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Electron Paramagnetic Resonance Imaging-Solo and Orchestra

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Medical Imaging Methods

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Abstract

Magnetic resonance is a physical phenomenon related to the possession of either electron or nuclear nonzero spin of molecules. It is the base of two important analytic methods, the application of which in biological and clinical research is completely different, despite this common basis, namely nuclear magnetic resonance (NMR) and electron paramagnetic (EPR, also called spin—ESR) resonance. Starting from this common physical root, this chapter compares the magnetic resonance-based, nuclear and electron-related techniques of imaging—NMR and EPR imaging (NMRI versus EPRI), focusing on the latter. EPRI is characterized from the very general perspective and described in detail including the basic modalities of the technique—continuous wave (CW), pulse or time-domain mode, and rapid scan (RS) EPRI. The description is supplemented with a handful of technical, software, and chemical details important for researchers, engineers, IT specialists and, hopefully, physicians who consider application of these techniques, equipment, programs, and “EPR reagents” in their work. The most recent biological and clinical aspects of EPRI are analyzed with a particular care, and pictured on the background of other related and not related research techniques, making the chapter a universal, interdisciplinary compendium of the common EPRI know-how.

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References

  1. Gerlach W, Stern O. Das Magnetische Moment Des Silberatoms. Z Phys. 1922;9(1):353–5.

    Article  ADS  Google Scholar 

  2. Pauli W. Über Den Zusammenhang Des Abschlusses Der Elektronengruppen Im Atom Mit Der Komplexstruktur Der Spektren. Z Phys. 1925;31(1):765–83.

    Article  ADS  MATH  Google Scholar 

  3. Uhlenbeck GE, Goudsmit S. Spinning electrons and the structure of spectra. Nature. 1926;117(2938):264–5.

    Article  ADS  Google Scholar 

  4. Plonka PM. Electron paramagnetic resonance as a unique tool for skin and hair research. Exp Dermatol. 2009;18(5):472–84.

    Article  Google Scholar 

  5. Eaton GR. Quantitative EPR. Berlin: Springer; 2014.

    Google Scholar 

  6. Geschwind S. Electron paramagnetic resonance. Berlin: Springer; 1972.

    Book  Google Scholar 

  7. Gilbert BC, Davies MJ, Murphy DM, Becker D. Electron paramagnetic resonance volume 19: a review of the recent literature: Royal Soc Chem; 2004.

    Google Scholar 

  8. Goldfarb D, Stoll S. EPR spectroscopy: fundamentals and methods. New York: Wiley; 2018.

    Google Scholar 

  9. Schweiger A, Jeschke G. Principles of pulse electron paramagnetic resonance. New York: Oxford University Press; 2001.

    Google Scholar 

  10. Weil JA, Bolton JR. Electron paramagnetic resonance: elementary theory and practical applications. New York: Wiley-Interscience; 2007.

    Google Scholar 

  11. Wertz JE, Bolton JR. Electron spin resonance: elementary theory and practical applications. London: Chapman and Hall; 1986.

    Book  Google Scholar 

  12. Sahu ID, McCarrick RM, Lorigan GA. Use of electron paramagnetic resonance to solve biochemical problems. Biochemistry. 2013;52(35):5967–84.

    Article  Google Scholar 

  13. Ahmad R, Kuppusamy P. Theory, instrumentation, and applications of electron paramagnetic resonance Oximetry. Chem Rev. 2010;110(5):3212–36.

    Article  Google Scholar 

  14. Epel B, Halpern HJ. In vivo pO2 imaging of tumors: Oxymetry with very low-frequency electron paramagnetic resonance. Methods Enzymol. 2015b;564:501–27.

    Article  Google Scholar 

  15. Sarna T, Plonka PM. Biophysical studies of melanin. In: Eaton SS, Eaton GR, Berliner LJ, editors. Biomedical EPR, part a: free radicals, metals, medicine, and physiology. New York: Springer; 2005. p. 125–46.

    Chapter  Google Scholar 

  16. Gustafsson H, Hallbeck M, Lindgren M, Kolbun N, Jonson M, Engström M, de Muinck E, Zachrisson H. Visualization of oxidative stress in ex vivo biopsies using electron paramagnetic resonance imaging. Magn Reson Med. 2015;73(4):1682–91.

    Article  Google Scholar 

  17. Pavelescu LA. On reactive oxygen species measurement in living systems. J Med Life. 2015;8:38–42.

    Google Scholar 

  18. Płonka PM. Paramagnetomics. In: Shukla AK, editor. Electron spin resonance spectroscopy in medicine. Singapore: Springer Singapore; 2019. p. 189–221.

    Chapter  Google Scholar 

  19. Zweier JL, Kuppusamy P. Electron paramagnetic resonance measurements of free radicals in the intact beating heart: a technique for detection and characterization of free radicals in whole biological tissues. Proc Natl Acad Sci U S A. 1988;85(15):5703–7.

    Article  ADS  Google Scholar 

  20. Khramtsov VV, Grigor’ev IA, Foster MA, Lurie DJ. In vitro and in vivo measurement of pH and Thiols by EPR-based techniques. Antioxid Redox Signal. 2004;6(3):667–76.

    Google Scholar 

  21. Rosen GM. Free radicals: biology and detection by spin trapping. Oxford: Oxford University Press; 1999.

    Google Scholar 

  22. Blank A, Halevy R, Shklyar M, Shtirberg L, Kuppusamy P. ESR micro-imaging of LiNc-BuO crystals in PDMS: spatial and spectral grain distribution. J Magn Reson. 2010;203(1):150–5.

    Article  ADS  Google Scholar 

  23. Bobko AA, Dhimitruka I, Eubank TD, Marsh CB, Zweier JL, Khramtsov VV. Trityl-based EPR probe with enhanced sensitivity to oxygen. Free Radic Biol Med. 2009;47(5):654–8.

    Article  Google Scholar 

  24. Epel B, Sundramoorthy SV, Halpern HJ. 250 MHz passive Q-modulator for reflection resonators. Concepts Magn Reson Part B: Magn Reson Eng. 2017a;47B(2):e21356.

    Article  Google Scholar 

  25. Epel B, Sundramoorthy SV, Krzykawska-Serda M, Magio MC, Tseytlin M, Eaton GR, Eaton SS, Rosen GM, Kao JY, Halpern HJ. Imaging Thiol redox status in murine tumors in vivo with rapid-scan electron paramagnetic resonance. J Magn Reson. 2017b;276:31–6.

    Article  ADS  Google Scholar 

  26. Epel B, Kotecha M, Halpern HJ. In vivo preclinical cancer and tissue engineering applications of absolute oxygen imaging using pulse EPR. J Magn Reson. 2017c;280:149–57.

    Article  ADS  Google Scholar 

  27. Epel B, Krzykawska-Serda M, Tormyshev V, Maggio MC, Barth ED, Pelizzari CA, Halpern HJ. Spin lattice relaxation EPR pO2 images may direct the location of radiation tumor boosts to enhance tumor cure. Cell Biochem Biophys. 2017d;75(3–4):295–8.

    Article  Google Scholar 

  28. Krzykawska-Serda M, Dąbrowski JM, Arnaut LG, Szczygieł M, Urbańska K, Stochel G, Elas M. The role of strong hypoxia in tumors after treatment in the outcome of Bacteriochlorin-based photodynamic therapy (PDT). Free Radic Biol Med. 2014;73:239–51.

    Article  Google Scholar 

  29. Serda M, Wu Y-K, Barth ED, Halpern HJ, Rawal VH. EPR imaging spin probe Trityl radical OX063: a method for its isolation from animal effluent, redox chemistry of its Quinone Methide oxidation product, and in vivo application in a mouse. Chem Res Toxicol. 2016;29(12):2153–6.

    Article  Google Scholar 

  30. Sotgiu A, Mäder K, Placidi G, Colacicchi S, Ursini CL, Alecci M. pH-sensitive imaging by low-frequency EPR: a model study for biological applications. Phys Med Biol. 1998;43(7):1921–30.

    Article  Google Scholar 

  31. Lopiano L, Chiesa M, Digilio G, Giraudo S, Bergamasco B, Torre E, Fasano M. Q-band EPR investigations of Neuromelanin in control and Parkinson’s disease patients. Biochim Biophys Acta. 2000;1500(3):306–12.

    Article  Google Scholar 

  32. Colacicchi S, Alecci M, Gualtieri G, Quaresima V, Ursini CL, Ferrari M, Sotgiu A. New experimental procedures for in vivo L-band and radio frequency EPR spectroscopy/imaging. J Chem Soc Perkin Trans. 1993;20(11):2077.

    Article  Google Scholar 

  33. Epel B, Sundramoorthy SV, Mailer C, Halpern H. A versatile high speed 250-MHz pulse imager for biomedical applications. Con Magn Reson Part B Magn Reson Eng. 2008;33B(3):163–76.

    Article  Google Scholar 

  34. Epel B, Redler G, Halpern HJ. How in vivo EPR measures and images oxygen. Adv Exp Med Biol. 2014;812

    Google Scholar 

  35. Krishna MC, Devasahayam N, Cook JA, Subramanian S, Kuppusamy P, Mitchell JB. Electron paramagnetic resonance for small animal imaging applications. ILAR J Nat Res Council Inst Lab Anim Resour. 2001;42(3):209–18.

    Article  Google Scholar 

  36. Eaton GR, Eaton SS, Ohno K. EPR Imaging and in Vivo EPR. 1st ed. Hoboken: CRC; 1991.

    Google Scholar 

  37. Williams BB, Halpern HJ. In vivo EPR imaging. Biomedical EPR, part A: free radicals, metals, medicine, and physiology. New York: Springer; 2005. p. 283–319.

    Book  Google Scholar 

  38. Qiao Z, Zheng Z, Pan X, Epel B, Redler G, Xia D, Halpern H. Optimization-based image reconstruction from sparsely sampled data in electron paramagnetic resonance imaging. J Magn Reson. 2018;294:24–34.

    Article  ADS  Google Scholar 

  39. Redler G, Epel B, Halpern HJ. Maximally spaced projection sequencing in electron paramagnetic resonance imaging. Concepts Magn Reson Part B: Magn Reson Eng. 2015;45(1):33–45.

    Article  Google Scholar 

  40. Danhier P, Gallez B. Electron paramagnetic resonance: a powerful tool to support magnetic resonance imaging research. Contr Media Mol Imag. 2015;10(4):266–81.

    Article  Google Scholar 

  41. Subramanian S, Devasahayam N, McMillan A, Matsumoto S, Munasinghe JP, Saito K, Mitchell JB, Chandramouli GVR, Krishna MC. Reporting of quantitative oxygen mapping in EPR imaging. J Magn Reson. 2012a;214(1):244–51.

    Article  ADS  Google Scholar 

  42. Subramanian S, Mitchell JB, Krishna MC. Time-domain radio frequency EPR imaging. In: Berliner LJ, editor. In vivo EPR (ESR): theory and application. Berlin: Springer Science & Business Media; 2012b. p. 153–97.

    Google Scholar 

  43. Berliner LJ, editor. In Vivo EPR (ESR), vol. 18. Springer: Boston, MA; 2003.

    Google Scholar 

  44. Dawkins AW, Nightingale NR, South GP, Sheppard RJ, Grant EH. The role of water in microwave absorption by biological material with particular reference to microwave hazards. Phys Med Biol. 1979;24(6):1168–76.

    Article  Google Scholar 

  45. Dayan N, Ishay Y, Artzi Y, Cristea D, Reijerse E, Kuppusamy P, Blank A. Advanced surface resonators for electron spin resonance of single microcrystals. Rev Sci Instrum. 2018;89(12):124707.

    Article  ADS  Google Scholar 

  46. Hou H, Krishnamurthy Nemani V. Monitoring oxygen levels in Orthotopic human Glioma Xenograft following Carbogen inhalation and chemotherapy by implantable resonator based Oximetry. Int J Cancer. 2014;136(7):1–27.

    Google Scholar 

  47. Pursley R, Enomoto A, Wu H, Brender JR, Pohida T, Subramanian S, Krishna MC, Devasahayam N. Towards reduction of SAR in scaling up in vivo pulsed EPR imaging to larger objects. J Magn Reson. 2019;299:42–8.

    Article  ADS  Google Scholar 

  48. Biller JR, Tseitlin M, Quine RW, Rinard GA, Weismiller HA, Elajaili H, Rosen GM, Kao JPY, Eaton SS, Eaton GR. Imaging of Nitroxides at 250 MHz using rapid-scan electron paramagnetic resonance. J Magn Reson. 2014;242:162–8.

    Article  ADS  Google Scholar 

  49. Subramanian S, Krishna MC. Dancing with the electrons: time-domain and CW in vivo EPR imaging. Magn Reson Insights. 2008;2:43–74.

    Google Scholar 

  50. Eaton SS, Shi Y, Woodcock L, Buchanan LA, McPeak J, Quine R, Rinard GA, Epel B, Haleprn HJ, Eaton GR. Rapid-Scan EPR imaging. J Magn Reson. 2017;280:140–8.

    Article  ADS  Google Scholar 

  51. Biller JR, Mitchell DG, Tseytlin M, Elajaili H, Rinard GA, Quine RW, Eaton SS, Eaton GR. Rapid scan electron paramagnetic resonance opens new avenues for imaging physiologically important parameters in vivo. J Vis Exp. 2016;115:e54068.

    Google Scholar 

  52. Möser J, Lips K, Tseytlin M, Eaton GR, Eaton SS, Schnegg A. Using rapid-scan EPR to improve the detection limit of quantitative EPR by more than one order of magnitude. J Magn Reson. 2017;281:17–25.

    Article  ADS  Google Scholar 

  53. Czoch R, Francik A. Instrumental effects in homodyne electron paramagnetic resonance spectrometers. Warszawa, Chichester: PWN Polish Scientific Publishers and Ellis Horwood Ltd Publishers; 1989.

    Google Scholar 

  54. Subramanian S, Krishna MC. Electron paramagnetic resonance imaging. Resonance. 2016;21(8):717–40.

    Article  Google Scholar 

  55. Froncisz W, Hyde S, Hyde JS. The loop-gap resonator: a new microwave lumped circuit ESR sample structure. J Magn Reson. 1982;521:515–21.

    ADS  Google Scholar 

  56. Chzhan M, Kuppusamy P, Samouilov A, He G, Zweier JL. A tunable reentrant resonator with transverse orientation of electric field Forin Vivo EPR spectroscopy. J Magn Reson. 1999;137(2):373–8.

    Article  ADS  Google Scholar 

  57. Devasahayam N, Subramanian S, Murugesan R, Cook JA, Afeworki M, Tschudin RG, Mitchell JB, Krishna MC. Parallel coil resonators for time-domain radiofrequency electron paramagnetic resonance imaging of biological objects. J Magn Reson. 2000;142(1):168–76.

    Article  ADS  Google Scholar 

  58. Rinard GA, Quine RW, Buchanan LA, Eaton SS, Eaton GR, Epel B, Sundramoorthy SV, Halpern HJ. Resonators for in vivo imaging: practical experience. Appl Magn Reson. 2017;48:11–2; 1227–1247

    Google Scholar 

  59. Matsumoto K-i I, Chandrika B, Lohman JABB, Mitchell JB, Krishna MC, Subramanian S. Application of continuous-wave EPR spectral-spatial image reconstruction techniques for in vivo Oxymetry: comparison of projection reconstruction and constant-time modalities. Magn Reson Med. 2003;50(4):865–74.

    Article  Google Scholar 

  60. Ahmad R, Clymer B, Deng Y, He G, Vikram D, Kuppusamy P, Zweier JL. Optimization of data acquisition for EPR imaging. J Magn Reson. 2006;179(2):263–72.

    Article  ADS  Google Scholar 

  61. Tseytlin M. Full cycle rapid scan EPR Deconvolution algorithm. J Magn Reson. 2017;281:272–8.

    Article  ADS  Google Scholar 

  62. Subramanian S, Krishna MC. Time-domain radio frequency EPR imaging. Biomedical EPR, part a: free radicals, metals, medicine, and physiology. New York: Springer; 2005. p. 321–82.

    Book  Google Scholar 

  63. Krishna MC, Matsumoto S, Yasui H, Saito K, Devasahayam N, Subramanian S, Mitchell JB. Electron paramagnetic resonance imaging of tumor pO2. Radiat Res. 2012;177(4):376–86.

    Article  ADS  Google Scholar 

  64. Subramanian S, Matsumoto K-I, Mitchell JB, Krishna MC. Radio frequency continuous-wave and time-domain EPR imaging and Overhauser-enhanced magnetic resonance imaging of small animals: instrumental developments and comparison of relative merits for functional imaging. NMR Biomed. 2004;17(5):263–94.

    Article  Google Scholar 

  65. Sun L, Savory JJ, Warncke K. Design and implementation of an FPGA-based timing pulse programmer for pulsed-electron paramagnetic resonance applications. Concepts Magn Reson Part B: Magn Reson Eng. 2013;43(3):100–9.

    Article  Google Scholar 

  66. Eaton GR, Eaton SS, Barr DP, Weber RT. Quantitative EPR: a practitioners guide. Wien: Springer; 2010.

    Book  Google Scholar 

  67. Tseitlin MP, Iyudin VS, Tseitlin OA. Advantages of digital phase-sensitive detection for upgrading an obsolete CW EPR spectrometer. Appl Magn Reson. 2009;35(4):569–80.

    Article  Google Scholar 

  68. Tadyszak K, Boś-Liedke A, Jurga J, Baranowski M, Mrówczyński R, Chlewicki W, Jurga S, Czechowski T. Overmodulation of projections as signal-to-noise enhancement method in EPR imaging. Magn Reson Chem. 2016;54(2):136–42.

    Article  Google Scholar 

  69. Koscielniak J, Devasahayam N, Moni MS, Kuppusamy P, Yamada K, Mitchell JB, Krishna MC, Subramanian S. 300 MHz continuous wave electron paramagnetic resonance spectrometer for small animal in vivo imaging. Rev Sci Instrum. 2000;71(11):4273–81.

    Article  ADS  Google Scholar 

  70. Sato-Akaba H, Abe H, Fujii H, Hirata H. Slice-selective images of free radicals in mice with modulated field gradient electron paramagnetic resonance (EPR) imaging. Magn Reson Med. 2008a;59(4):885–90.

    Article  Google Scholar 

  71. Sato-Akaba H, Fujii H, Hirata H. Development and testing of a CW-EPR apparatus for imaging of short-lifetime Nitroxyl radicals in mouse head. J Magn Reson. 2008b;193:191–8.

    Article  ADS  Google Scholar 

  72. Sato-Akaba H, Kuwahara Y, Fujii H, Hirata H. Half-life mapping of Nitroxyl radicals with three-dimensional electron paramagnetic resonance imaging at an interval of 3.6 seconds. Anal Chem. 2009;81(17):7501–6.

    Article  Google Scholar 

  73. Tseitlin M, Rinard GA, Quine RW, Eaton SS, Eaton GR. Rapid frequency scan EPR. J Magn Reson. 2011;211(2):156–61.

    Article  ADS  Google Scholar 

  74. Czechowski T, Chlewicki W, Baranowski M, Jurga K, Szczepanik P, Szulc P, Kedzia P, Szostak M, Malinowski P, Wosinski S, Prukala W, Jurga J. Two-dimensional spectral–spatial EPR imaging with the rapid scan and modulated magnetic field gradient. J Magn Reson. 2014;243:1–7.

    Article  ADS  Google Scholar 

  75. Durand S, Frapart Y-M, Kerebel M. Electron paramagnetic resonance image reconstruction with Total variation and Curvelets regularization. Inv Probl. 2017;33:114002.

    Article  ADS  MathSciNet  MATH  Google Scholar 

  76. Giuseppe S, Di G, Placidi J, Brivati A, Alecci M, Sotgiu A. Pulsed EPR imaging: image reconstruction using selective acquisition sequences. Phys Med Biol. 1999;44(6):N137–44.

    Article  Google Scholar 

  77. Williams BB, Pan X, Halpern HJ. EPR imaging: the relationship between CW spectra acquired from an extended sample subjected to fixed stepped gradients and the radon transform of the resonance density. J Magn Reson. 2005;174(1):88–96.

    Article  ADS  Google Scholar 

  78. Marr RB, Chen C-N, Lauterbur PC. On two approaches to 3D reconstruction in NMR zeugmatography. In: Herman GT, Natterer F, editors. Mathematical aspects of computerized tomography, Lecture notes in medical informatics, vol. 8. Berlin: Springer; 1981. p. 225–40.

    Chapter  Google Scholar 

  79. Sivakumar S, Aart A, Krishna MC. Evaluation of algebraic iterative algorithms for reconstruction of electron magnetic resonance images. Iccvgip. 2004;2014:353–8.

    Google Scholar 

  80. Qiao Z, Redler G, Epel B, Qian Y, Halpern H. 3D pulse EPR imaging from sparse-view projections via constrained, Total variation minimization. J Magn Reson. 2015;258:49–57.

    Article  ADS  Google Scholar 

  81. Ohno K. Application of ESR imaging to a continuous flow method for study on kinetics of short-lived radicals. J Magn Reson. 1982;49(1):56–63.

    ADS  Google Scholar 

  82. Sotgiu A, Gazzillo D, Momo F. ESR imaging: spatial Deconvolution in the presence of an asymmetric hyperfine structure. J Phys C Solid State Phys. 1987;20(36):6297–304.

    Article  ADS  Google Scholar 

  83. Momo F, Colacicchi S, Sotgiu A. Limits of Deconvolution in enhancing the resolution in EPR imaging experiments. Meas Sci Technol. 1993;4(1):60–4.

    Article  ADS  Google Scholar 

  84. He G, Deng Y, Li H, Kuppusamy P, Zweier JL. EPR/NMR co-imaging for anatomic registration of free-radical images. Magn Reson Med. 2002;47(3):571–8.

    Article  Google Scholar 

  85. MJR H, Day AR. Imaging of paramagnetic Centres in Diamond. Solid State Commun. 1979;30(4):211–3.

    Article  ADS  Google Scholar 

  86. Berliner LJ, Fujii H. Magnetic resonance imaging of biological specimens by electron paramagnetic resonance of Nitroxide spin labels. Science. 1985;227(4686):517–9.

    Article  ADS  Google Scholar 

  87. Fujii H, Berliner LJ. One- and two-dimensional EPR imaging studies on phantoms and plant specimens. Magn Reson Med. 1985;2(3):275–82.

    Article  Google Scholar 

  88. Bacic G, Nilges MJ, Magin RL, Walczak T, Swartz HM. In vivo localized ESR spectroscopy reflecting metabolism. Magn Reson Med. 1989;10(2):266–72.

    Article  Google Scholar 

  89. Chen K, Glockner JF, Morse PD, Swartz HM. Effects of oxygen on the metabolism of Nitroxide spin labels in cells. Biochemistry. 1989;28(6):2496–501.

    Article  Google Scholar 

  90. Chen K, Morse PD, Swartz HM. Kinetics of enzyme-mediated reduction of lipid soluble nitroxide spin labels by living cells. BBA-Biomembranes. 1988;943(3):477–84.

    Article  Google Scholar 

  91. Dobrucki JW, Sutherland RM, Swartz HM. Nonperturbing test for cytotoxicity in isolated cells and spheroids, using electron paramagnetic resonance. Magn Reson Med. 1991;19(1):42–55.

    Article  Google Scholar 

  92. Halpern HJ, Jaffe DR, Nguyen TD, Haraf DJ, Spencer DP, Bowman MK, Weichselbaum RR, Diamond AM. Measurement of bioreduction rates of cells with distinct responses to ionizing radiation and Cisplatin. BBA Mol Cell Res. 1991;1093(2-3):121–4.

    Google Scholar 

  93. Mitchell JB, Samuni A, Krishna MC, DeGraff WG, Ahn MS, Samuni U, Russo A. Biologically active metal-independent superoxide dismutase mimics. Biochemistry. 1990;29(11):2802–7.

    Article  Google Scholar 

  94. Suzuki-Nishimura T, Swartz HM. Characterization of redox activity in resting and activated mast cells by reduction and Reoxidation of lipophilic Nitroxides. Gen Pharmacol. 1998;31(4):617–23.

    Article  Google Scholar 

  95. Swartz HM, Khan N, Khramtsov VV. Use of electron paramagnetic resonance spectroscopy to evaluate the redox state in vivo. Antioxid Redox Signal. 2009;9(10):1757–71.

    Article  Google Scholar 

  96. Kuppusamy P, Li H, Ilangovan G, Cardounel AJ, Zweier JL, Yamada K, Krishna MC, Mitchell JB. Noninvasive imaging of tumor redox status and its modification by tissue glutathione levels. Cancer Res. 2002;62(1):307–12.

    Google Scholar 

  97. Kuppusamy P, Wang P, Jay L, Zweier JL, Krishna MC, Mitchell JB, Ma L, Trimble CE, Hsia CJC. Electron paramagnetic resonance imaging of rat heart with Nitroxide and Polynitroxyl-albumin. Biochemistry. 1996;2960(22):7051–7.

    Article  Google Scholar 

  98. Plonka PM, Wisniewska M, Stefan C, Elas M, Rosen GM. X-band and S-band EPR detection of nitric oxide in murine Endotoxaemia using spin trapping by Ferro-Di(N-(Dithiocarboxy)Sarcosine). Acta Biochim Pol. 2003;50(3):799–806.

    Google Scholar 

  99. Subczynski WK, Lukiewicz S, Hyde JS. Murine in vivo L-band ESR spin-label Oximetry with a loop-gap resonator. Magn Reson Med. 1986;3(5):747–54.

    Article  Google Scholar 

  100. Halpern HJ, Spencer DP, Van Polen J, Bowman MK, Nelson AC, Dowey EM, Teicher BA. Imaging radio frequency electron-spin-resonance spectrometer with high resolution and sensitivity for in vivo measurements. Rev Sci Instrum. 1989;60(6):1040–50.

    Article  ADS  Google Scholar 

  101. Fuchs J, Freisleben HJ, Groth N, Herrling T, Zimmer G, Milbradt R, Packer L. One- and two-dimensional electron paramagnetic resonance imaging in skin. Free Radic Res Comms. 1991;15(5):245–53.

    Article  Google Scholar 

  102. Takeshita K, Utsumi H, Hamada A. ESR measurement of radical clearance in lung of whole mouse. Biochem Biophys Res Commun. 1991;177(2):874–80.

    Article  Google Scholar 

  103. Alecci M, Ferrai M, Quaresima V, Sotgiu A, Ursini CL, Quaresimna V. Simultaneous 280 MHz EPR imaging of rat organs during Nitroxide free radical clearance. Biophys J. 1994;67(1):1274–9.

    Article  Google Scholar 

  104. Quaresima V, Alecci M, Ferrari M, Sotgiu A. Whole rat paramagnetic resonance imaging of a Nitroxide free radical by a radio frequency (280 MHz) spectrometer. Biochem Biophys Res Commun. 1992;183(2):829–35.

    Article  Google Scholar 

  105. Oikawa K, Ogata T, Togashi H, Yokoyama H, Ohya-Nishiguchi H, Kamada H. A 3D- and 4D-ESR imaging system for small animals. Appl Radiat Isot. 1996;47(11–12):1605–9.

    Article  Google Scholar 

  106. Yokoyama H, Itoh O, Ogata T, Obara H, Ohya-Nishiguchi H, Kamada H. Temporal brain imaging by a rapid scan ESR-CT system in rats receiving intraperitoneal injection of a methyl ester nitroxide radical. Magn Reson Imaging. 1997;15(9):1079–84.

    Article  Google Scholar 

  107. Halpern HJ, Peric M, Yu C, Barth ED, Chandramouli GVR, Makinen MW, Rosen GM. In vivo spin-label murine pharmacodynamics using low-frequency. Biophys J. 1996;71(July):403–9.

    Article  Google Scholar 

  108. Kuppusamy P, Chzhan M, Vij K, Shteynbuk M, Lefer DJ, Giannella E, Zweier JL. Three-dimensional spectral-spatial EPR imaging of free radicals in the heart: a technique for imaging tissue metabolism and oxygenation. Proc Natl Acad Sci U S A. 1994;91(8):3388–92.

    Article  ADS  Google Scholar 

  109. Kuppusamy P, Chzhan M, Samouilov A, Wang PH, Zweier JL. Mapping the spin-density and Lineshape distribution of free radicals using 4D spectral-spatial EPR imaging. J Magn Reson B. 1995;107(2):116–25.

    Article  Google Scholar 

  110. Kuppusamy P, Afeworki M, Shankar RA, Coffin D, Krishna MC, Hahn SM, Mitchell JB, Zweier JL. In vivo electron paramagnetic resonance imaging of tumor heterogeneity and oxygenation in a murine model. Cancer Res. 1998;58(7):1562–8.

    Google Scholar 

  111. Ardenkjaer-Larsen JH, Laursen I, Leunbach I. EPR and DNP properties of certain novel single electron contrast agents intended for Oximetric imaging. J Magn Reson. 1998;12:1–12.

    Article  ADS  Google Scholar 

  112. Kuppusamy P, Wang P, Chzhan M, Zweier JL. High resolution electron paramagnetic resonance imaging of biological samples with a single line paramagnetic label. Magn Reson Med. 1997;37(4):479–83.

    Article  Google Scholar 

  113. Petersson JS, Järvi A, Vahasalo S, Golman K, Ardenkjær-Larsen JH, Ehnholm G, Wistrand LG, Petersson JS, Järvi A, Vahasalo S. Overhauser-enhanced MR imaging (OMRI). Acta Radiol. 1998;39(1):10–7.

    Article  Google Scholar 

  114. Hyodo F, Chuang K-H, Goloshevsky AG, Sulima A, Griffiths GL, Mitchell JB, Koretsky AP, Krishna MC. Brain redox imaging using blood-brain barrier-permeable Nitroxide MRI contrast agent. J Cereb Blood Flow Metab. 2008a;28(6):1165–74.

    Article  Google Scholar 

  115. Sano H, Naruse M, Matsumoto KI, Oi T, Hideo U, Tetsuo OI, Utsumi H. A new Nitroxyl-probe with high retention in the brain and its application for brain imaging. Free Radic Biol Med. 2000;28(6):959–69.

    Article  Google Scholar 

  116. Utsumi H, Sano H, Naruse M, Matsumoto KI, Ichikawa K, Oi T. Nitroxyl probes for brain research and their application to brain imaging. Methods Enzymol. 2002;352:494–506.

    Article  Google Scholar 

  117. Hu H, Sosnovsky G, Li SW, Rao NUM, Morse PD, Swartz HM. Development of Nitroxides for selective localization inside cells. BBA Mol Cell Res. 1989;1014(3):211–8.

    Google Scholar 

  118. Dhimitruka I, Bobko AA, Eubank TD, Komarov DA, Khramtsov VV. Phosphonated Trityl probes for concurrent in vivo tissue oxygen and PH monitoring using electron paramagnetic resonance-based techniques. J Am Chem Soc. 2013;135(15):5904–10.

    Article  Google Scholar 

  119. Khramtsov VV, Bobko AA, 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):4758–71.

    Article  Google Scholar 

  120. Khan N, Hou H, Swartz HM, Kuppusamy P. Direct and repeated measurement of heart and brain oxygenation using in vivo EPR Oximetry. 1st ed. New York: Elsevier Inc.; 2015.

    Google Scholar 

  121. Swartz HM. The clinical aspects of oxygen and methods related to its measurement. Adv Exp Med Biol. 2014;812:vii–viii.

    Google Scholar 

  122. Williams BB, Khan N, Zaki B, Hartford A, Ernstoff MS, Swartz HM. Clinical electron paramagnetic resonance (EPR) Oximetry using India ink. Adv Exp Med Biol. 2010;662:149–56.

    Article  Google Scholar 

  123. Krzykawska-Serda M, Miller RC, Elas M, Epel B, Barth ED, Maggio M, Halpern HJ. Correlation between hypoxia proteins and EPR-detected hypoxia in tumors. Adv Exp Med Biol. 2017;977:319–25.

    Article  Google Scholar 

  124. Epel B, Maggio MC, Barth ED, Miller RC, Pelizzari CA, Krzykawska-Serda M, Sundramoorthy SV, Aydogan B, Weichselbaum RR, Tormyshev VM, Halpern HJ. Oxygen-guided radiation therapy. Int J Radiat Oncol Biol Phys. 2018;14:1–8.

    Google Scholar 

  125. Epel B, Halpern HJ. Comparison of pulse sequences for R1–based electron paramagnetic resonance oxygen imaging. J Magn Reson. 2015;254:56–61.

    Article  ADS  Google Scholar 

  126. Epel B, Haney CR, Hleihel D, Wardrip C, Barth ED, Halpern HJ. Electron paramagnetic resonance oxygen imaging of a rabbit tumor using localized spin probe delivery. Med Phys. 2010;37(6):2553.

    Article  Google Scholar 

  127. Redler G, Barth ED, Bauer KS, Kao JPY, Rosen GM, Halpern HJ. In of differential tumor targeting using Cis-3,4-Di(Acetoxymethoxycarbonyl)-2,2,5,5-Tetramethyl-1-Pyrrolidinyloxyl. Magn Reson Med. 2014a;71(4):1650–6.

    Article  Google Scholar 

  128. Redler G, Epel B, Halpern HJ. Principal component analysis enhances SNR for dynamic electron paramagnetic resonance oxygen imaging of cycling hypoxia in vivo. Magn Reson Med. 2014b;71(1):440–50.

    Article  Google Scholar 

  129. Yasui H, Matsumoto S, Devasahayam N, Munasinghe JP, Choudhuri R, Saito K, Subramanian S, Mitchell JB, Krishna MC. Low-field magnetic resonance imaging to visualize chronic and cycling hypoxia in tumor-bearing mice. Cancer Res. 2010;70(16):6427–36.

    Article  Google Scholar 

  130. Christodoulou AG, Redler G, Clifford B, Liang ZP, Halpern HJ, Epel B. Fast dynamic electron paramagnetic resonance (EPR) oxygen imaging using low-rank tensors. J Magn Reson. 2016;270:176–82.

    Article  ADS  Google Scholar 

  131. Matsumoto S, Hyodo F, Subramanian S, Devasahayam N, Munasinghe J, Hyodo E, Gadisetti C, Cook JA, Mitchell JB, Krishna MC. Low-field paramagnetic resonance imaging of tumor oxygenation and glycolytic activity in mice. J Clin Investig. 2008;118(5):1965–73.

    Google Scholar 

  132. Kotecha M, Epel B, Ravindran S, Dorcemus D, Nukavarapu S, Halpern H. Noninvasive absolute EPR oxygen imaging for the assessment of tissue graft oxygenation. Tissue Eng Part C Methods. 2018;24(1):14–9.

    Article  Google Scholar 

  133. Gorodetsky AA, Kirilyuk IA, Khramtsov VV, Komarov DA. Functional electron paramagnetic resonance imaging of ischemic rat heart: monitoring of tissue oxygenation and pH. Magn Reson Med. 2015;76(1):350–8.

    Article  Google Scholar 

  134. Matsumoto A, Matsumoto K-i, Matsumoto S, Hyodo F, Sowers AL, Koscielniak JW, Devasahayam N, Subramanian S, Mitchell JB, Krishna MC. Intracellular hypoxia of tumor tissue estimated by noninvasive electron paramagnetic resonance Oximetry technique using paramagnetic probes. Biol Pharm Bull. 2011a;34(1):142–5.

    Article  Google Scholar 

  135. Matsumoto S, Yasui H, Mitchell JB, Krishna MC. Imaging Cycling Tumor Hypoxia. Cancer Res. 2010;70(24):10019–23.

    Article  Google Scholar 

  136. Matsumoto K-i, Hyodo F, Anzai K, Mitchell JB, Krishna MC. Brain Redox Imaging. In: Modo M, Bulte JWM, editors. Magnetic Resonance Neuroimaging, vol. 711. Totowa, NJ, USA: Humana Press; 2011. p. 397–411.

    Chapter  Google Scholar 

  137. Matsumoto S, Batra S, Saito K, Yasui H, Choudhuri R, Gadisetti C, Subramanian S, Devasahayam N, Munasinghe JP, Mitchell JB, Krishna MC. Antiangiogenic agent sunitinib transiently increases tumor oxygenation and suppresses cycling hypoxia. Cancer Res. 2011;71(20):6350–9.

    Article  Google Scholar 

  138. Flood AB, Wood VA, Schreiber W, Williams BB, Swartz HM. Guidance for academics to transfer ‘bench-ready’ medical technology into usual clinical practice: case study: sensors and spectrometer used in EPR Oximetry. Adv Exp Med Biol. 2018;1072:233–9.

    Article  Google Scholar 

  139. Swartz HM, Khan N, Buckey J, Comi R, Gould L, Grinberg O, Hartford A, Hopf H, Hou H, Hug E, Iwasaki A, Lesniewski P, Salikhov I, Walczak T. Clinical applications of EPR: overview and perspectives. NMR Biomed. 2004;17(5):335–51.

    Article  Google Scholar 

  140. He G, Samouilov A, Kuppusamy P, Zweier JL. In vivo EPR imaging of the distribution and metabolism of Nitroxide radicals in human skin. J Magn Reson. 2001;148(1):155–64.

    Article  ADS  Google Scholar 

  141. Swartz HM, Williams BB, Hou H, Khan N, Jarvis LA, Chen EY, Schaner PE, Ali A, Gallez B, Kuppusamy P, Flood AB. Direct and repeated clinical measurements of pO2 for enhancing cancer therapy and other applications. Adv Exp Med Biol. 2016;923:95–104.

    Article  Google Scholar 

  142. Nel J, Desmet CM, Driesschaert B, Saulnier P, Lemaire L, Gallez B. Preparation and evaluation of Trityl-loaded lipid Nanocapsules as oxygen sensors for electron paramagnetic resonance Oximetry. Int J Pharm. 2019;554:87–92.

    Article  Google Scholar 

  143. Kmiec MM, Hou H, Kuppusamy LM, Drews TM, Prabhat AM, Petryakov SV, Demidenko E, Schaner PE, Buckey JC, Blank A, Kuppusamy P. Transcutaneous oxygen measurement in humans using a paramagnetic skin adhesive film. Magn Reson Med. 2018;81(2):781–94.

    Article  Google Scholar 

  144. Bobko AA, Eubank TD, Driesschaert B, Khramtsov VV. In vivo EPR assessment of PH, pO2, redox status, and concentrations of phosphate and glutathione in the tumor microenvironment. J Vis Exp. 2018;133:2–11.

    Google Scholar 

  145. Khramtsov VV, Gillies RJ. Janus-faced tumor microenvironment and redox. Antioxid Redox Signal. 2014;21(5):723–9.

    Article  Google Scholar 

  146. Komarov DA, Ichikawa Y, Yamamoto K, Stewart NJ, Matsumoto S, Yasui H, Kirilyuk IA, Khramtsov VV, Inanami O, Hirata H. In vivo extracellular pH mapping of tumors using electron paramagnetic resonance. Anal Chem. 2018;90(23):13938–45.

    Article  Google Scholar 

  147. Khramtsov VV, Caia GL, Shet K, Kesselring E, Petryakov S, Zweier JL, Samouilov A. Variable field proton-electron double-resonance imaging: application to PH mapping of aqueous samples. J Magn Reson. 2010;202(2):267–73.

    Article  ADS  Google Scholar 

  148. Elajaili H, Biller JR, Rosen GR, Kao J, Tseytlin M, Buchanan L, Rinard G, Quine R, McPeak J, Shi Y, Eaton SS, Eaton GR. Imaging disulfide Dinitroxides at 250 MHz to monitor Thiol redox status. J Magn Reson. 2015a;260:77–82.

    Article  ADS  Google Scholar 

  149. Elajaili HB, Biller JR, Tseytlin M, Dhimitruka I, Khramtsov V, Eaton SS, Eaton GR. Electron spin relaxation times and rapid scan EPR imaging of PH-sensitive amino substituted Trityl radicals. Magn Reson Chem. 2015b;53(4):280–4.

    Article  Google Scholar 

  150. Efimova OV, Sun Z, Petryakov S, Kesselring E, Caia GL, Johnson D, Zweier JL, Khramtsov VV, Samouilov A. Variable radio frequency proton-electron double-resonance imaging: application to PH mapping of aqueous samples. J Magn Reson. 2011;209(2):227–32.

    Article  ADS  Google Scholar 

  151. Potapenko DI, Foster MA, Lurie DJ, Kirilyuk IA, Hutchison JMS, Grigor’ev I a, Bagryanskaya EG, Khramtsov VV. Real-time monitoring of drug-induced changes in the stomach acidity of living rats using improved PH-sensitive Nitroxides and low-field EPR techniques. J Magn Reson. 2006;182(1):1–11.

    Article  ADS  Google Scholar 

  152. Samouilov A, Efimova OV, Bobko AA, Sun Z, Petryalov S, Eubank TD, Trifomov DG, Kirilyuk IA, Takahasji W, Zweier JL, Khramtsov VV. In vivo proton–electron double-resonance imaging of extracellular tumor PH using an advanced Nitroxide probe. Anal Chem. 2014;86(2):1045–52.

    Article  Google Scholar 

  153. Goodwin J, Yachi K, Nagane M, Yasui H, Miyake Y, Inanami O, Bobko A, Khramtsov VV, Hirata H. In vivo tumour extracellular PH monitoring using electron paramagnetic resonance: the effect of X-ray irradiation. NMR Biomed. 2014;27(4):453–8.

    Article  Google Scholar 

  154. Khramtsov VV, Yelinova VI, Weiner LM, Berezina TA, Martin VV, Volodarsky LB. Quantitative determination of SH groups in low- and high-molecular-weight compounds by an electron spin resonance method. Anal Biochem. 1989;182(1):58–63.

    Article  Google Scholar 

  155. Khramtsov VV. Functional EPR spectroscopy and imaging of nitroxides. In: Pifat-Mrzljak G. (eds) Supramolecular structure and function 9. Springer, Dordrecht. 2007, 181-208

    Google Scholar 

  156. Bobko AA, Evans J, Denko NC, Khramtsov VV. Concurrent longitudinal EPR monitoring of tissue oxygenation, acidosis and reducing capacity in a mouse Xenograft tumor models. Cell Biochem Biophys. 2017a;75(2):247–53.

    Article  Google Scholar 

  157. Bobko AA, Eubank TD, Driesschaert B, Dhimitruka I, Evans J, Mohammad R, Tchekneva EE, Dikov MM, Khramtsov VV. Interstitial inorganic phosphate as a tumor microenvironment marker for tumor progression. Sci Rep. 2017b;7:1–12.

    Article  Google Scholar 

  158. Bobko AA, Eubank TD, Voorhees JL, Efimova OV, Igor A, Petryakov S, Trofimiov DG, Marsh CB, Zweier JL, Samouilov A, Khramtsov VV. In vivo monitoring of pH, redox status, and glutathione using L-band EPR for assessment of therapeutic effectiveness in solid tumors. Magn Reson Med. 2012;67(6):1827–36.

    Article  Google Scholar 

  159. Roshchupkina GI, Bobko AA, Bratasz A, Reznikov VA, Kuppusamy P, Khramtsov VV. In vivo EPR measurement of glutathione in tumor-bearing mice using improved disulfide Biradical probe. Free Radic Biol Med. 2008;45(3):312–20.

    Article  Google Scholar 

  160. Khramtsov VV. In vivo molecular electron paramagnetic resonance-based spectroscopy and imaging of tumor microenvironment and redox using functional paramagnetic probes. Antioxid Redox Signal. 2017;28(15):2017–7329.

    Google Scholar 

  161. Bobko AA, Dhimitruka I, Zweier J, Khramtsov VV. Fourier transform EPR spectroscopy of Trityl radicals for multifunctional assessment of chemical microenvironment. Angew Chem Int Ed Engl. 2014;53(10):2735–8.

    Article  Google Scholar 

  162. Krishna MC, Matsumoto S, Saito K, Matsuo M, Mitchell JB, Ardenkjaer-Larsen JH. Magnetic resonance imaging of tumor oxygenation and metabolic profile. Acta Oncologica. 2013;52(7):1248–56.

    Article  Google Scholar 

  163. Takakusagi Y, Matsumoto S, Saito K, Matsuo M, Kishimoto S, Wojtkowiak JW, DeGraff W, Kesarwala AH, Choudhuri R, Devasahayam N, Subramanian S, Munasinghe JP, Gillies RJ, Mitchell JB, Hart CP, Murali C. Krishna. Pyruvate induces transient tumor hypoxia by enhancing mitochondrial oxygen consumption and potentiates the anti-tumor effect of a hypoxia-activated Prodrug TH-302. PLoS One. 2014;9(9):e107995.

    Article  ADS  Google Scholar 

  164. Wojtkowiak JW, Cornnell HC, Matsumoto S, Saito K, Takakusagi Y, Dutta P, Kim M, Zhang X, Leos R, Bailey KM, Martinez G, Lloyd MC, Weber C, Mitchell JB, Lynch RM, Baker AF, Gatenby RA, Rejniak KA, Hart C, Krishna MC, Gillies RJ. Pyruvate sensitizes pancreatic tumors to hypoxia-activated Prodrug TH-302. Cancer Metab. 2015;3:1–13.

    Article  Google Scholar 

  165. Matsumoto S, Saito K, Takakusagi Y, Matsuo M, Munasinghe JP, Morris HD, Lizak MJ, Merkle H, Yasukawa K, Devasahayam N, Suburamanian S, Mitchell JB, Krishna MC. In vivo imaging of tumor physiological, metabolic, and redox changes in response to the anti-Angiogenic agent Sunitinib: longitudinal assessment to identify transient vascular renormalization. Antioxid Redox Signal. 2014;21(8):1145–55.

    Article  Google Scholar 

  166. Saito K, Matsumoto S, Yasui H, Devasahayam N, Subramanian S, Munasinghe JP, Vyomesh P, Silvio Gutkind J, Mitchell JB, Krishna MC. Longitudinal imaging studies of tumor microenvironment in mice treated with the MTOR inhibitor Rapamycin. PLoS One. 2012;7(11):e49456.

    Article  ADS  Google Scholar 

  167. Naz S, Kishimoto S, Mitchell JB, Krishna MC. Imaging metabolic processes to predict radiation responses. Semin Radiat Oncol. 2019;29(1):81–9.

    Article  Google Scholar 

  168. Kishimoto S, Matsumoto K-I, Saito K, Enomoto A, Matsumoto S, Mitchell J, Devasahayam N, Krishna MC. Pulsed EPR imaging: applications in the studies of tumor physiology. Antioxid Redox Signal. 2018;28(15):1378–93.

    Article  Google Scholar 

  169. Neveu MA, De Preter G, Marchand V, Bol A, Brender JR, Saito K, Kishimoto S, Porporato PE, Sonveaux P, Grégoire V, Feron O, Jordan BF, Krishna MC, Gallez B. Multimodality imaging identifies distinct metabolic profiles in vitro and in vivo. Neoplasia. 2016;18(12):742–52.

    Article  Google Scholar 

  170. Matsumoto S, Saito K, Hironobu Y, Douglas Morris H, Munasinghe JP, Lizak M, Merkle H, Ardenkjaer-Larsen JH, Choudhuri R, Devasahayam N, Subramanian S, Koretsky AP, Mitchell JB, Krishna MC. EPR oxygen imaging and hyperpolarized 13C MRI of pyruvate metabolism as noninvasive biomarkers of tumor treatment response to a glycolysis inhibitor 3-Bromopyruvate. Magn Reson Med. 2013;69(5):1443–50.

    Article  Google Scholar 

  171. Saito K, Matsumoto S, Takakusagi Y, Matsuo M, Morris HD, Lizak MJ, Munasinghe JP, Devasahayam N, Subramanian S, Mitchell JB, Krishna MC. 13C-MR spectroscopic imaging with hyperpolarized [1-13C]pyruvate detects early response to radiotherapy in SCC tumors and HT-29 tumors. Clin Cancer Res. 2015;21(22):5073–81.

    Article  Google Scholar 

  172. Hyodo F, Soule BP, Matsumoto K-i, Matusmoto S, John A, Hyodo E, Sowers AL, Krishna MC, Mitchell JB, John A. Assessment of tissue redox status using metabolic responsive contrast agents and magnetic resonance imaging. J Pharm Pharmacol. 2008c;60(8):1049–60.

    Article  Google Scholar 

  173. Utsumi H, Muto E, Masuda S, Hamada A. In vivo ESR measurement of free radicals in whole mice. Biochem Biophys Res Commun. 1990;172(3):1342.

    Article  Google Scholar 

  174. Utsumi H, Yamada K-i I. In vivo electron spin resonance-computed tomography/Nitroxyl probe technique for non-invasive analysis of oxidative injuries. Arch Biochem Biophys. 2003;416(1):1–8.

    Article  Google Scholar 

  175. Emoto MC, Matsuoka Y, Yamada K, Sato-Akaba H, Fujii HG. Non-invasive imaging of the levels and effects of glutathione on the redox status of mouse brain using electron paramagnetic resonance imaging. Biochem Biophys Res Commun. 2017;485(4):802–6.

    Article  Google Scholar 

  176. Hyodo F, Matsumoto K-I, Matsumoto A, Mitchell JB, Krishna MC. Probing the intracellular redox status of tumors with magnetic resonance imaging and redox-sensitive contrast agents. Cancer Res. 2006;66(20):9921–8.

    Article  Google Scholar 

  177. Tun X, Ichikawa K, Yamada K-I, Mutsumoto Y, Utsumi H, Yasukawa K, Oda F, Kanbe T, Shigemi R. In vivo imaging of the intra- and extracellular redox status in rat stomach with indomethacin-induced gastric ulcers using Overhauser-enhanced magnetic resonance imaging. Antioxid Redox Signal. 2018;8:1–44.

    Google Scholar 

  178. Davis RM, Matsumoto S, Bernardo M, Sowers A, Matsumoto K-I, Krishna MC, Mitchell JB. Magnetic resonance imaging of organic contrast agents in mice: capturing the whole-body redox landscape. Free Radic Biol Med. 2011a;50(3):459–68.

    Article  Google Scholar 

  179. Matsumoto K-i, Mitchell JB, Krishna MC. Comparative studies with EPR and MRI on the in vivo tissue redox status estimation using redox-sensitive Nitroxyl probes: influence of the choice of the region of interest. Free Radic Res. 2018;5762:1–8.

    Google Scholar 

  180. Hyodo F, Davis RM, Hyodo E, Matsumoto S, Krishna MC, Mitchell JB. The relationship between tissue oxygenation and redox status using magnetic resonance imaging. Int J Oncol. 2012;41(6):2103–8.

    Article  Google Scholar 

  181. Takeshita K, Kawaguchi K, Fujii-Aikawa K, Ueno M, Okazaki S, Ono M, Krishna MC, Kuppusamy P, Ozawa T, Ikota N. Heterogeneity of regional redox status and relation of the redox status to oxygenation in a tumor model, evaluated using electron paramagnetic resonance imaging. Cancer Res. 2010;70(10):4133–40.

    Article  Google Scholar 

  182. Kubota H, Komarov DA, Yasui H, Matsumoto S, Inanami O, Kirilyuk IA, Khramtsov VV, Hirata H. Feasibility of in vivo three-dimensional mapping using Dicarboxy-PROXYL and CW-EPR-based single-point imaging. MAGMA. 2017;30(3):291–8.

    Article  Google Scholar 

  183. Davis RM, Sowers AL, Degraff W, Bernardo M, Krishna MC, Mitchell JB. A novel Nitroxide is an effective brain redox imaging contrast agent and in vivo Radioprotector. Free Radic Biol. 2011b;51(3):780–90.

    Article  Google Scholar 

  184. Emoto MC, Sato-Akaba H, Hirata H, Fujii HG. Dynamic changes in the distribution and time course of blood–brain barrier-Permeative Nitroxides in the mouse head with EPR imaging: visualization of blood flow in a mouse model of ischemia. Free Radic Biol Med. 2014;74:222–8.

    Article  Google Scholar 

  185. Fujii H, Sato-Akaba H, Kawanishi K, Hirata H. Mapping of redox status in a brain-disease mouse model by three-dimensional EPR imaging. Magn Reson Med. 2011;65(1):295–303.

    Article  Google Scholar 

  186. Yordanov AT, Yamada K-i, Krishna MC, Russo A, Yoo J, English S, Mitchell JB, Brechbiel MW. Acyl-protected Hydroxylamines as spin label generators for EPR brain imaging. J Med Chem. 2002;45(11):2283–8.

    Article  Google Scholar 

  187. Meredith P, Sarna T. The physical and chemical properties of Eumelanin. Pigment Cell Res. 2006;19(6):572–94.

    Article  Google Scholar 

  188. Glass K, Ito S, Wilby PR, Sota T, Atsushi N, Russell Bowers C, Vinther J, Dutta S, Summons R, Briggs DEG, Wakamatsu K, Simon JD. Direct chemical evidence for Eumelanin pigment from the Jurassic period. Proc Natl Acad Sci U S A. 2012;109(26):10218–23.

    Article  ADS  Google Scholar 

  189. Commoner B, Townsend J, Pake GW. Free radicals in biological materials. Nature. 1954;174:689–91.

    Article  ADS  Google Scholar 

  190. Lukiewicz S, Pilas B. A new method of measuring oxygenation in pigmented tumors growing in situ. P. 65 in III European workshop on melanin pigmentation. Prague, Czech: Charles University; 1981.

    Google Scholar 

  191. Berliner LJ, Fujii H, Wan X, Lukiewicz SJ. Feasibility study of imaging a living murine tumor by electron paramagnetic resonance. Magn Reson Med. 1987;4(4):380–4.

    Article  Google Scholar 

  192. Katsuda H, Kobayashi T, Saito H, Matsunaga T, Ikeya M. Electron spin resonance imaging of mouse B16 melanoma. Chem Pharm Bull. 1990;38(10):2838–40.

    Article  Google Scholar 

  193. Vanea E, Charlier N, Dewever J, Dinguizli M, Feron O, Baurain J-F, Gallez B. Molecular electron paramagnetic resonance imaging of melanin in melanomas: a proof-of-concept. NMR Biomed. 2008;21(3):296–300.

    Article  Google Scholar 

  194. Godechal Q, Gallez B. The contribution of electron paramagnetic resonance to melanoma research. J Skin Cancer. 2011;2011:273280.

    Article  Google Scholar 

  195. Godechal Q, Leveque P, Marot L, Baurain JF, Gallez B. Optimization of EPR imaging for visualization of human skin melanoma in various stages of invasion. Exp Dermatol. 2012;21(5):341–6.

    Article  Google Scholar 

  196. Godechal Q, Ghanem GE, Cook MG, Bernard G, Ghanem E, Cook G, Gallez B. Electron paramagnetic resonance spectrometry and imaging in melanomas: comparison between pigmented and nonpigmented human malignant melanomas. Mol Imaging. 2013;12(4):218–23.

    Article  Google Scholar 

  197. Godechal Q, Mignion L, Karroum O, Magat J, Danhier P, Morandini R, Ghanem GE, Leveque P, Gallez B. Influence of paramagnetic melanin on the MRI contrast in melanoma: a combined high-field (11.7 T) MRI and EPR study. Contr Media Mol Imag. 2014;9(2):154–60.

    Article  Google Scholar 

  198. Fan Q, Cheng K, Hu X, Ma X, Zhang R, Yang M, Lu X, Xing L, Huang W, Gambhir SS, Cheng Z. Transferring biomarker into molecular probe: melanin nanoparticle as a naturally active platform for multimodality imaging. J Am Chem Soc. 2014;136(43):15185–94.

    Article  Google Scholar 

  199. Nakagawa K, Minakawa S, Sawamura D, Hara H. Characterization of melanin radicals in paraffin-embedded malignant melanoma and nevus Pigmentosus using X-band EPR and EPR imaging. Anal Sci. 2017;33(12):1357–61.

    Article  Google Scholar 

  200. Hyodo F, Naganuma T, Eto H, Murata M, Utsumi H, Matsuo M. In vivo melanoma imaging based on dynamic nuclear polarization enhancement in melanin pigment of living mice using in vivo dynamic nuclear polarization magnetic resonance imaging. Free Radic Biol Med. 2019;134:99–105.

    Article  Google Scholar 

  201. Utsumi H, Hyodo F. Free radical imaging using in vivo dynamic nuclear polarization-MRI, vol. 564. 1st ed. New York: Elsevier Inc.; 2015.

    Google Scholar 

  202. Al Khatib M, Harir M, Costa J, Baratto MC, Schiavo I, Trabalzini L, Pollini S, Rossolini GM, Basosi R, Pogni R. Spectroscopic characterization of natural melanin from a Streptomyces Cyaneofuscatus strain and comparison with melanin enzymatically synthesized by Tyrosinase and Laccase. Molecules. 2018;23(8):E1916.

    Article  Google Scholar 

  203. Pustelny K, Bielanska J, Plonka PM, Rosen GM, Elas M. In vivo spin trapping of nitric oxide from animal tumors. Nitric Oxide. 2007;16(2):202–8.

    Article  Google Scholar 

  204. Towner R, Smith N. Vivo and in situ detection of macromolecular free radicals using Immuno-spin trapping and molecular MRI. Antioxid Redox Signal. 2017;28(15):187.

    Google Scholar 

  205. Bézière N, Decroos C, Mkhitaryan K, Kish E, Richard F, Bigot-Marchand S, Durand S, Cloppet F, Chauvet C, Corvol M-T, Rannou F, Xu-Li Y, Mansuy D, Peyrot F, Frapart Y-M. First combined in vivo X-ray tomography and high-resolution molecular electron paramagnetic resonance (EPR) imaging of the mouse knee joint taking into account the disappearance kinetics of the EPR probe. Mol Imaging. 2012;11(3):220–8.

    Article  Google Scholar 

  206. Nakagawa K, Epel B. Location of radical species in a black pepper seed investigated by CW EPR and 9 GHz EPR-imaging. Spectrochim Acta A Mol Biomol Spectrosc. 2014;131:342–6.

    Article  ADS  Google Scholar 

  207. Nakagawa K, Epel B. Investigation of the distribution of stable paramagnetic species in an apple seed using X-band EPR and EPR imaging. J Oleo Sci. 2017;66(3):315–9.

    Article  Google Scholar 

  208. Shin CS, Dunnam CR, Borbat PP, Dzikovski B, Barth ED, Halpern HJ, Freed JH. ESR microscopy for biological and biomedical applications. Nanosci Nanotech Lett. 2011;3(4):561–7.

    Article  Google Scholar 

  209. Hashem M, Weiler-Sagie M, Kuppusamy P, Neufeld G, Neeman M, Blank A. Electron spin resonance microscopic imaging of oxygen concentration in cancer spheroids. J Magn Reson. 2015;256:77–85.

    Article  ADS  Google Scholar 

  210. Lilledahl MB, Gustafsson H, Ellingsen PG, Zachrisson H, Hallbeck M, Hagen VS, Kildemo M, Lindgren M. Combined imaging of oxidative stress and microscopic structure reveals new features in human atherosclerotic plaques. J Biomed Opt. 2015;20(2):020503.

    Article  Google Scholar 

  211. Matsumoto K-i, Subramanian S, Murugesan R, Mitchell JB, Krishna MC. Spatially resolved biologic information from in vivo EPRI, OMRI, and MRI. Antioxid Redox Signal. 2007;9(8):1125–41.

    Article  Google Scholar 

  212. Gonet M, Epel B, Elas M. Data processing of 3D and 4D in-vivo electron paramagnetic resonance imaging co-registered with ultrasound. 3D printing as a registration tool. Comput Electr Eng. 2019;74:130–7.

    Article  Google Scholar 

  213. Tseytlin M, Stolin A, Guggilapu P, Bobko A, Khramtsov V, Tseytlin O, Raylman 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):1–18.

    Article  Google Scholar 

  214. Eto H, Hyodo F, Kosem N, Kobayashi R, Yasukawa K, Nakao M, Kiniwa M, Utsumi H. Redox imaging of skeletal muscle using in vivo DNP-MRI and its application to an animal model of local inflammation. Free Radic Biol Med. 2015;89:1097–104.

    Article  Google Scholar 

  215. Hyodo F, Murugesan R, Matsumoto K-i, Hyodo E, Subramanian S, Mitchell JB, Krishna MC. Monitoring redox-sensitive paramagnetic contrast agent by EPRI, OMRI and MRI. J Magn Reson. 2008b;190(1):105–12.

    Article  ADS  Google Scholar 

  216. Matsumoto S, Yasui H, Batra S, Kinoshita Y, Bernardo M, Munasinghe JP, Utsumi H, Choudhuri R, Devasahayam N, Subramanian S, Mitchell JB, Krishna MC. Simultaneous imaging of tumor oxygenation and microvascular permeability using Overhauser enhanced MRI. Proc Natl Acad Sci U S A. 2009;106(42):17898–903.

    Article  ADS  Google Scholar 

  217. Ahn K-H, Scott G, Stang P, Conolly S, Hristov D. Multiparametric imaging of tumor oxygenation, redox status, and anatomical structure using Overhauser-enhanced MRI-Prepolarized MRI system. Magn Reson Med. 2011;65(5):1416–22.

    Article  Google Scholar 

  218. Ichikawa K, Yasukawa K. Imaging in vivo redox status in high spatial resolution with OMRI. Free Radic Res. 2012;46(8):1004–10.

    Article  Google Scholar 

  219. Gorodetskii AA, Eubank TD, Driesschaert B, Poncelet M, Ellis E, Khramtsov VV, Bobko AA. Oxygen-induced leakage of spin polarization in Overhauser-enhanced magnetic resonance imaging: application for Oximetry in tumors. J Magn Reson. 2018;297:42–50.

    Article  ADS  Google Scholar 

  220. Niidome T, Chijiiwa N, Yamasaki T, Yamada K-i, Utsumi H, Mori T, Ichikawa K, Naganuma T, Niidome T, Katayama Y, Chijiiwa N. Change in Overhauser effect-enhanced MRI signal in response to UPA highly expressing in tumor. Chem Lett. 2014;43(7):999–1001.

    Article  Google Scholar 

  221. Decroos C, Li Y, Bertho G, Frapart Y, Mansuy D, Boucher J-L. Oxidation of Tris-(p-Carboxyltetrathiaaryl)methyl radical EPR probes: evidence for their oxidative decarboxylation and molecular origin of their specific ability to react with O2∗−. Chem Commun (Camb). 2009;(11):1416–8.

    Google Scholar 

  222. Dhimitruka I, Grigorieva O, Zweier JL, Khramtsov VV. Synthesis, structure, and EPR characterization of Deuterated derivatives of Finland Trityl radical. Bioorg Med Chem Lett. 2010;20(13):3946–9.

    Article  Google Scholar 

  223. Dhimitruka I, Velayutham M, Bobko AA, Khramtsov VV, Villamena FA, Hadad CM, Zweier JL. Large-scale synthesis of a persistent Trityl radical for use in biomedical EPR applications and imaging. Bioorg Med Chem Lett. 2007;17(24):6801–5.

    Article  Google Scholar 

  224. Rogozhnikova OY, Vasiliev VG, Troitskaya TI, Trukhin DV, Mikhalina TV, Halpern HJ, Tormyshev VM. Generation of Trityl radicals by Nucleophilic quenching of Tris(2,3,5,6-Tetrathiaaryl)methyl Cations and practical and convenient large-scale synthesis of persistent Tris(4-Carboxy-2,3,5,6-Tetrathiaaryl)methyl radical. Eur J Org Chem. 2013;(16):3347–55.

    Google Scholar 

  225. Tormyshev VM, Rogozhnikova OY, Bowman MK, Trukhin DV, Troitskaya TI, Vasiliev VG, Shundrin LA, Halpern HJ. 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. Eur J Org Chem. 2014;2014(2):371–80.

    Article  Google Scholar 

  226. Trukhin DV, Rogozhnikova OY, Troitskaya T, Vasiliev VG, Bowman MK, Tormyshev VM, Troitskayaa TI, Vasiliev VG, Bowman MK, Tormyshev VM. Facile and high-yielding synthesis of TAM Biradicals and Monofunctional TAM radicals. Synlett. 2015;27(6):893–9.

    Article  Google Scholar 

  227. Liu Y, Villamena FA, Zweier JL. Highly stable dendritic Trityl radicals as oxygen and pH probe. Chem Commun. 2008;1(36):4336–8.

    Article  Google Scholar 

  228. Liu W, Nie J, Tan X, Liu H, Yu N, Han G, Zhu Y, Villamena FA, Song Y, Zweier JL, Liu Y. Synthesis and characterization of PEGylated Trityl radicals: effect of PEGylation on physicochemical properties. J Org Chem. 2017;82(1):588–96.

    Article  Google Scholar 

  229. Liu Y, Villamena FA, Sun J, Wang T. Esterified Trityl radicals as intracellular oxygen probes. Free Radic Biol Med. 2009;46(7):876–83.

    Article  Google Scholar 

  230. Driesschaert B, Bobko AA, Eubank TD, Samouilov A, Khramtsov VV, Zweier JL. Poly-arginine conjugated Triarylmethyl radical as intracellular spin label. Bioorg Med Chem Lett. 2016;26(7):1742–74.

    Article  Google Scholar 

  231. Tan X, Tao S, Liu W, Rockenbauer A, Villamena FA, Zweier JL, Song Y, Liu Y. Synthesis and characterization of the Perthiatriarylmethyl radical and its dendritic derivatives with high sensitivity and selectivity to superoxide radical. Chem Eur J. 2018;24(27):6865.

    Article  Google Scholar 

  232. Driesschaert B, Bobko AA, Khramtsov V, Zweier JL. Nitro-Triarylmethyl radical as dual oxygen and superoxide probe. Cell Biochem Biophys. 2017;75(2):241–6.

    Article  Google Scholar 

  233. Liu Y, Song Y, Rockenbauer A, Sun J, Hemann C, Villamena FA, Zweier JL. Synthesis of Trityl radical-conjugated disulfide Biradicals for measurement of Thiol concentration. J Org Chem. 2011;76(10):3853–60.

    Article  Google Scholar 

  234. Charlier N, Driesschaert B, Wauthoz N, Beghein N, Préat V, Amighi K, Marchand-Brynaert J, Gallez B. Nano-emulsions of fluorinated Trityl radicals as sensors for EPR Oximetry. J Magn Reson. 2009;197(2):176–80.

    Article  ADS  Google Scholar 

  235. Dhimitruka I, Alzarie YA, Hemann C, Samouilov A, Zweier JL. Trityl radicals in Perfluorocarbon emulsions as stable, sensitive, and biocompatible Oximetry probes. Bioorg Med Chem Lett. 2016;26(23):5685–8.

    Article  Google Scholar 

  236. Lampp L, Rogozhnikova OY, Trukhin DV, Tormyshev VM, Bowman MK, Devasahayam N, Krishna MC, Mäder K, Imming P. A radical containing injectable in-situ-Oleogel and Emulgel for prolonged in-vivo oxygen measurements with CW EPR. Free Radic Biol Med. 2019;130:120–7.

    Article  Google Scholar 

  237. Meenakshisundaram G, Eteshola E, Pandian RP, Bratasz A, Lee SC, Kuppusamy P. Fabrication and physical evaluation of a polymer- encapsulated paramagnetic probe for biomedical Oximetry. Biomed Microdevices. 2009;11:773–82.

    Article  Google Scholar 

  238. Desmet CM, Tran LBA, Danhier P, Gallez B. Characterization of a clinically used charcoal suspension for in vivo EPR Oximetry. MAGMA. 2018;32(2):205–12.

    Article  Google Scholar 

  239. Kocherginsky N, Swartz HM. Nitroxide spin labels: reactions in biology and chemistry. Boca Raton: CRC Press; 1995.

    Google Scholar 

  240. Liu Y, Villamena FA, Rockenbauer A, Zweier JL. Trityl-Nitroxide Biradicals as unique molecular probes for the simultaneous measurement of redox status and oxygenation. Chem Commun (Camb). 2010a;46(4):628–30.

    Article  Google Scholar 

  241. Liu Y, Villamena FA, Song Y, Sun J, Rockenbauer A, Zweier JL. Synthesis of (14)N- and (15)N-labeled Trityl-Nitroxide Biradicals with strong spin-spin interaction and improved sensitivity to redox status and oxygen. J Org Chem. 2010;75(22):7796–802.

    Article  Google Scholar 

  242. Matsumoto K-I, Hyodo F, Matsumoto A, Koretsky AP, Sowers AL, Mitchell JB, Krishna MC. High-resolution mapping of tumor redox status by magnetic resonance imaging using Nitroxides as redox-sensitive contrast agents. Clin Cancer Res. 2006;12(8):2455–62.

    Article  Google Scholar 

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Acknowledgements

We acknowledge the support of grants from the National Science Centre OPUS No. 2015/17/B/NZ7/03005 to ME and 2018/29/B/NZ5/02954 to MKS. ME is partially supported by Horizon2020 grant no 668776. Faculty of Biochemistry, Biophysics, and Biotechnology of Jagiellonian University was a partner of the Leading National Research Center (KNOW) supported by the Ministry of Science and Higher Education., grant KNOW 35p/10/2015 to PMP.

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  1. Department of Biophysics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland

    Martyna Elas, Martyna Krzykawska-Serda, Michał Gonet, Anna Kozińska & Przemysław M. Płonka

  2. Novilet, Poznań, Poland

    Michał Gonet

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  1. Martyna Elas
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  2. Martyna Krzykawska-Serda
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Correspondence to Martyna Elas .

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  1. Department of Physics, Ewing Christian College, Prayagraj, Uttar Pradesh, India

    Ashutosh Kumar Shukla

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Elas, M., Krzykawska-Serda, M., Gonet, M., Kozińska, A., Płonka, P.M. (2019). Electron Paramagnetic Resonance Imaging-Solo and Orchestra. In: Shukla, A. (eds) Medical Imaging Methods. Springer, Singapore. https://doi.org/10.1007/978-981-13-9121-7_1

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