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.

非常有必要研究癌症对氧化还原和氧稳态的干扰，因为 肿瘤中的低氧核心与化疗和放射治疗的抵抗、转移、 以及癌症的总体寿命。该研究项目的长期目标是开发氧化还原反应探针。 这一目标在癌症缺氧研究中尚未满足需求。本研究项目的总体目标是(1) 合成和表征两个连接在顺磁移动剂上的含EuII的探针和(2)研究 这些探针用于氧化还原响应性多模式成像的潜力 测量和顺磁漂移增强。支持这项拟议研究的基本原理是 只有当EuII处于还原环境中时，T1加权信号才会出现，顺磁信号 只有当EuII在氧化环境中被氧化为EuIII时才会存在，从而使试剂氧化还原- 对两种成像方式都有反应。这一提议的预期结果是成功地合成和 两种在欧盟配位环境中不同的显像剂的表征。这一结果预计将 产生积极影响，因为迫切需要新的氧化还原反应探头。该计划的目标 建议有望通过追求两个具体目标来实现：(1)合成和表征EuII- 含有连接到含有DyIII的顺磁移动剂的隐酸盐和(2)合成和表征 一种与含DyIII的顺磁移动剂相连的含EuII的甘氨酸四酰胺络合物。由此产生的 新的络合物将具有重要意义，因为它们有望实现对氧化还原变化的监控 治疗产生的环境，从而帮助治疗的开发和选择以及 增加对氧化还原动态平衡与人类健康关系的基本认识。 此外，由于氧化还原动态平衡与诊断、机制理解和 癌症的治疗结果，这项建议预计将最大化回报的许多其他投资 NIH，与NCI的任务特别相关。 拟议的研究项目旨在帮助科尔宾发展她在合成化学方面的技能，以 最好为她在学术界的独立职业生涯做好准备，这是奖学金培训的一个重要目标 计划。韦恩州立大学化学系的艾伦研究小组是完美的 此研究的环境是因为它具有协作性、创新性，并且配备了所有的Corbin设备 将需要完成她的研究，包括最先进的仪器。除了建议的 研究项目中，培训计划还包括专业发展机会、培训中 负责任地进行研究，参加国际科学会议。