Separation of extra- and intracellular metabolites using hyperpolarized 13C diffusion weighted MR

Koelsch, Bertram L.; Sriram, Renuka; Keshari, Kayvan R.; Swisher, Christine Leon; Criekinge, Mark Van; Sukumar, Subramaniam; Vigneron, Daniel B.; Wang, Zhen J.; Larson, Peder E. Z.; Kurhanewicz, John

doi:10.1016/j.jmr.2016.07.002

Cited by 21 publications

(39 citation statements)

References 44 publications

(70 reference statements)

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“…The increased rate of decay of the lactate signal, which could not be explained by the accelerated decay of the [1‐ 13 C]pyruvate polarization, demonstrated that lactate labeled intracellularly had been released into the extracellular space. The export of hyperpolarized 13 C‐labeled lactate has been observed previously in studies on tumor cells in vitro . Further evidence for the release of labeled lactate in the tumor came from the effects of the inhibition of MCT activity with 4‐CIN.…”

Section: Discussionmentioning

confidence: 91%

Analysis of ¹³C and ¹⁴C labeling in pyruvate and lactate in tumor and blood of lymphoma‐bearing mice injected with ¹³C‐ and ¹⁴C‐labeled pyruvate

et al. 2018

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Measurements of hyperpolarized 13C label exchange between injected [1‐13C]pyruvate and the endogenous tumor lactate pool can give an apparent first‐order rate constant for the exchange. The determination of the isotope flux, however, requires an estimate of the labeled pyruvate concentration in the tumor. This was achieved here by measurement of the tumor uptake of [1‐14C]pyruvate, which showed that <2% of the injected pyruvate reached the tumor site. Multiplication of this estimated labeled pyruvate concentration in the tumor with the apparent first‐order rate constant for hyperpolarized 13C label exchange gave an isotope flux that showed good agreement with a flux determined directly by the injection of non‐polarized [3‐13C]pyruvate, rapid excision of the tumor after 30 s and measurement of 13C‐labeled lactate concentrations in tumor extracts. The distribution of labeled lactate between intra‐ and extracellular compartments and the blood pool was investigated by imaging, by measurement of the labeled lactate concentration in blood and tumor, and by examination of the effects of a gadolinium contrast agent and a lactate transport inhibitor on the intensity of the hyperpolarized [1‐13C]lactate signal. These measurements showed that there was significant export of labeled lactate from the tumor, but that labeled lactate in the blood pool produced by the injection of hyperpolarized [1‐13C]pyruvate showed only relatively low levels of polarization. This study shows that measurements of hyperpolarized 13C label exchange between pyruvate and lactate in a murine tumor model can provide an estimate of the true isotope flux if the concentration of labeled pyruvate that reaches the tumor can be determined.

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Section: Discussionmentioning

confidence: 91%

Analysis of ¹³C and ¹⁴C labeling in pyruvate and lactate in tumor and blood of lymphoma‐bearing mice injected with ¹³C‐ and ¹⁴C‐labeled pyruvate

et al. 2018

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“…[78] As a result, diffusion weighted imaging (DWI) can be used to differentiate between intra- and extra-cellular HP metabolites, giving further insight into the metabolic processes and cellular transporters at play.…”

Section: Physical and Biological Properties Of Polarized Agentsmentioning

confidence: 99%

Magnetic resonance imaging with hyperpolarized agents: methods and applications

et al. 2017

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In the past decade, hyperpolarized (HP) contrast agents have been under active development for MRI applications to address the twin challenges of functional and quantitative imaging. Both HP helium (3He) and xenon (129Xe) gases have reached the stage where they are under study in clinical research. HP 129Xe, in particular, is poised for larger scale clinical research to investigate asthma, chronic obstructive pulmonary disease, and fibrotic lung diseases. With advances in polarizer technology and unique capabilities for imaging of 129Xe gas exchange into lung tissue and blood, HP 129Xe MRI is attracting new attention. In parallel, HP 13C and 15N MRI methods have steadily advanced in a wide range of pre-clinical research applications for imaging metabolism in various cancers and cardiac disease. The HP [1-13C] pyruvate MRI technique, in particular, has undergone phase I trials in prostate cancer and is poised for investigational new drug trials at multiple institutions in cancer and cardiac applications. This review treats the methodology behind both HP gases and HP 13C and 15N liquid state agents. Gas and liquid phase HP agents share similar technologies for achieving non-equilibrium polarization outside the field of the MRI scanner, strategies for image data acquisition, and translational challenges in moving from pre-clinical to clinical research. To cover the wide array of methods and applications, this review is organized by numerical section into 1) a brief introduction, 2) the physical and biological properties of the most common polarized agents with a brief summary of applications and methods of polarization, 3) methods for image acquisition and reconstruction specific to improving data acquisition efficiency for HP MRI, 4) the main physical properties that enable unique measures of physiology or metabolic pathways, followed by a more detailed review of the literature describing the use of HP agents to study 5) metabolic pathways in cancer and cardiac disease and 6) lung function in both pre-clinical and clinical research studies, 7) some future directions and challenges, and 8) an overall summary.

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“…Since angiogenesis is a hallmark of cancer, analogous phenomena need to be considered in patient studies . For instance, if a measured AIF is to be extracted for modeling, differential flow suppression between tumor and blood may impact the accuracy of k PL estimation …”

Section: Discussionmentioning

confidence: 99%

Pulse sequence considerations for quantification of pyruvate‐to‐lactate conversion k_PL in hyperpolarized ¹³C imaging

et al. 2019

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Hyperpolarized 13C MRI takes advantage of the unprecedented 50 000‐fold signal‐to‐noise ratio enhancement to interrogate cancer metabolism in patients and animals. It can measure the pyruvate‐to‐lactate conversion rate, kPL, a metabolic biomarker of cancer aggressiveness and progression. Therefore, it is crucial to evaluate kPL reliably. In this study, three sequence components and parameters that modulate kPL estimation were identified and investigated in model simulations and through in vivo animal studies using several specifically designed pulse sequences. These factors included a magnetization spoiling effect due to RF pulses, a crusher gradient‐induced flow suppression, and intrinsic image weightings due to relaxation. Simulation showed that the RF‐induced magnetization spoiling can be substantially improved using an inputless kPL fitting. In vivo studies found a significantly higher apparent kPL with an additional gradient that leads to flow suppression (kPL,FID‐Delay,Crush/kPL,FID‐Delay = 1.37 ± 0.33, P < 0.01, N = 6), which agrees with simulation outcomes (12.5% kPL error with Δv = 40 cm/s), indicating that the gradients predominantly suppressed flowing pyruvate spins. Significantly lower kPL was found using a delayed free induction decay (FID) acquisition versus a minimum‐TE version (kPL,FID‐Delay/kPL,FID = 0.67 ± 0.09, P < 0.01, N = 5), and the lactate peak had broader linewidth than pyruvate (Δωlactate/Δωpyruvate = 1.32 ± 0.07, P < 0.000 01, N = 13). This illustrated that lactate's T2*, shorter than that of pyruvate, can affect calculated kPL values. We also found that an FID sequence yielded significantly lower kPL versus a double spin‐echo sequence that includes spin‐echo spoiling, flow suppression from crusher gradients, and more T2 weighting (kPL,DSE/kPL,FID = 2.40 ± 0.98, P < 0.0001, N = 7). In summary, the pulse sequence, as well as its interaction with pharmacokinetics and the tissue microenvironment, can impact and be optimized for the measurement of kPL. The data acquisition and analysis pipelines can work synergistically to provide more robust and reproducible kPL measures for future preclinical and clinical studies.

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Separation of extra- and intracellular metabolites using hyperpolarized 13C diffusion weighted MR

Cited by 21 publications

References 44 publications

Analysis of ¹³C and ¹⁴C labeling in pyruvate and lactate in tumor and blood of lymphoma‐bearing mice injected with ¹³C‐ and ¹⁴C‐labeled pyruvate

Analysis of ¹³C and ¹⁴C labeling in pyruvate and lactate in tumor and blood of lymphoma‐bearing mice injected with ¹³C‐ and ¹⁴C‐labeled pyruvate

Magnetic resonance imaging with hyperpolarized agents: methods and applications

Pulse sequence considerations for quantification of pyruvate‐to‐lactate conversion k_PL in hyperpolarized ¹³C imaging

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Separation of extra- and intracellular metabolites using hyperpolarized 13C diffusion weighted MR

Cited by 21 publications

References 44 publications

Analysis of 13C and 14C labeling in pyruvate and lactate in tumor and blood of lymphoma‐bearing mice injected with 13C‐ and 14C‐labeled pyruvate

Analysis of 13C and 14C labeling in pyruvate and lactate in tumor and blood of lymphoma‐bearing mice injected with 13C‐ and 14C‐labeled pyruvate

Magnetic resonance imaging with hyperpolarized agents: methods and applications

Pulse sequence considerations for quantification of pyruvate‐to‐lactate conversion kPL in hyperpolarized 13C imaging

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Analysis of ¹³C and ¹⁴C labeling in pyruvate and lactate in tumor and blood of lymphoma‐bearing mice injected with ¹³C‐ and ¹⁴C‐labeled pyruvate

Analysis of ¹³C and ¹⁴C labeling in pyruvate and lactate in tumor and blood of lymphoma‐bearing mice injected with ¹³C‐ and ¹⁴C‐labeled pyruvate

Pulse sequence considerations for quantification of pyruvate‐to‐lactate conversion k_PL in hyperpolarized ¹³C imaging