The PASADENA (parahydrogen and synthesis allow dramatically enhanced nuclear alignment) is a new generation of ultra-sensitive, ultra-fast in vivo MR imaging techniques that we will now optimize for use in oncology. An advantage of this technique is the increase in signal to noise (over 10,000 fold), which overcomes previous sensitivity limitations of MRI and the persistence of polarization through chemical reactions, allowing sub-second MR spectroscopy examinations with similar sensitivity enhancement. In a close collaboration between our Laboratory at HMRI and Professor Weitekamp's Group at California Institute of Technology, we propose to address five central issues, in two phases, necessary for successful introduction of Clinical Trials of PASADENA molecular brain imaging:
R21 Specific Aims : (1) Develop novel carbon (and nitrogen) spin labels as in vivo PASADENA imaging reagents. (2) Capture maximum MR signal by optimizing spin-physics and polarizer design. (3) Create sub-second in vivo 13C and 15N animal and human imaging, spectroscopy and chemical mapping sequences at 4.7 Tesla (Bruker-Paravision) and 1.5T GE LX clinical MR scanners. (4) Demonstrate efficacy of PASADENA in normal in vivo brain and in an animal model of brain tumor. Then R33 Specific Aim: (5) Demonstrate the superiority of several PASADENA contrast agents in defining tumor growth, heterogeneity, angiogenesis and prediction of a positive response to therapy, when compared to conventional MRI, 1H MRS and 1-13C glucose MRS in vivo. Adaptation of experimental procedures, including collaborations with other Academic Institutions, with Industry, Good Manufacturing Practices, toxicity testing and submission of FDA- IND applications for clinical trials will be conducted during R33 to accelerating clinical acceptance of this novel technique. Milestones are provided for achieving each of these goals. 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. Parahydrogen induced polarization, which involve no harmful radiation and can be performed at lower magnetic fields, will reduce the need for ever more powerful and costly ultra- high field MRI scanner currently being constructed, thereby bringing MR imaging to third world and other societies that are currently excluded from modern health care on grounds of cost. ? ? ?
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