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Evaluations of Tumor Acidosis Within In Vivo Tumor Models Using Parametric Maps Generated with AcidoCEST MRI

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We aimed to develop pixelwise maps of tumor acidosis to aid in evaluating extracellular tumor pH (pHe) in cancer biology.


MCF-7 and MDA-MB-231 mouse models were imaged during a longitudinal study. AcidoCEST MRI and a series of image processing methods were used to produce parametric maps of tumor pHe, and tumor pHe was also measured with a pH microsensor.


Sufficient contrast-to-noise for producing pHe maps was achieved by using standard image processing methods. A comparison of pHe values measured with acidoCEST MRI and a pH microsensor showed that acidoCEST MRI measured tumor pHe with an accuracy of 0.034 pH units. The MCF-7 tumor model was found to be more acidic compared to the MDA-MB-231 tumor model. The pHe was not related to tumor size during the longitudinal study.


These results show that acidoCEST MRI can create pixelwise tumor pHe maps of mouse models of cancer.

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  1. Gillies R, Raghunand N, Karczmar G, Bhujwalla ZM (2002) MRI of the tumor microenvironment. J Magn Reson Im 16:430–50

    Article  Google Scholar 

  2. Warburg O (1956) On the origin of cancer cells. Science 123:309–14

    Article  CAS  PubMed  Google Scholar 

  3. Mahoney BP, Raghunand N, Baggett B, Gillies RJ (2003) Tumor acidity, ion trapping and chemotherapeutics. I. Acid pH affects the distribution of chemotherapeutic agents in vitro. Biochem Pharmacol 66:1207–18

    Article  CAS  PubMed  Google Scholar 

  4. Raghunand N, Mahoney BP, Gillies RJ (2003) Tumor acidity, ion trapping and chemotherapeutics. II. pH-dependent partition coefficients predict importance of ion trapping on pharmacokinetics of weakly basic chemotherapeutic agents. Biochem Pharmacol 66:1219–29

    Article  CAS  PubMed  Google Scholar 

  5. Ashby BS (1966) pH studies in human malignant tumours. Lancet 288:312–5

    Article  Google Scholar 

  6. Martin GR, Jain RK (1994) Noninvasive measurement of interstitial pH profiles in normal and neoplastic tissue using fluorescence ratio imaging microscopy. Cancer Res 54:5670–4

    CAS  PubMed  Google Scholar 

  7. Dellian M, Helmlinger G, Yuan F, Jain RK (1996) Fluorescence ratio imaging of interstitial pH in solid tumours: effect of glucose on spatial and temporal gradients. Br J Cancer 74:1206–15

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Khramtsov VV, Grigor’ev IA, Foster MA et al (2000) Biological applications of spin pH probes. Cell Mol Biol 46:1361–74

    CAS  PubMed  Google Scholar 

  9. Gallagher FA, Kettunen MI, Day SE et al (2008) Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate. Nature 453:940–3

    Article  CAS  PubMed  Google Scholar 

  10. Vāvere AL, Biddlecombe GB, Spees WM et al (2009) A novel technology for the imaging of acidic prostate tumors by positron emission tomography. Cancer Res 69:4510–6

    Article  PubMed  Google Scholar 

  11. Visser EP, Disselhorst JA, Brom M et al (2009) Spatial resolution and sensitivity of the Inveon small-animal PET scanner. J Nucl Med 50:139–47

    Article  PubMed  Google Scholar 

  12. Gillies RJ, Liu Z, Bhujwalla Z (1994) 31P-MRS measurements of extracellular pH of tumors using 3-aminopropylphosphonate. Am J Physiol 267:C195–203

    CAS  PubMed  Google Scholar 

  13. Martinez GV, Zhang X, Garcia-Martin ML et al (2011) Imaging the extracellular pH of tumors by MRI after injection of a single cocktail of T1 and T2 contrast agents. NMR Biomed 24:1380–91

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Yoo B, Pagel MD (2008) An overview of responsive MRI contrast agents for molecular imaging. Front Biosci 13:1733–52

    Article  CAS  PubMed  Google Scholar 

  15. Hingorani DV, Randtke EA, Pagel MD (2013) A catalyCEST MRI contrast agent that detects the enzyme-catalyzed creation of a covalent bond. J Am Chem Soc 135:6396–8

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Liepinsch E, Otting G (1996) Proton exchange rates from amino acid side chains—implications for image contrast. Magn Reson Med 35:30–42

    Article  Google Scholar 

  17. Ward KM, Balaban RS (2000) Determination of pH using water protons and chemical exchange dependent saturation transfer (CEST). Magn Reson Med 44:799–802

    Article  CAS  PubMed  Google Scholar 

  18. Aime S, Barge A, Delli Castelli D et al (2002) Paramagnetic lanthanide(III) complexes as pH-sensitive chemical exchange saturation transfer (CEST) contrast agents for MRI applications. Magn Reson Med 47:639–48

    Article  CAS  PubMed  Google Scholar 

  19. Liu G, Li Y, Sheth VR, Pagel MD (2012) Imaging in vivo extracellular pH with a single PARACEST MRI contrast agent. Mol Imaging 11:47–57

    PubMed  Google Scholar 

  20. Longo DL, Dastrù W, Digilio G et al (2011) Iopamidol as a responsive MRI-chemical exchange saturation transfer contrast agent for pH mapping of kidneys: in vivo studies in mice at 7 T. Magn Reson Med 65:202–11

    Article  CAS  PubMed  Google Scholar 

  21. Chen LQ, Howison CM, Jeffery JJ et al (2013) Evaluations of extracellular pH within in vivo tumors using acidoCEST MRI. Magn Reson Med. doi:10.1002/mrm.25053

    Google Scholar 

  22. Stancanello J, Terreno E, Castelli DD et al (2008) Development and validation of a smoothing-splines-based correction method for improving the analysis of CEST-MR images. Contrast Media Mol Imaging 3:136–49

    Article  CAS  PubMed  Google Scholar 

  23. Liu G, Ali M, Yoo B et al (2009) PARACEST MRI with improved temporal resolution. Magn Reson Med 61:399–408

    Article  PubMed  Google Scholar 

  24. Bhujwalla ZM, Artemov D, Ballesteros P et al (2002) Combined vascular and extracellular pH imaging of solid tumors. NMR Biomed 15:114–9

    Article  CAS  PubMed  Google Scholar 

  25. Ocak I, Baluk P, Barrett T et al (2007) The biologic basis of in vivo angiogenesis imaging. Frontiers Biosci 12:3601–16

    Article  CAS  Google Scholar 

  26. Liu G, Song X, Chan KWY, McMahon MT (2013) Nuts and bolts of chemical exchange saturation transfer MRI. NMR Biomed 26:810–28

    Article  PubMed Central  PubMed  Google Scholar 

  27. Sun PZ, Benner T, Kumar A, Sorensen AG (2008) Investigation of optimizing and translating pH-sensitive pulsed-chemical exchange saturation transfer (CEST) imaging to a 3 T clinical scanner. Magn Reson Med 60:834–41

    Article  PubMed  Google Scholar 

  28. Zhou J, Blakeley JO, Hua J et al (2008) Practical data acquisition method for human brain tumor amide proton transfer (APT) imaging. Magn Reson Med 60:842–9

    Article  PubMed Central  PubMed  Google Scholar 

  29. Chiche J, Ilc K, Laferriere J et al (2009) Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res 69:358–68

    Article  CAS  PubMed  Google Scholar 

  30. Gillies RJ, Gatenby RA (2007) Hypoxia and adaptive landscapes in the evolution of carcinogenesis. Cancer Met Rev 26:311–7

    Article  CAS  Google Scholar 

  31. Jingjing L, Feng F, Zhengyu J (2014) Cancer diagnosis and treatment guidance: role of MRI and MRI probes in the era of molecular imaging. Curr Pharma Biotech 14:714–22

    Article  Google Scholar 

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This research was supported by the Phoenix Friends of the Arizona Cancer Center, the Community Foundation of Southern Arizona, and the Better Than Ever Program, R01CA167183-01 and P50 CA95060. L.Q.C. was supported through the Anne Rita Monahan Foundation. K.M.J. was supported through the Cardiovascular Biomedical Engineering Training Grant, T32HL007955. B.M. was supported through the NIH Minority Access to Research Careers grant T34 GM008718. The authors acknowledge the assistance of the Experimental Mouse Shared Services of the University of Arizona Cancer Center.

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Correspondence to Mark D. Pagel.

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Chen, L.Q., Randtke, E.A., Jones, K.M. et al. Evaluations of Tumor Acidosis Within In Vivo Tumor Models Using Parametric Maps Generated with AcidoCEST MRI. Mol Imaging Biol 17, 488–496 (2015).

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