West Virginia University Logo


Studies conducted in the IMMR center apply state-of-the-art magnetic resonance approaches to biomedicine with a focus on in vivo investigation of various animal models of diseases. These approaches rely on both commercially-available and newly-developed instruments for small animal studies. Commercially-available instruments include proton magnetic resonance imaging (MRI), low-field electron paramagnetic resonance (EPR) spectroscopy1, and a double-resonance technique termed proton-electron double-resonance imaging (PEDRI) or Overhauser-enhanced MRI (OMRI)2. Our newly-developed, proprietary instruments include a rapid-scan EPR imager (EPRI)3 and combined positron emission tomography (PET)-EPRI scanner4 (under construction).

Beyond anatomical resolution provided by MRI, these approaches report on multiple functional parameters of the microenvironment in living tissues when combined with specially designed paramagnetic probes5-6. Most of these probes are synthesized at the IMMR center and provide unparalleled opportunity for in vivo monitoring of tissue oxygenation, acidity (pH), interstitial inorganic phosphate (Pi), redox, and its major intracellular redox component, glutathione (GSH) – all parameters being significantly affected by various physiological and/or pathological states. The chemists in the IMMR center are constantly working on designing and synthesizing new molecular probes to enhance functional sensitivity, biocompatibility, and targeting.


The journal cover art created by Dr. T. D. Eubank illustrates the sensing of the cellular microenvironment with nitroxyl and trityl spin probes. Khramtsov VV., Bobko AA, Tseytlin M, Driesschaert, B. 2017, Analyt. Chem., 89, 4758-4771.


NIH-supported primary applications of Principal Investigators at the IMMR center are dedicated to multifunctional profiling of tumor tissue microenvironment (TME) during cancer progression and therapeutic intervention1, 6-7. Tissue hypoxia, acidosis, and highly-reducing redox status are well-established hallmarks of cancer while interstitial inorganic phosphate (Pi) has been recently recognized as a new potential marker of tumor progression and aggressiveness7. Based on thorough examination of recent literature and experimental data accumulated in our laboratories, we published a new hypothesis of a Janus-faced tumor microenvironment (TME) and its role in tumorigenesis8.

Janus-faced tumor microenvironment. The key components of the chemical TME, oxygen, pH, redox and GSH, are shown in red. Hypoxia-induced acidosis potentiates accumulation of free metal ions such as Fe3+ and Cu2+. In its turn, a high reducing capacity of TME promotes metal ion reduction to Fenton-active state, e.g. via γglutamyltransferase (GGT)/GSH-dependent generation of reducing cysteinyl-glycine dipeptide, GlyCysS¯. A cycling local hypoxia in TME facilitates further electron transfer to oxygen with formation of O2•- radical, triggering radical reaction cascade of O2•- dismutation to H2O2 followed by OH-radical formation via Fenton reaction. Low-reactive ROS, H2O2 and O2•-, penetrate into tumor cells by diffusion or via anion channels, latter contributing to increase of intracellular pH (pHi) with corresponding decrease in oxidizing potential of ROS. In a contrary, low acidic pHe in TME enhances ROS oxidizing potential towards surrounding cells that may result in oxidative damage and mutagenesis as well as adaptive response (e.g., increase of GSH) and changing cellular phenotype. Increase in H2O2, O2•-, GSH and pH has been shown contribute into the triggering cells in proliferation stage. Compared to normal cells, cancer cells are well protected against oxidative stress, in part by elevated GSH content and activities of GSH-dependent antioxidant enzymes, including glutathione peroxidases (GPx1 and GPx4 denote peroxidases that target hydrogen peroxide and lipid peroxide, correspondingly) and glutathione reductase, GSSG-Rx (Khramtsov & Gillies, 2014, ARS, 21, 723–729).


Noninvasive spatially- and temporally-resolved in vivo monitoring of critical parameters of tissue microenvironment provides unique insights into the role of TME in cancer aggression, metastatic activity, and treatment efficacy and creates novel opportunity for designing TME-targeted anticancer therapies.


  1. Khramstov, V. V., In vivo molecular EPR-based spectroscopy and imaging of tumor microenvironment and redox using functional paramagnetic probes. Antioxid Redox Signal 2018, 28 (15), 1365-1377.
  2. Kishimoto, S.; Krishna, M. C.; Khramtsov, V. V.; Utsumi, H.; Lurie, D. J., In vivo application of proton electron double resonance imaging. Antioxid Redox Signal 2018, 28 (15), 1345-1364.
  3. Biller, J. R.; Mitchell, D. G.; Tseytlin, M.; Elajaili, H.; Rinard, G. A.; Quine, R. W.; Eaton, S. S.; Eaton, G. R., Rapid Scan Electron Paramagnetic Resonance Opens New Avenues for Imaging Physiologically Important Parameters In Vivo. J Vis Exp 2016, (115).
  4. Tseytlin, M.; Stolin, A. V.; Guggilapu, P.; Bobko, A. A.; Khramtsov, V. V.; Tseytlin, O.; Raylman, R. R., A combined positron emission tomography (PET)-electron paramagnetic resonance imaging (EPRI) system: initial evaluation of a prototype scanner. Phys Med Biol 2018, 63 (10), 105010.
  5. Khramtsov, V. V.; Bobko, A. A.; Tseytlin, M.; Driesschaert, B., Exchange Phenomena in the Electron Paramagnetic Resonance Spectra of the Nitroxyl and Trityl Radicals: Multifunctional Spectroscopy and Imaging of Local Chemical Microenvironment. Anal Chem 2017, 89 (9), 4758-4771.
  6. Bobko, A. A.; Eubank, T. D.; Driesschaert, B.; Khramtsov, V. V., In Vivo EPR Assessment of pH, pO2, Redox Status, and Concentrations of Phosphate and Glutathione in the Tumor Microenvironment. J Vis Exp 2018, (133).
  7. Bobko, A. A.; Eubank, T. D.; Driesschaert, B.; Dhimitruka, I.; Evans, J.; Mohammad, R.; Tchekneva, E. E.; Dikov, M. M.; Khramtsov, V. V., Interstitial Inorganic Phosphate as a Tumor Microenvironment Marker for Tumor Progression. Sci Rep 2017, 7, 41233.
  8. Khramtsov, V. V.; Gillies, R. J., Janus-Faced Tumor Microenvironment and Redox. Antioxid Redox Signal 2014, 21, 723-729.