High resolution images of molecular oxygenation have been shown to provide crucial guides to the delivery and monitoring of cancer therapy in model systems. Stroke and myocardial infarction therapies may similarly benefit. EPR imaging (EPRl) of oxygen (EPROI) provides a unique combination of spatial resolution, oxygen resolution, time resolution and uniform sensitivity with depth in tissue. This Center focuses on the optimization of In Vivo EPR Oxygen Imaging anticipating human images. It is a consortium between the Universities of Chicago, Denver, Maryland, and the Novosibirsk Institute of Organic Chemistry, Russia. EPROI requires coordinated development of multidisciplinary technologies: instrumentation for spectroscopic imaging, spin probes to sample and report the tissue fluid environment and imaging strategies to optimally sample and analyze the image information obtained- The Center is built on this multidisciplinary effort from medical physicists, engineers, biologists, radiation oncologists, physical and organic chemists, statisticians and imaging mathematicians. In the past 5 years the Center: 1) implemented T1/R1 sensitive pulse sequences that free trityl based EPR oxygen images from confounding variations;2) developed and made routine highly sensitive Electron Spin Echo pulse imaging as a Tl and T2 readout;3) enhanced signal to noise ratio per unit time (SNR/t) of pulse imaging with novel technical methods;4) developed methods for large object imaging;5) applied novel nitroxide sensitive rapid scan imaging to animal systems;6) made significant progress toward the development of unusually narrow line trityls;7) synthesized novel very narrow line deuterated nitroxides for pH and thiol imaging. These achievements prepare the Center for the promise of its final funding cycle, work toward human application. Toward that end we propose the following Technology Research and Development Projects: 1) Higher SNR/t for enhanced spatial and p02 resolution EPROI;2) Rapid EPROI acquisition - time resolved three dimensional oxygen image movies;3) Enhanced registration of EPROI with multimodality imaging for better definition of tissue and tumor microenvironment;4) Commercial small animal pulse oxygen and rapid scan imaging systems to accelerate pharmaceutical development and the development of a human imager prototype. The last aim fulfills the Center mission of commercial migration of the EPRl technology. We will work with Bruker BioSpin on a commercial small animal imaging system.

Public Health Relevance

This proposal will improve the sensitivity and accuracy of electron paramagnetic resonance imaging (EPRl) of oxygen (EPROI) in the tissues and tumors of living animals. Molecular oxygen availability determines resistance to radiation therapy and is a determinant of stroke, heart attack and peripheral vascular disease. We will work with Bruker BioSpin to develop an animal EPROI to accelerate development of anti-angiogenic drugs and to investigate radiation therapy dose painting in preclinical animal models.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Biotechnology Resource Grants (P41)
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Special Emphasis Panel (ZEB1-OSR-E (M2))
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Sastre, Antonio
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University of Chicago
Schools of Medicine
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Redler, Gage; Epel, Boris; Halpern, Howard J (2014) EPR image based oxygen movies for transient hypoxia. Adv Exp Med Biol 812:127-33
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
Tormyshev, Victor M; Rogozhnikova, Olga Yu; Bowman, Michael K et al. (2014) Preparation of Diversely Substituted Triarylmethyl Radicals by the Quenching of Tris(2,3,5,6-tetrathiaaryl)methyl Cations with C-, N-, P-, and S-Nucleophiles. European J Org Chem 2014:371-380
Redler, Gage; Epel, Boris; Halpern, Howard J (2014) Principal component analysis enhances SNR for dynamic electron paramagnetic resonance oxygen imaging of cycling hypoxia in vivo. Magn Reson Med 71:440-50
Epel, Boris; Redler, Gage; Halpern, Howard J (2014) How in vivo EPR measures and images oxygen. Adv Exp Med Biol 812:113-9
Epel, Boris; Bowman, Michael K; Mailer, Colin et al. (2014) Absolute oxygen R1e imaging in vivo with pulse electron paramagnetic resonance. Magn Reson Med 72:362-8
Elajaili, Hanan B; Biller, Joshua R; Eaton, Sandra S et al. (2014) Frequency dependence of electron spin-lattice relaxation for semiquinones in alcohol solutions. J Magn Reson 247:81-7
Redler, Gage; Epel, Boris; Halpern, Howard J (2014) What we learn from in vivo EPR oxygen images. Adv Exp Med Biol 812:121-6
Redler, Gage; Barth, Eugene D; Bauer Jr, Kenneth S et al. (2014) In vivo electron paramagnetic resonance imaging of differential tumor targeting using cis-3,4-di(acetoxymethoxycarbonyl)-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl. Magn Reson Med 71:1650-6
Sundramoorthy, Subramanian V; Epel, Boris; Halpern, Howard J (2014) Orthogonal resonators for pulse in vivo electron paramagnetic imaging at 250 MHz. J Magn Reson 240:45-51

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