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Concurrent Longitudinal EPR Monitoring of Tissue Oxygenation, Acidosis, and Reducing Capacity in Mouse Xenograft Tumor Models

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Abstract

Tissue oxygenation, extracellular acidity, and tissue reducing capacity are among crucial parameters of tumor microenvironment (TME) of significant importance for tumor pathophysiology. In this paper, we demonstrate the complementary application of particulate lithium octa-n-butoxy-naphthalocyanine and soluble nitroxide paramagnetic probes for monitoring of these TME parameters using electron paramagnetic resonance (EPR) technique. Two different types of therapeutic interventions were studied: hypothermia and systemic administration of metabolically active drug. In summary, the results demonstrate the utility of EPR technique for non-invasive concurrent longitudinal monitoring of physiologically relevant chemical parameters of TME in mouse xenograft tumor models, including that under therapeutic intervention.

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References

  1. Tatum, J. L., Kelloff, G. J., Gillies, R. J., Arbeit, J. M., Brown, J. M., Chao, K. S., et al. (2006). Hypoxia: Importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy. International Journal of Radiation Biology, 82(10), 699–757.

    Article  CAS  PubMed  Google Scholar 

  2. Warburg, O. (1956). On the origin of cancer cells. Science, 123(3191), 309–314.

    Article  CAS  PubMed  Google Scholar 

  3. Matsumoto, K., Hyodo, F., Matsumoto, A., Koretsky, A. P., Sowers, A. L., Mitchell, J. B., & Krishna, M. C. (2006). High-resolution mapping of tumor redox status by magnetic resonance imaging using nitroxides as redox-sensitive contrast agents. Clinical Cancer Research, 12(8), 2455–2462.

    Article  CAS  PubMed  Google Scholar 

  4. Khramtsov, V. V., & Gillies, R. J. (2014). Janus-Faced tumor microenvironment and redox. Antioxidants and Redox Signaling, 21(5), 723–729.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bailey, K. M., Wojtkowiak, J. W., Cornnell, H. H., Ribeiro, M. C., Balagurunathan, Y., Hashim, A. I., & Gillies, R. J. (2014). Mechanisms of buffer therapy resistance. Neoplasia (New York, N.Y.), 16(4), 354–364.e3.

    Article  CAS  Google Scholar 

  6. Ribeiro, Md L C, Silva, A. S., Bailey, K. M., Kumar, N. B., Sellers, T. A., Gatenby, R. A., et al. (2012). Buffer therapy for cancer. Journal of Nutrition and Food Sciences, 2, 6.

    PubMed  PubMed Central  Google Scholar 

  7. Robey, I. F., Baggett, B. K., Kirkpatrick, N. D., Roe, D. J., Dosescu, J., Sloane, B. F., et al. (2009). Bicarbonate increases tumor pH and inhibits spontaneous metastases. Cancer Research, 69(6), 2260–2268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bobko, A. A., Eubank, T. D., Voorhees, J. L., Efimova, O. V., Kirilyuk, I. A., Petryakov, S., et al. (2012). In vivo monitoring of pH, redox status, and glutathione using l-band EPR for assessment of therapeutic effectiveness in solid tumors. Magnetic Resonance in Medicine, 67(6), 1827–1836.

    Article  CAS  PubMed  Google Scholar 

  9. Jain, R. K. (2013). Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. Journal of Clinical Oncology, 31(17), 2205–2218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fukumura, D., & Jain, R. K. (2007). Tumor microvasculature and microenvironment: Targets for anti-angiogenesis and normalization. Microvascular Research, 74(2–3), 72–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Denko, N. C. (2014). Hypoxic regulation of metabolism offers new opportunities for anticancer therapy. Expert Review of Anticancer Therapy, 14(9), 979–981.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Roshchupkina, G. I., Bobko, A. A., Bratasz, A., Reznikov, V. A., Kuppusamy, P., & Khramtsov, V. V. (2008). In vivo EPR measurement of glutathione in tumor-bearing mice using improved disulfide biradical probe. Free Radical Biology and Medicine, 45(3), 312–320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chen, D., Bobko, A. A., Gross, A. C., Evans, R., Marsh, C. B., Khramtsov, V. V., et al. (2014). Involvement of tumor macrophage HIFs in chemotherapy effectiveness: mathematical modeling of oxygen, pH, and glutathione. PLos One, 9(10), e107511.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Dhimitruka, I., Bobko, A. A., Eubank, T. D., Komarov, D. A., & Khramtsov, V. V. (2013). Phosphonated trityl probes for concurrent in vivo tissue oxygen and pH monitoring using electron paramagnetic resonance-based techniques. Journal of the American Chemical Society, 135(15), 5904–5910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bratasz, A., Pandian, R. P., Deng, Y., Petryakov, S., Grecula, J. C., Gupta, N., & Kuppusamy, P. (2007). In vivo imaging of changes in tumor oxygenation during growth and after Treatment. Magnetic Resonance in Medicine, 57(5), 950–959.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Eubank, T. D., Roberts, R. D., Khan, M., Curry, J. M., Nuovo, G. J., Kuppusamy, P., & Marsh, C. B. (2009). GM-CSF inhibits breast cancer growth and metastasis by invoking an anti-angiogenic program in tumor-educated macrophages. Cancer Research, 69(5), 2133–2140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pandian, R. P., Dolgos, M., Marginean, C., Woodward, P. M., Hammel, P. C., Manoharan, P. T., & Kuppusamy, P. (2009). Molecular packing and magnetic properties of lithium naphthalocyanine crystals: hollow channels enabling permeability and paramagnetic sensitivity to molecular oxygen. Journal of Materials Chemistry, 19(24), 4138–4147.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Goodwin, J., Yachi, K., Nagane, M., Yasui, H., Miyake, Y., Inanami, O., et al. (2014). In vivo tumour extracellular pH monitoring using electron paramagnetic resonance: the effect of X-ray irradiation. NMR in Biomedicine, 27(4), 453–458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Samouilov, A., Efimova, O. V., Bobko, A. A., Sun, Z., Petryakov, S., Eubank, T. D., et al. (2014). In vivo proton-electron double-resonance imaging of extracellular tumor pH using an advanced nitroxide probe. Analytical Chemistry, 86(2), 1045–1052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nias, A. H., Perry, P., Photiou, A., & Reghebi, K. (1986). Effect of hypothermia on radiosensitization. International Journal of Radiation Biology and Related Studies in Physics, Chemistry and Medicine, 50(2), 241–251.

    Article  CAS  Google Scholar 

  21. Nias, A. H., Perry, P. M., & Photiou, A. R. (1988). Modulating the oxygen tension in tumours by hypothermia and hyperbaric oxygen. Journal of the Royal Society of Medicine, 81(11), 633–636.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Sealy, R., Harrison, G. G., Morrell, D., Korrubel, J., Gregory, A., Barry, L., et al. (1986). A feasibility study of a new approach to clinical radiosensitisation: Hypothermia and hyperbaric oxygen in combination with pharmacological vasodilatation. British Journal of Radiology, 59(707), 1093–1098.

    Article  CAS  PubMed  Google Scholar 

  23. Evans, G. R., Gherardini, G., Gurlek, A., Langstein, H., Joly, G. A., Cromeens, D. M., et al. (1997). Drug-induced vasodilation in an in vitro and in vivo study: The effects of nicardipine, papaverine, and lidocaine on the rabbit carotid artery. Plastic and Reconstructive Surgery, 100(6), 1475–1481.

    Article  CAS  PubMed  Google Scholar 

  24. Shinozawa, S., Araki, Y., & Oda, T. (1980). Papaverine-induced changes in physiological characters of Ehrlich ascites tumor cell membranes. Physiological Chemistry and Physics, 12(4), 291–297.

    CAS  PubMed  Google Scholar 

  25. Pandian, R. P., Parinandi, N. L., Ilangovan, G., Zweier, J. L., & Kuppusamy, P. (2003). Novel particulate spin probe for targeted determination of oxygen in cells and tissues. Free Radical Biology and Medicine, 35(9), 1138–1148.

    Article  CAS  PubMed  Google Scholar 

  26. Serajuddin, A. T., & Rosoff, M. (1984). pH-Solubility profile of papaverine hydrochloride and its relationship to the dissolution rate of sustained-release pellets. Journal of Pharmaceutical Sciences, 73(9), 1203–1208.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was partially supported by NIH grants CA194013, CA192064, and U54GM104942.

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Correspondence to Valery V. Khramtsov.

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Bobko, A.A., Evans, J., Denko, N.C. et al. Concurrent Longitudinal EPR Monitoring of Tissue Oxygenation, Acidosis, and Reducing Capacity in Mouse Xenograft Tumor Models. Cell Biochem Biophys 75, 247–253 (2017). https://doi.org/10.1007/s12013-016-0733-x

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  • DOI: https://doi.org/10.1007/s12013-016-0733-x

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