Imaging of localized oxygen concentration (oximetry) and pH are key to the timing and sculpting of radiation treatment of tumors, improvement of wound healing, and design of therapy for peripheral vascular disease and for drug design. Electron paramagnetic resonance (EPR) imaging using trityl or nitroxide radical probes is under development for pre-clinical and clinical oximetry. Pulsed methods have been used to improve signal-to-noise and reduce the time to acquire an image with trityl radicals. Nitroxide radicals have advantages over trityl radicals because they can be prepared with structures that facilitate crossing the blood-brain barrier or targeting of intracellular spaces. Nitroxides also can be designed to monitor local pH, which has dramatic impact on therapeutic interventions for tumors. With current EPR methodology it is difficult to apply pulse methods to nitroxides because these radicals have shorter electron spin relaxation times than trityls.
In Aim 1 a new method is proposed to improve the signal-to-noise in pulsed imaging of nitroxides which will enhance measurement of pO2. It is based on a bimodal resonator design where excitation and detection resonators are decoupled by tuning to different frequencies. Rapid sinusoidal scans will be used to permit excitation of the spins at the frequency of resonator 1 and detection of a two-pulse echo at the frequency of resonator 2. The method will be tested on phantoms at the University of Denver.
In Aim 2 the proposed method will be implemented for in vivo oximetry in mouse tumors at the University of Chicago EPR Center, working collaboratively with co- mentor Prof. Halpern. The proposed new method will be quantitatively compared with the currently used methods. The time spent by the PI in Chicago will also be used to acquire practical skills in animal handling and designing in vivo experiments.
In Aim 3 the PI will design and implement rapid scan EPR imaging experiments to measure pH using nitroxide radicals for which spectra are pH-dependent which can be targeted for either extracellular or intracellular domains. Complementary MRI scans will be used for co-registration of anatomical features, as well as for PI training purposes. This work will not be dependent on the outcome of Aims 1 and 2, so it can be done in parallel. Throughout the grant period the PI will take courses in biology, chemistry, and fundamentals of medicine to complement his strong background in mathematics and physics and bring him to a level where he can design and interpret tumor physiology imaging experiments, and evaluate drug and radiation therapies as an independent PI. The work on Aims 1, 2, and 3 will be performed increasingly independently during the three year award period. The work will provide the preliminary results needed to write an R01 proposal related to imaging in brain.

Public Health Relevance

Mark Tseytlin has a strong background in mathematics and physics and has developed electron paramagnetic resonance methods that have been used in collaborative studies of local oxygen concentration in tumors. The goal of the K25 proposal is to enhance his background in biology, chemistry, and ultimately tumor physiology, and develop methods for pO2 and pH imaging so that he can select important problems and become a leader in imaging tumors and designing therapeutic interventions.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Mentored Quantitative Research Career Development Award (K25)
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Special Emphasis Panel (ZEB1-OSR-B (M2))
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Erim, Zeynep
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West Virginia University
Schools of Medicine
United States
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Möser, J; Lips, K; Tseytlin, M et al. (2017) Using rapid-scan EPR to improve the detection limit of quantitative EPR by more than one order of magnitude. J Magn Reson 281:17-25
Tseytlin, Mark (2017) Concept of Phase Cycling in Pulsed Magnetic Resonance Using Sinusoidal Magnetic Field Modulation. Z Phys Chem (N F) 231:689-703
Biller, Joshua R; Mitchell, Deborah G; Tseytlin, Mark et al. (2016) Rapid Scan Electron Paramagnetic Resonance Opens New Avenues for Imaging Physiologically Important Parameters In Vivo. J Vis Exp :
Tseytlin, Mark; Epel, Boris; Sundramoorthy, Subramanian et al. (2016) Decoupling of excitation and receive coils in pulsed magnetic resonance using sinusoidal magnetic field modulation. J Magn Reson 272:91-99
Elajaili, Hanan; Biller, Joshua R; Rosen, Gerald M et al. (2015) Imaging disulfide dinitroxides at 250 MHz to monitor thiol redox status. J Magn Reson 260:77-82
Elajaili, Hanan B; Biller, Joshua R; Tseitlin, Mark et al. (2015) Electron spin relaxation times and rapid scan EPR imaging of pH-sensitive amino-substituted trityl radicals. Magn Reson Chem 53:280-4
Biller, Joshua R; Tseitlin, Mark; Mitchell, Deborah G et al. (2015) Improved sensitivity for imaging spin trapped hydroxyl radical at 250 MHz. Chemphyschem 16:528-31
Yu, Zhelin; Tseytlin, Mark; Eaton, Sandra S et al. (2015) Multiharmonic electron paramagnetic resonance for extended samples with both narrow and broad lines. J Magn Reson 254:86-92
Biller, Joshua R; Tseitlin, Mark; Quine, Richard W et al. (2014) Imaging of nitroxides at 250MHz using rapid-scan electron paramagnetic resonance. J Magn Reson 242:162-8
Yu, Zhelin; Quine, Richard W; Rinard, George A et al. (2014) Rapid-scan EPR of immobilized nitroxides. J Magn Reson 247:67-71

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