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.

非常需要研究癌症中氧化还原和氧稳态的破坏，因为 肿瘤中的低氧核心与化疗和放疗抗性，转移， 和癌症的总体寿命。该研究项目的长期目标是开发氧化还原响应探针 针对癌症缺氧研究中未满足的需求。本研究项目的总体目标是（1） 合成和表征两个含EuII的探针，并将其与顺磁位移剂连接，以及（2）研究 这些探针用于氧化还原响应多模式成像的潜力 测量和顺磁位移增强。支持拟议研究的基本原理是， T1加权信号仅在EuII处于还原环境中时存在， 将仅在EuII在氧化环境中氧化成EuIII时存在，从而使试剂氧化还原- 对两种成像模式都有反应。这一建议的预期成果是成功地进行综合， 表征在Eu配位环境中不同的两种成像剂。预计这一结果将 具有积极的影响，因为迫切需要新的氧化还原响应探针。的目标 建议预期通过追求两个具体目标来实现：（1）合成和表征EuII- 含有与含DyIII顺磁位移剂连接的穴状化合物，和（2）合成和表征 连接到含Dy III顺磁位移剂的含Eu II四酰胺甘氨酸络合物。所得 新的复合物将是重要的，因为它们有望使监测氧化还原的变化， 治疗产生的环境，因此有助于治疗的开发和选择， 增加对氧化还原稳态与人类健康之间关系的基本认识。 此外，由于氧化还原稳态与诊断、机制理解和 癌症的治疗结果，这一建议预计将最大限度地提高回报，在许多其他投资的 NIH和NCI的使命特别相关。 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， 最好的准备，她在学术界的独立职业生涯，这是一个重要的目标，奖学金培训 计划韦恩州立大学化学系的艾伦研究小组是最完美的 这项研究的环境，因为它是协作，创新，并与所有设备科尔宾成立 需要完成她的研究包括最先进的仪器除了拟议的 研究项目，培训计划还包括专业发展机会、 负责任地进行研究，并参加国际科学会议。