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

描述（由申请人提供）：本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疾病和病理的相关性的问题，而且还将提供有关患者结果和治疗反应的预测因子（通常称为生物标志物），早在给药后几分钟，具有前所未有的1毫米3的空间分辨率。这项工作将利用高分辨率核磁共振和核磁共振设备在细胞和啮齿动物癌症模型中进行。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PASADENA（对氢和合成允许显著增强核排列）技术的磁共振超极化和自旋顺序转移的新想法，从商业上可用的超极化129Xe气体到13C和15N生物核，使用自旋存储的银涂层纳米多孔气凝胶。这些方法将使新一代超灵敏、超快速的体内磁共振成像技术成为可能，这些技术将被优化用于肿瘤学。这些超极化技术的一个优点是将核磁共振和核磁共振的灵敏度提高了50万倍，克服了以往核磁共振的灵敏度限制。通过化学反应的持续极化将使亚秒级磁共振光谱检查具有类似的灵敏度增强。我建议解决非侵入性和非放射性超极化分子成像临床试验成功引入所必需的核心问题：(1)利用PASADENA和129Xe的自旋顺序，开发了新的胆碱、谷氨酸、谷氨酰胺、葡萄糖和琥珀酸盐的氮和碳自旋标记作为体内对比成像试剂；(2)利用亚秒13C和15N成像、光谱和化学位移成像（CSI），在4.7T的人类癌症体内和体外模型中验证了13C和15N超极化剂对癌症早期检测和药物治疗的疗效。(3)与体内常规MRI、1H MRS和1-13C葡萄糖MRS相比，几种PASADENA对比剂在确定肿瘤生长、异质性和预测治疗阳性反应方面具有优势。亚秒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的影响。

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.