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Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate

Nature volume 453, pages 940–943 (2008)Cite this article

Abstract

As alterations in tissue pH underlie many pathological processes, the capability to image tissue pH in the clinic could offer new ways of detecting disease and response to treatment1. Dynamic nuclear polarization is an emerging technique for substantially increasing the sensitivity of magnetic resonance imaging experiments2,3. Here we show that tissue pH can be imaged in vivo from the ratio of the signal intensities of hyperpolarized bicarbonate (H13CO3-) and 13CO2 following intravenous injection of hyperpolarized H13CO3-. The technique was demonstrated in a mouse tumour model, which showed that the average tumour interstitial pH was significantly lower than the surrounding tissue. Given that bicarbonate is an endogenous molecule that can be infused in relatively high concentrations into patients4, we propose that this technique could be used clinically to image pathological processes that are associated with alterations in tissue pH, such as cancer, ischaemia and inflammation.

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Figure 1: Imaging of pH in vitro.
Figure 2: Measurements of tumour pH in vivo.
Figure 3: Demonstration that H 13 CO 3 and 13 CO 2 are in rapid chemical exchange in the reaction catalysed by carbonic anhydrase.
Figure 4: Imaging of tumour pH in vivo.

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Acknowledgements

We thank R. McLaughlin and T. Witney for comments on the manuscript and S. Vowler for help with statistics. F.A.G. is in receipt of a Cancer Research UK and Royal College of Radiologists (UK) clinical research training fellowship, and S.E.D. a National Institutes of Health-Cambridge studentship. The work was supported by a Cancer Research UK Programme grant (to K.M.B.; C197/A3514). The polarizer and related materials were provided by GE Healthcare.

Author Contributions F.A.G. and S.E.D. operated the polarizer and J.H.A.-L. and K.G. provided advice on its use. M.I.K. conducted the MRI experiments and D.-E.H. prepared the animals. M.I.K. and F.A.G. analysed the data. R.I.Z., P.R.J., M.K. and M.H.L. devised the bicarbonate formulation. F.A.G. and K.M.B. wrote the paper and K.M.B. devised and organized the study.

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Author notes

  1. Sam E. Day

    Present address: Present address: Laboratory of Functional and Molecular Imaging, National Institute for Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1065, USA.,

  2. Ferdia A. Gallagher and Mikko I. Kettunen: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK ,

    Ferdia A. Gallagher, Mikko I. Kettunen, Sam E. Day, De-En Hu & Kevin M. Brindle

  2. Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK,

    Ferdia A. Gallagher, Mikko I. Kettunen, Sam E. Day, De-En Hu & Kevin M. Brindle

  3. Department of Radiology, University of Cambridge, Level 5, Box 219, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK,

    Ferdia A. Gallagher

  4. GE Healthcare, The Grove Centre GC/18, White Lion Road, Amersham HP7 9LL, UK ,

    Jan Henrik Ardenkjær-Larsen

  5. Imagnia AB, Box 8225, SE-200 41 Malmö, Sweden ,

    René in ‘t Zandt, Pernille R. Jensen, Magnus Karlsson, Klaes Golman & Mathilde H. Lerche

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Correspondence to Kevin M. Brindle.

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Competing interests

The hyperpolarizer is on loan from GE Healthcare and is the subject of a research agreement between the University of Cambridge, Cancer Research UK and GE Healthcare. GE Healthcare also supplied the trityl radical used in the hyperpolarization process. Imagnia AB has supplied information about formulations for polarizing bicarbonate.

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Gallagher, F., Kettunen, M., Day, S. et al. Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate. Nature 453, 940–943 (2008). https://doi.org/10.1038/nature07017

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