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

描述（由申请人提供）：该提案的长期目标不仅将回答关于分子、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学的相关性的问题，而且还将提供关于早在药物施用后几分钟的患者结果和对治疗的反应的预测因子（通常称为生物标志物），具有前所未有的1 mm 3的空间分辨率。拟议的工作将利用高分辨率NMR和MRI设备在细胞和啮齿动物癌症模型中进行。为了获得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（仲氢和合成允许显着增强的核排列）技术和一个新的想法，自旋顺序转移从市售的超极化129氚气体到13 C和15 N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MR成像技术成为可能，这些技术将被优化用于肿瘤学。这些超极化技术的优点是NMR和MRI灵敏度增加> 50，000倍，这克服了MRI先前的灵敏度限制。通过化学反应的极化的持续性将允许具有类似灵敏度增强的亚秒级MR光谱检查。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需的核心问题：（1）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物作为使用PASADENA和129 π的自旋阶的体内造影成像试剂，（2）使用亚秒级13 C和15 N成像、光谱学和化学位移成像（CSI），在4.7T下在人体癌症的体内和体外模型中证明13 C和15 N超极化剂用于早期检测癌症和对药物治疗的响应的功效，和（3）证明了几种PASADENA造影剂在定义肿瘤生长、异质性和预测对治疗的阳性反应方面优于常规MRI、1H MRS和1- 13 C葡萄糖MRS。本提案中开发的亚秒级成像技术将对肿瘤学的所有领域产生深远影响，在这些领域中，当前的成像技术对早期诊断不够精确或不敏感。

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.