Synthesis and characterization of linked Eu(II)-containing complexes and paramagnetic shift reagents for hypoxia imaging

用于缺氧成像的含铕 (II) 连接络合物和顺磁位移试剂的合成和表征

• 批准号: 10241300
• 负责人: Brooke Anne Corbin
• 金额: $ 2.09万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-01-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241300
• 关键词: Academia; Biological; Breast Carcinoma; Chemicals; Chemistry; Chemoresistance; Chemotherapy and/or radiation; Clinical; Clinical Research; Complex; Contrast Media; Development; Diagnosis; Diagnostic; Early Diagnosis; Electron Spin Resonance Spectroscopy; Environment; Equipment; Europium; Fellowship; Goals; Health; Homeostasis; Human; Hypoxia; Image; International; Investments; Knowledge; Ligands; Link; Longevity; Magnetic Resonance Imaging; Malignant Neoplasms; Mass Spectrum Analysis; Measurement; Medicine; Metals; Methods; Mission; Monitor; Multimodal Imaging; NMR Spectroscopy; Neoplasm Metastasis; Organic Synthesis; Outcome; Oxidation-Reduction; Oxides; Oxygen; Protons; Public Health; Radiation therapy; Reagent; Reporting; Research; Research Project Grants; Resistance; Signal Transduction; Survival Rate; Synthesis Chemistry; System; Techniques; Training; United States National Institutes of Health; Universities; Water; base; career; contrast enhanced; design; imaging agent; imaging modality; improved; in vivo; innovation; instrumentation; meetings; multimodality; non-invasive imaging; oxidation; preclinical study; radiation resistance; response; responsible research conduct; skills; therapy development; therapy outcome; tumor; tumor progression

There is a great need to study disruptions to redox and oxygen homeostasis in cancer because the presence of hypoxic cores in tumors have been correlated to chemotherapy and radiation therapy resistance, metastases, and overall cancer longevity. The long-term goal of the research project is to develop redox-responsive probes that target unmet needs in the study of hypoxia in cancer. The overall objectives of this research project are (1) to synthesize and characterize two EuII-containing probes tethered to a paramagnetic shift agent and (2) to study the potential of these probes for use in redox-responsive multi-modal imaging using both relaxivity measurements and paramagnetic-shift enhancement. The rationale that underpins the proposed research is that the T1-weighted signal will only be present when EuII is in reducing environments, and the paramagnetic signal will only be present once EuII is oxidized to EuIII in oxidizing environments, thus rendering the agent redox- responsive for both imaging modalities. The expected outcome of this proposal is the successful synthesis and characterization of two imaging agents that differ in Eu coordination environments. This outcome is expected to have a positive impact because there is a critical need for new redox-responsive probes. The objectives of the proposal are expected to be achieved by pursuing two specific aims: (1) to synthesize and characterize a EuII- containing cryptate linked to a DyIII-containing paramagnetic-shift agent and (2) to synthesize and characterize a EuII-containing tetraamide glycinate complex linked to a DyIII-containing paramagnetic-shift agent. The resulting new complexes will be significant because they are expected to enable monitoring of changes in redox environments resulting from therapies, consequently aiding in treatment development and selection as well as increasing the basic understanding of the relationship between redox homeostasis and human health. Furthermore, because redox homeostasis is relevant to the diagnosis, mechanistic understanding, and therapeutic outcome of cancer, this proposal is expected to maximize returns in many other investments of the NIH and is specifically pertinent to the NCI’s mission. The proposed research project was designed to aid Corbin in developing her skillset in synthetic chemistry to best prepare her for an independent career in academia, which is a significant goal of the fellowship training plan. The Allen Research Group in the Chemistry Department at Wayne State University is the perfect environment for this research because it is collaborative, innovative, and set up with all the equipment Corbin will need to complete her research, including state-of-the-art instrumentation. In addition to the proposed research project, the training plan also includes professional development opportunities, training in the responsible conduct of research, and attending international scientific meetings.

由于存在 肿瘤中的低氧核心与化学疗法和放射治疗的耐药性，转移， 和整体癌症寿命。研究项目的长期目标是制定氧化还原响应性问题 该目标在研究癌症缺氧的研究中未满足的需求。该研究项目的总体目标是（1） 综合并表征两个含EUII的问题，这些问题系在一起到顺磁性转移剂和（2） 这些问题在氧化还原响应的多模式成像中使用的潜力都使用了两种松弛性 测量和顺磁性换档增强。拟议研究的基础的理由是 T1加权信号只有在EUII处于还原环境中，而Parmagnetic Signal才会存在 只有在氧化环境中将EUII氧化为EUIII，才会出现，从而使试剂氧化还原 对两种成像方式的反应。该提案的预期结果是成功的综合和 在欧盟协调环境中不同的两个成像剂的表征。这种结果有望 有积极的影响，因为对新的氧化还原响应问题有迫切需要。目标的目标 预计将通过追求两个具体目标来实现建议：（1）合成和表征EUII- 含有与含Dyiii的含氧磁磁性转移剂链接的隐质，（2）合成和表征 含EUII的四酰胺乙二醇化合物复合物与含DyiII的顺磁性移位剂相关。结果 新的复合物将很重要，因为它们有望能够监视氧化还原的变化 疗法产生的环境，因此有助于治疗开发和选择以及 增加对氧化还原稳态与人类健康之间关系的基本了解。 此外，因为氧化还原稳态与诊断，机械理解和 癌症的治疗结果，预计该建议将在许多其他投资中最大化回报 NIH，特别与NCI的使命有关。 拟议的研究项目旨在帮助Corbin发展合成化学方面的技能 最好的准备她为学术界的独立职业做好准备，这是奖学金培训的重要目标 计划。韦恩州立大学化学系的艾伦研究小组是完美的 这项研究的环境是因为它是协作，创新的，并且与所有设备Corbin建立 将需要完成她的研究，包括最先进的仪器。除了提议 研究项目，培训计划还包括专业发展机会，培训 负责任的研究进行，并参加国际科学会议。