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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
5R00CA134749-04
Application #
8088064
Study Section
Subcommittee G - Education (NCI)
Program Officer
Tandon, Pushpa
Project Start
2008-09-17
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$241,530
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Coffey, Aaron M; Shchepin, Roman V; Feng, Bibo et al. (2017) A pulse programmable parahydrogen polarizer using a tunable electromagnet and dual channel NMR spectrometer. J Magn Reson 284:115-124
Kovtunov, Kirill V; Truong, Milton L; Barskiy, Danila A et al. (2014) Long-lived spin States for low-field hyperpolarized gas MRI. Chemistry 20:14629-32
Nikolaou, Panayiotis; Coffey, Aaron M; Walkup, Laura L et al. (2014) XeNA: an automated 'open-source' (129)Xe hyperpolarizer for clinical use. Magn Reson Imaging 32:541-50
Shchepin, Roman V; Chekmenev, Eduard Y (2014) Toward hyperpolarized molecular imaging of HIV: synthesis and longitudinal relaxation properties of (15) N-Azidothymidine. J Labelled Comp Radiopharm 57:621-4
Shchepin, Roman V; Pham, Wellington; Chekmenev, Eduard Y (2014) Dephosphorylation and biodistribution of 1-¹³C-phospholactate in vivo. J Labelled Comp Radiopharm 57:517-24
Barskiy, Danila A; Kovtunov, Kirill V; Koptyug, Igor V et al. (2014) The feasibility of formation and kinetics of NMR signal amplification by reversible exchange (SABRE) at high magnetic field (9.4 T). J Am Chem Soc 136:3322-5
Nikolaou, Panayiotis; Coffey, Aaron M; Barlow, Michael J et al. (2014) Temperature-ramped (129)Xe spin-exchange optical pumping. Anal Chem 86:8206-12
Nikolaou, Panayiotis; Coffey, Aaron M; Ranta, Kaili et al. (2014) Multidimensional mapping of spin-exchange optical pumping in clinical-scale batch-mode 129Xe hyperpolarizers. J Phys Chem B 118:4809-16
Truong, Milton L; Coffey, Aaron M; Shchepin, Roman V et al. (2014) Sub-second proton imaging of 13C hyperpolarized contrast agents in water. Contrast Media Mol Imaging 9:333-41
Coffey, Aaron M; Kovtunov, Kirill V; Barskiy, Danila A et al. (2014) High-resolution low-field molecular magnetic resonance imaging of hyperpolarized liquids. Anal Chem 86:9042-9

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