Electron resonance imaging

Electron resonance imaging (ERI) is a preclinical imaging method, together with positron emission tomography (PET), computed tomography scan (CT scan), magnetic resonance imaging (MRI), and other techniques. ERI is dedicated to imaging small laboratory animals and its unique feature is the ability to detect free radicals.[1][2] This technique could also be used for other purposes such as material science, quality of food, etc.[3]

For in vivo imaging purposes, ERI is a minimally invasive method. It requires an intravenous injection of the external substances, called spin probes[4] (usually nitroxide or triarylmethyl compounds). The main advantage of ERI modality is the ability of mapping the tissue microenvironment parameters e.g. oxygen partial pressure (pO2), redox status, oxidative stress, thiol concentration, pH, inorganic phosphorus, viscosity, etc.[5][6][7][8] ERI is commonly used to research in the areas of oncology, neurodegenerative disorders and drug development.

Origin

ERI is a preclinical application of electron paramagnetic resonance imaging (EPRI).[9][2] The term "ERI" was introduced in order to distinguish a commercial device from EPRI devices that are normally used in the academic domain.

Electron paramagnetic resonance (EPR) spectroscopy is dedicated to the research of substances with unpaired electrons. It was first introduced in 1944, approximately the same time as the similar phenomenon - nuclear magnetic resonance (NMR).[10][11] Owing to hardware and software limitations, EPR was not developing as rapidly as NMR. This led to a huge gap between these two methods. Therefore, to underline a breakthrough in preclinical imaging, by presenting EPRI as a complementary method to the present ones, the term "ERI" was introduced.[5][6]

In vivo applications

Oxygen imaging

One of the many possible applications of ERI is the ability to measure the absolute value of oxygen.[12] The width of the EPR signal from oxygen-sensitive spin probes depends linearly from the oxygen concentration in tissues.[13] Therefore, the information about the oxygen value is collected directly from the examined areas. Oxygen mapping is commonly used for planning and improving the effectiveness of radiotherapy treatments.[14][15] Trityl spin probes are the most suitable for the use in oxygen imaging.[16][17]

Redox status and oxidative stress

The unique property of ERI is the ability to track reactive oxygen species (ROS).[18] Those particles are versatile and are constantly generated in living organisms. ROS plays a special role in oxidative and reduction mechanisms. In a normal physiological state, the number of ROS is controlled by antioxidants. Factors that increase the number of ROS (e.g. ionizing radiation, metal ions, etc.) will cause their overproduction. This state leads to an imbalance between those particles and is therefore called the oxidative stress.[19][20]

Pharmacokinetics

ERI allows for dynamic measurements and 3D tracking of the spin probe.[6] In this case, the term "dynamics" refers to the fast repetition of the imaging process, and the tracking of changes in the signal intensity for each location that is imaged over time. Owing to the high temporal resolution and sensitivity of the method, it is possible to distinguish both the inflow and outflow phases of the spin probe, the bio-distribution, and the time to reach a maximum concentration of the spin probe.[6]

Spin probes

In natural conditions, free radicals are characterised with an extremely short lifespan, so in order to capture the EPR signal, an external molecule with a stable free radical must be delivered. Usually it happens by injection into the animal's body. There are two main classes of spin probes used for imaging: nitroxide and triarylmethyl (TAM, trityl) radicals.

Nitroxide radicals are sensitive to oxygen concentration, pH, thiol concentrations, viscosity and polarity.[2] The issue with these type of spin probes is their fast reduction, which sometimes leads to loss of the EPR signal. Triarylmethyl radicals are characterised by a far longer lifespan, and an increased stability towards reducing and oxidising biological agents. They are perfect for measuring the oxygen concentration, pH, thiol concentrations, inorganic phosphate and redox status.

Although, the aforementioned spin probes are the most popular choice, there are many more that can be used in ERI. One of many examples is melanin – a polymeric pigment that contains a mixture of eumelanin and pheomelanin.[21][22] This is the only substance that occurs in natural conditions and allows for the registration of the EPR signal, without the need to deliver extraneous spin probes.

References
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  2. Eaton GR, Eaton SS. Introduction to EPR imaging using magnetic-field gradients. Concepts Magn Reson. 1995;7(1):49–67.
  3. Kotecha, Mrignayani, Boris Epel, Sriram Ravindran, Deborah Dorcemus, Syam Nukavarapu, and Howard Halpern. (2018). "Noninvasive Absolute Electron Paramagnetic Resonance Oxygen Imaging for the Assessment of Tissue Graft Oxygenation". Tissue Engineering Part C: Methods. 24 (1): 14–19. doi:10.1089/ten.TEC.2017.0236. PMC 5756934. PMID 28844179.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  8. Lawrence J. Berliner, Narasimham L. Parinandi (2020). Measuring oxidants and oxidative stress in biological systems, Biological Magnetic Resonance 34 (2020). Biological Magnetic Resonance. Vol. 34. doi:10.1007/978-3-030-47318-1. ISBN 978-3-030-47317-4. PMID 33411425. S2CID 221071036.
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  13. Halpern, H. J., C. Yu, M. Peric, E. Barth, D. J. Grdina, and B. A. Teicher. (20 December 1994). "Oxymetry Deep in Tissues with Low-Frequency Electron Paramagnetic Resonance." Proceedings of the National Academy of Sciences of the United States of America 91, no. 26 (December 20, 1994): 13047–51". Proceedings of the National Academy of Sciences. 91 (26): 13047–13051. doi:10.1073/pnas.91.26.13047. PMC 45578. PMID 7809170.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. Elas M, et al. EPR oxygen images predict tumor control by a 50% tumor control radiation dose. Cancer Res. 2013 Sep 1;73(17):5328-35.
  15. Epel, Boris, Matthew C. Maggio, Eugene D. Barth, Richard C. Miller, Charles A. Pelizzari, Martyna Krzykawska-Serda, Subramanian V. Sundramoorthy. (March 2019). "Oxygen-Guided Radiation Therapy." International Journal of Radiation Oncology, Biology, Physics 103, no. 4 (15 2019): 977–84". International Journal of Radiation Oncology, Biology, Physics. 103 (4): 977–984. doi:10.1016/j.ijrobp.2018.10.041. PMC 6478443. PMID 30414912.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. Tormyshev, Victor M., Alexander M. Genaev, Georgy E. Sal’nikov, Olga Yu Rogozhnikova, Tatiana I. Troitskaya, Dmitry V. Trukhin, Victor I. Mamatyuk, Dmitry S. Fadeev, and Howard J. Halpern. (2012). "Triarylmethanols Bearing Bulky Aryl Groups and the NOESY/EXSY Experimental Observation of Two-Ring-Flip Mechanism for Helicity Reversal of Molecular Propellers." European Journal of Organic Chemistry 2012, no. 3 (January 2012)". European Journal of Organic Chemistry. 2012 (3): 623–629. doi:10.1002/ejoc.201101243. PMC 3843112. PMID 24294110.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  18. Emoto MC, Matsuoka Y, Yamada KI, Sato-Akaba H4, 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 Apr 15;485(4):802-806.
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  20. Fujii H, Sato-Akaba H, Kawanishi K, Hirata H. Mapping of redox status in a brain-disease mouse model by three-dimensional EPR imaging: EPR Imaging of Nitroxides in Mouse Head. Magn Reson Med. 2011;65(1):295–303.
  21. 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.
  22. Charlier N, Desoil M, Gossuin Y, Gillis P, Gallez B. Electron Paramagnetic Resonance Imaging of Melanin in Honey Bee. Cell Biochem Biophys. 2020
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