Novel hyperpolarized C-13 and N-15 biomarkers for metabolic MR imaging of cancer

用于癌症代谢 MR 成像的新型超极化 C-13 和 N-15 生物标志物

• 批准号: 7914685
• 负责人: Eduard Chekmenev
• 金额: $ 24.84万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-17 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914685
• 关键词: 2,4-Dinitrophenol; Address; Biological Markers; Biology; Cell Nucleus; Cells; Contrast Media; Detection; Devices; Early Diagnosis; Equilibrium; Equipment; Estrogens; Event; Gases; Hour; Housing; Human; Image; Injection of therapeutic agent; Label; Liquid substance; Magnetic Resonance; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant Neoplasms; Medicine; Metabolic; Metabolic Marker; Metabolism; Methods; Mole the mammal; Monitor; Neoplasms; Normal tissue morphology; Nuclear; Patients; Pharmaceutical Preparations; Physiologic pulse; Physiological; Production; Protons; Reagent; Relaxation; Research; Rodent Model; Scanning; Site; Solutions; Tamoxifen; Temperature; Time; Tissues; Veins; Work; catalyst; design; diagnostic accuracy; in vivo; molecular imaging; next generation; novel; research study; response; singlet state; tumor; uptake

DESCRIPTION (Provided by applicant): The long term goal of this proposal would answer not only the questions about cancer metabolic disorder at molecular, cellular and tissue level and its correlation with genetic disorder and pathology, but would also provide the predictors (often termed biomarkers) about the patient outcome and response to therapy as early as several minutes after drug administration with unprecedented spatial resolution of 1 mm3. The proposed work will be done in cellular and rodent models of cancer utilizing high resolution NMR and MRI equipment. To achieved unprecedented spatial resolution, high contrast and signal to noise I propose to use magnetic resonanse hyperpolarization utilizing PASADENA (parahydrogen and synthesis allow dramatically enhanced nuclear alignment) technique and a novel idea of spin order transfer from commercially availabe hyperpolarized 129Xe gas to 13C and 15N bionuclei using spin storage of silver coated nanoporous aerogels. These methods would enable a new generation of ultrasensitive, ultra-fast in vivo MR imaging techniques that will be optimized for use in oncology. An advantage of these hyperpolarization techniques is the increase in NMR and MRI sensitivity by >50,000 fold, which overcomes previous sensitivity limitations of MRI. The persistence of polarization through chemical reactions would allow sub-second MR spectroscopy examinations with similar sensitivity enhancement. I propose to address the central issues, necessary for successful introduction of Clinical Trials of non-invasive and non-radioactive hyperpolarized molecular imaging: (1) develop novel nitrogen and carbon spin labels of choline, glutamate, glutamine, glucose and succinate as in vivo contrast imaging reagents using PASADENA and spin order of 129Xe, (2) demonstrate efficacy of 13C and 15N hyperpolarized agents for early detection of cancer and response to drug treatment using sub-second 13C and 15N imaging, spectroscopy and chemical shift imaging (CSI) in in vivo and in virto models of human cancer at 4.7T, and (3) demonstrate the superiority of several PASADENA contrast agents in defining tumor growth, heterogeneity and prediction of a positive response to therapy, when compared to conventional MRI, 1H MRS and 1-13C glucose MRS in vivo. Sub-second imaging techniques developed in this proposal will have far-reaching impact on all areas of oncology in which current imaging technologies are insufficiently precise or insensitive to early diagnosis.

描述（由申请人提供）：该提案的长期目标不仅是在分子、细胞和组织水平上回答有关癌症代谢紊乱及其与遗传性疾病和病理学的相关性的问题，而且还将提供预测因子（通常称为生物标志物） ）在给药后几分钟即可以前所未有的 1 mm3 空间分辨率了解患者的治疗结果和治疗反应。拟议的工作将利用高分辨率 NMR 和 MRI 设备在癌症的细胞和啮齿动物模型中完成。为了实现前所未有的空间分辨率、高对比度和信噪比，我建议使用磁共振超极化，利用 PASADENA（仲氢和合成可显着增强核排列）技术以及从商用超极化 129Xe 气体到 13C 和 15N 自旋顺序转移的新想法使用银涂覆的纳米多孔气凝胶的旋转存储的生物核。这些方法将使新一代超灵敏、超快速体内 MR 成像技术成为可能，并针对肿瘤学应用进行优化。这些超极化技术的优点是 NMR 和 MRI 灵敏度提高了 50,000 倍以上，克服了 MRI 以前的灵敏度限制。通过化学反应产生的偏振持久性将允许亚秒级磁共振波谱检查具有类似的灵敏度增强。我建议解决成功引入非侵入性和非放射性超极化分子成像临床试验所必需的核心问题：（1）开发体内胆碱、谷氨酸、谷氨酰胺、葡萄糖和琥珀酸的新型氮和碳自旋标记使用 PASADENA 和 129Xe 自旋顺序的对比成像试剂，(2) 证明了 13C 和 15N 超极化试剂对于早期检测癌症和对药物治疗的反应的功效在 4.7T 人类癌症体内和体外模型中进行亚秒 13C 和 15N 成像、光谱学和化学位移成像 (CSI)，以及 (3) 证明了几种 PASADENA 造影剂在定义肿瘤生长、异质性和预测方面的优越性与体内常规 MRI、1H MRS 和 1-13C 葡萄糖 MRS 相比，对治疗有积极反应。该提案中开发的亚秒级成像技术将对当前成像技术不够精确或对早期诊断不敏感的所有肿瘤学领域产生深远影响。