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

非常需要用于磁共振成像(MRI)的阳性造影剂 在异质环境中的缺氧，就像在许多肿瘤中发现的那样，用于预测 治疗结果，开发新的治疗方法，并能够测试与我们的 集体对低氧与人类健康的基本认识。我们的长远目标是发展 MRI阳性造影剂通过专注于含EuII的复合体来填补诊断医学中的这一空白 这些都是最有前途的研究领域之一。这个应用程序的总体目标是建立 将我们新的基于19F-EuII的络合物转化为有用的低氧响应所需的基础工作 氟位置对Eu配体影响的造影剂及其表征 体外和体内缺氧指数。支持这项拟议研究的基本原理是，欧- 含氟标记的络合物(T1或19F)作为氧化的函数影响MRI 正如我们最近在体外和体内证明的那样，Eu的状态。这样做的预期结果是 建议建立基于19F-EuII的造影剂，并定义低氧指数。这一结果是 预计将产生积极影响，为美国国立卫生研究院了解人类的使命做出贡献 疾病。我们计划通过追求三个具体目标来实现该建议的目标：(1)综合 从我们最初的成功开始，合理设计了一系列氧化还原活性的基于Eu的多模式造影剂 (2)多峰弛豫度和体外低氧指数随温度变化的特征 氧化还原活性的19F-Eu探针用于MRI；以及(3)为了确定健康小鼠的体内缺氧指数，低氧 小鼠，骨肉瘤小鼠模型。基于19F-EuII的新探测器将具有重要意义，因为它们 有望使治疗引起的缺氧变化能够被成像，从而帮助 评估治疗效果，影响癌症患者的护理和管理。此外， 由于缺氧与一系列疾病有关，这一提议预计将在 美国国立卫生研究院的许多其他投资。

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.