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

描述(由申请人提供)：这项提案的长期目标不仅将回答分子、细胞和组织水平上的癌症代谢紊乱及其与遗传紊乱和病理的相关性的问题，而且还将最早在给药后几分钟以前所未有的1mm3的空间分辨率提供关于患者结局和治疗反应的预测指标(通常称为生物标志物)。这项拟议的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完成。为了获得前所未有的空间分辨率、高对比度和信噪比，我提议利用Pasadena(仲氢和合成允许显著增强的核排列)技术来使用磁共振超极化，并提出了一个新的想法，即使用银涂层纳米孔气凝胶的自旋存储，从商业上可获得的超极化的129Xe气体到13C和15N生物核的自旋顺序转移。这些方法将使新一代超灵敏、超快的活体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核磁共振和核磁共振的灵敏度提高了50,000倍，这克服了以前核磁共振的灵敏度限制。化学反应中的持续偏振将允许进行亚秒级的磁共振波谱检查，并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中心问题：(1)利用帕萨迪纳和129Xe的自旋顺序，开发胆碱、谷氨酸、谷氨酰胺、葡萄糖和琥珀酸的新型氮和碳自旋标记作为活体对比显像剂，(2)利用4.7T人体癌症的亚秒级13C和15N成像、光谱和化学位移成像(CSI)，展示13C和15N超极化试剂在癌症早期检测和药物治疗反应方面的有效性。以及(3)与体内常规MRI、1H MRS和1-13C葡萄糖MRS相比，展示了几种帕萨迪纳造影剂在确定肿瘤生长、异质性和预测治疗阳性反应方面的优越性。这项提案中开发的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.