂。这个结果是 预计将通过为 NIH 理解人类的使命做出贡献而产生积极影响 疾病。我们计划通过实现三个具体目标来实现该提案的目标：（1）综合 我们在最初成功的基础上合理设计了一系列氧化还原活性铕基多峰造影剂 代理人; (2) 表征多模式弛豫度和体外缺氧指数的温度依赖性 用于 MRI 的氧化还原活性 19F-Eu 探针； (3) 定义健康小鼠的体内缺氧指数，缺氧 小鼠和骨肉瘤小鼠模型。新的基于 19F-EuII 的探针将具有重要意义，因为它们 预计能够对治疗引起的缺氧变化进行成像，从而有助于 评估治疗效果并影响癌症患者的护理和管理。此外， 由于缺氧与多种疾病有关，因此该提议预计将在以下方面实现最大化回报： NIH 的许多其他投资。