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Using Hyperpolarized NMR to Understand Biochemistry from Cells to Humans

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Dynamic Hyperpolarized Nuclear Magnetic Resonance

Part of the book series: Handbook of Modern Biophysics ((HBBT))

Abstract

This chapter describes the development and preclinical testing of hyperpolarized 13C-labeled probes and the required steps necessary for their translation to patient studies, with an emphasis on the preclinical platforms and techniques necessary to achieve this goal. The chapter starts with a description of nuclear magnetic resonance (NMR) spectroscopic and biochemical techniques used for studying metabolism in human cells and tissues in order to identify pathways that could be probed using new hyperpolarized 13C-labeled probes, followed by a description of the in vitro and in vivo preclinical testing and optimization of new hyperpolarized probes along with a discussion of some of the biochemical questions that have been investigated using preclinical hyperpolarized 13C MRI. The role preclinical studies have played in the clinical translation of [1-13C]pyruvate and how they provided the motivation for several ongoing applications to pathologies in patients is also described. Finally, the role of preclinical studies for developing the best approaches for analyzing the dynamic hyperpolarized MR data and providing an understanding of the underlying biochemistry of the pathologies being studied is described. After reading this chapter and completing the associated problem set, the reader should have a basic knowledge of how hyperpolarized 13C MRI probes are developed, optimized, and used to investigate biomedical questions.

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Abbreviations

ATP:

Adenosine triose phosphate

DNP:

Dynamic nuclear polarization

FDA:

Food and Drug Administration

FDG:

Fluoro deoxy glucose

GMP:

Good manufacturing practice

HP:

Hyperpolarization

HR-MAS:

High resolution-magic angle spinning

IND:

Investigational new drug

LDH:

Lactate dehydrogenase

NCI:

National Cancer Institute

PBS:

Phosphate buffered saline

PDH:

Pyruvate dehydrogenase

PET:

Positron emission tomography

RF:

Radio frequency

SNR:

Signal to noise ratio

TR:

Repetition time

TRAMP:

Transgenic adenocarcinoma of the murine prostate

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Further Reading

  • Bottomley, P.A., Griffiths, J.R.: Handbook of magnetic resonance spectroscopy in vivo: MRS theory, practice and applications. Wiley, Chichester (2016)

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Acknowledgements

Grants/People: We would like to acknowledge the funding sources P41 EB013598 (NIH) and PC160630 (DoD) and the members of the Hyperpolarized MRI Technology Resource Center and the Pre-Clinical MR Imaging and Spectroscopy Core.

Author information

Authors and Affiliations

  1. Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA

    Renuka Sriram, Celine Baligand & John Kurhanewicz

Authors
  1. Renuka Sriram
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  2. Celine Baligand
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  3. John Kurhanewicz
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Corresponding author

Correspondence to John Kurhanewicz .

Editor information

Editors and Affiliations

  1. Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, CA, USA

    Thomas Jue

  2. Diagnostic Radiology and Nuclear Medicine, University of Maryland, Baltimore, Baltimore, MD, USA

    Dirk Mayer

Problems

Problems

  1. 1.

    Hyperpolarized [1-13C] dehydroascorbate (DHA) is a probe used to interrogate the redox status of the cell. In in vivo systems, the cyclic regeneration of the reactive oxygen species and its reductants serve to continuously reduce and oxidize ascorbic acid as shown below.

    figure a

    What are all the components that will be required to estimate the apparent zero-order reaction rate of hyperpolarized DHA in a simple enzyme solution?

  2. 2.

    In order to test the hypothesis that increased cellular production of lactate and its efflux occur in renal cell cancers is associated with cancer aggressiveness, we designed a cell culture bioreactor study using UOK262 cells, which were established from a highly aggressive metastatic RCC. The figure below shows the bioreactor set-up containing UOK262 cells encapsulated in alginate beads with continuous flow of media and continuous infusion of hyperpolarized agent over a 90 s time period.

    figure b

    The figure on the left is a schematic of the cells encapsulated in alginate microspheres being perfused in a bioreactor. The figure to the right represents hyperpolarized 13C spectra under two different conditions from the bioreactor. The bottom 13C spectra in the figure (below) is of alginate microspheres devoid of cells, infused with co-hyperpolarized [1-13C]lactate and [1-13C]pyruvate. Only one peak was observed for the [1-13C]lactate signal (bottom spectra). While two peaks were observed in the alginate microspheres with UOK262 cells when infused with HP [1-13C]pyruvate only (top spectra). The top inset (2.5× magnification, with black arrows) clearly shows that there are two distinct peaks for lactate (although the chemical shift difference is very small—0.031 ± 0.0005 ppm), where the chemical shift of the downfield peak coincides with that of the signal of lactate in empty alginate microspheres. A series of studies were performed to try to identify the origin of these two lactate resonances.

    1. (a)

      Increasing the cell density in the bioreactor resulted in an increase in the upfield lactate peak.

    2. (b)

      Stopping the flow of media in the bioreactor resulted in an increase in the downfield resonance.

    3. (c)

      The downfield lactate resonance decreased when the cells were pretreated with DIDS, a small molecule blocker of MCT4 transporter.

      Based on the above hyperpolarized 13C studies, what could be the explanation for the two lactate peaks observed when hyperpolarized [1-13C]lactate is metabolically produced by UOK262 cells after injection of hyperpolarized [1-13C]pyruvate? Please make sure you explain all of the experimental findings.

  3. 3.

    What are some biological challenges with live animal imaging studies involving hyperpolarized MRI and interpreting the subsequent metabolites?

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Sriram, R., Baligand, C., Kurhanewicz, J. (2021). Using Hyperpolarized NMR to Understand Biochemistry from Cells to Humans. In: Jue, T., Mayer, D. (eds) Dynamic Hyperpolarized Nuclear Magnetic Resonance. Handbook of Modern Biophysics. Springer, Cham. https://doi.org/10.1007/978-3-030-55043-1_6

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