Reynolds, S. orcid.org/0000-0002-6463-8471, Kazan, S.M., Anton, A. orcid.org/0000-0002-1356-4513 et al. (5 more authors) (2022) Kinetic modelling of dissolution dynamic nuclear polarisation 13C magnetic resonance spectroscopy data for analysis of pyruvate delivery and fate in tumours. NMR in Biomedicine, 35 (5). e4650. ISSN 0952-3480
Abstract
Dissolution dynamic nuclear polarisation (dDNP) of 13C-labelled pyruvate in magnetic resonance spectroscopy/imaging (MRS/MRSI) has the potential for monitoring tumour progression and treatment response. Pyruvate delivery, its metabolism to lactate and efflux were investigated in rat P22 sarcomas following simultaneous intravenous administration of hyperpolarised 13C-labelled pyruvate (13C1-pyruvate) and urea (13C-urea), a nonmetabolised marker. A general mathematical model of pyruvate-lactate exchange, incorporating an arterial input function (AIF), enabled the losses of pyruvate and lactate from tumour to be estimated, in addition to the clearance rate of pyruvate signal from blood into tumour, Kip, and the forward and reverse fractional rate constants for pyruvate-lactate signal exchange, kpl and klp. An analogous model was developed for urea, enabling estimation of urea tumour losses and the blood clearance parameter, Kiu. A spectral fitting procedure to blood time-course data proved superior to assuming a gamma-variate form for the AIFs. Mean arterial blood pressure marginally correlated with clearance rates. Kiu equalled Kip, indicating equivalent permeability of the tumour vasculature to urea and pyruvate. Fractional loss rate constants due to effluxes of pyruvate, lactate and urea from tumour tissue into blood (kpo, klo and kuo, respectively) indicated that T1s and the average flip angle, θ, obtained from arterial blood were poor surrogates for these parameters in tumour tissue. A precursor-product model, using the tumour pyruvate signal time-course as the input for the corresponding lactate signal time-course, was modified to account for the observed delay between them. The corresponding fractional rate constant, kavail, most likely reflected heterogeneous tumour microcirculation. Loss parameters, estimated from this model with different TRs, provided a lower limit on the estimates of tumour T1 for lactate and urea. The results do not support use of hyperpolarised urea for providing information on the tumour microcirculation over and above what can be obtained from pyruvate alone. The results also highlight the need for rigorous processes controlling signal quantitation, if absolute estimations of biological parameters are required.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/4.0/) which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
Keywords: | dynamic nuclear polarisation; mathematical modelling; P22 rat sarcoma; precursor-product; pyruvate metabolism; rate constant; tumour microcirculation; urea |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Infection and Immunity (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 06 Dec 2021 10:06 |
Last Modified: | 01 Jul 2022 15:30 |
Status: | Published |
Publisher: | Wiley |
Refereed: | Yes |
Identification Number: | 10.1002/nbm.4650 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:181205 |