The overall goal of this project is to advance the proton-electron double-resonance technique, PEDRI, to a level allowing for functional mapping of physiologically-critical parameters, such as pH, oxygen, redox and intracellular glutathione (GSH), in animals and, potentially, in humans. To reach this goal we will use a new concept of Variable Radio Frequency (VRF) PEDRI in combination with an array of specific paramagnetic probes. This will allow for functional mapping within MRI high quality spatial resolution and short acquisition time. This new proposal is a logical extension of our recent R21 which was successful in validating the concept of functional PEDRI. The success of this proposal will open possibilities for bringing this new PEDRI technique into the leading research and clinical MRI centers. This proposal has promising potential taking into account that VRF PEDRI system allows for the simplified design by elimination of the field cycling coil assembly and its power supplies which will result in a complete utilization of the gap in the magnet system of conventional MRIs.
The specific aims are: (SA1) To enable Variable Radio Frequency PEDRI for in vivo functional imaging. We will focus on the further development and optimization of VRF PEDRI, which is an instrumentally-innovative modification of PEDRI and has been found to be highly efficient for functional applications during the exploratory R21 phase. (SA2) To design PEDRI-oriented pH, oxygen, redox and GSH sensitive paramagnetic probes. The probes with functionally-dependent ratiometric spectral parameters, including dual function probes, with extended aqueous solubility and stability will be synthesized. Synthesis and optimization of the probes is absolutely essential for the overall efficiency of functional PEDRI applications. (SA3) To map in real-time the parameters of a tumor microenvironment using VRF PEDRI. The capacity of the VRF PEDRI for in vivo pH and oxygen mapping will be demonstrated for the most effective probes in PyMT transgenic mice that spontaneously-develop breast cancer. We plan to perform VRF PEDRI imaging and construct real-time, spatially-resolved and stage-specific signature profiles of tumor pO2, pH, redox, and GSH as the mammary tumors progress to malignancy. In summary, the success of this project may have a significant impact on the future of in vivo functional imaging applications to medicine.

Public Health Relevance

This project will advance the proton-electron double-resonance imaging technique, PEDRI, to a level allowing for functional mapping of physiologically-critical parameters, such as pH, oxygen, redox and intracellular glutathione (GSH), in animals and, potentially, in humans. The functional imaging technique will be applied in PyMT transgenic mice that spontaneously-develop breast cancer. This will allow for construction of real-time, spatially-resolved and stage-specific signature profiles of tumor pO2, pH, redox, and GSH as the mammary tumors progress to malignancy. This novel technique may have a significant impact on future applications relating to biomedical imaging.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB014542-02
Application #
8458951
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Sastre, Antonio
Project Start
2012-04-15
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$323,567
Indirect Cost
$111,392
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Tseitlin, Mark; Biller, Joshua R; Elajaili, Hanan et al. (2014) New spectral-spatial imaging algorithm for full EPR spectra of multiline nitroxides and pH sensitive trityl radicals. J Magn Reson 245:150-5
Samouilov, Alexandre; Efimova, Olga V; Bobko, Andrey A et al. (2014) In vivo proton-electron double-resonance imaging of extracellular tumor pH using an advanced nitroxide probe. Anal Chem 86:1045-52
Khramtsov, Valery V; Gillies, Robert J (2014) Janus-faced tumor microenvironment and redox. Antioxid Redox Signal 21:723-9
Goodwin, Jonathan; Yachi, Katsuya; Nagane, Masaki et al. (2014) In vivo tumour extracellular pH monitoring using electron paramagnetic resonance: the effect of X-ray irradiation. NMR Biomed 27:453-8
Bobko, Andrey A; Dhimitruka, Ilirian; Zweier, Jay L et al. (2014) Fourier transform EPR spectroscopy of trityl radicals for multifunctional assessment of chemical microenvironment. Angew Chem Int Ed Engl 53:2735-8
Takahashi, Wataru; Bobko, Andrey A; Dhimitruka, Ilirian et al. (2014) Proton-Electron Double-Resonance Imaging of pH using phosphonated trityl probe. Appl Magn Reson 45:817-826
Koda, Shunichi; Goodwin, Jonathan; Khramtsov, Valery V et al. (2012) Electron paramagnetic resonance-based pH mapping using spectral-spatial imaging of sequentially scanned spectra. Anal Chem 84:3833-7