Dataset Information

Detection of metabolic change in glioblastoma cells after radiotherapy using hyperpolarized ¹³ C-MRI.

ABSTRACT: Dynamic nuclear polarization (DNP) of ¹³ C-labeled substrates enables the use of magnetic resonance imaging (MRI) to monitor specific enzymatic reactions in tumors and offers an opportunity to investigate these differences. In this study, DNP-MRI chemical shift imaging with hyperpolarized [1-¹³ C] pyruvate was conducted to evaluate the metabolic change in glycolytic profiles after radiation of two glioma stem-like cell-derived gliomas (GBMJ1 and NSC11) and an adherent human glioblastoma cell line (U251) in an orthotopic xenograft mouse model. The DNP-MRI showed an increase in Lac/Pyr at 6 and 16 h after irradiation (18% ± 4% and 14% ± 3%, respectively; mean ± SEM) compared with unirradiated controls in GBMJ1 tumors, whereas no significant change was observed in U251 and NSC11 tumors. Metabolomic analysis likewise showed a significant increase in lactate in GBMJ1 tumors at 16 h. An immunoblot assay showed upregulation of lactate dehydrogenase-A expression in GBMJ1 following radiation exposure, consistent with DNP-MRI and metabolomic analysis. In conclusion, our preclinical study demonstrates that the DNP-MRI technique has the potential to be a powerful diagnostic method with which to evaluate GBM tumor metabolism before and after radiation in the clinical setting.

SUBMITTER: Kawai T

PROVIDER: S-EPMC8243917 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Detection of metabolic change in glioblastoma cells after radiotherapy using hyperpolarized 13 C-MRI.

Kawai Tatsuya T Brender Jeffrey R JR Lee Jennifer A JA Kramp Tamalee T Kishimoto Shun S Krishna Murali C MC Tofilon Philip P Camphausen Kevin A KA

NMR in biomedicine 20210503 7

Dynamic nuclear polarization (DNP) of 13 C-labeled substrates enables the use of magnetic resonance imaging (MRI) to monitor specific enzymatic reactions in tumors and offers an opportunity to investigate these differences. In this study, DNP-MRI chemical shift imaging with hyperpolarized [1-13 C] pyruvate was conducted to evaluate the metabolic change in glycolytic profiles after radiation of two glioma stem-like cell-derived gliomas (GBMJ1 and NSC11) and an adherent human ...[more]

PMID: 33939204

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Project description:BackgroundHyperpolarized 13 C MRI quantitatively measures enzyme-catalyzed metabolism in cancer and metabolic diseases. Whole-abdomen imaging will permit dynamic metabolic imaging of several abdominal organs simultaneously in healthy and diseased subjects.PurposeImage hyperpolarized [1-13 C]pyruvate and products in the abdomens of healthy volunteers, overcoming challenges of motion, magnetic field variations, and spatial coverage. Compare hyperpolarized [1-13 C]pyruvate metabolism across abdominal organs of healthy volunteers.Study typeProspective technical development.SubjectsA total of 13 healthy volunteers (8 male), 21-64 years (median 36).Field strength/sequenceA 3 T. Proton: T1 -weighted spoiled gradient echo, T2 -weighted single-shot fast spin echo, multiecho fat/water imaging. Carbon-13: echo-planar spectroscopic imaging, metabolite-specific echo-planar imaging.AssessmentTransmit magnetic field was measured. Variations in main magnetic field (ΔB0 ) determined using multiecho proton acquisitions were compared to carbon-13 acquisitions. Changes in ΔB0 were measured after localized shimming. Improvements in metabolite signal-to-noise ratio were calculated. Whole-organ regions of interests were drawn over the liver, spleen, pancreas, and kidneys by a single investigator. Metabolite signals, time-to-peak, decay times, and mean first-order rate constants for pyruvate-to-lactate (kPL ) and alanine (kPA ) conversion were measured in each organ.Statistical testsLinear regression, one-sample Kolmogorov-Smirnov tests, paired t-tests, one-way ANOVA, Tukey's multiple comparisons tests. P ≤ 0.05 considered statistically significant.ResultsProton ΔB0 maps correlated with carbon-13 ΔB0 maps (slope = 0.93, y-intercept = -2.88, R2 = 0.73). Localized shimming resulted in mean frequency offset within ±25 Hz for all organs. Metabolite SNR significantly increased after denoising. Mean kPL and kPA were highest in liver, followed by pancreas, spleen, and kidneys (all comparisons with liver were significant).Data conclusionWhole-abdomen coverage with hyperpolarized carbon-13 MRI was feasible despite technical challenges. Multiecho gradient echo 1 H acquisitions accurately predicted chemical shifts observed using carbon-13 spectroscopy. Carbon-13 acquisitions benefited from local shimming. Metabolite energetics in the abdomen compiled for healthy volunteers can be used to design larger clinical trials in patients with metabolic diseases.Evidence level2 TECHNICAL EFFICACY: Stage 1.

Project description:The detection and treatment monitoring of inflammatory states remain challenging in part due to the multifactorial mechanisms of immune activation and spectrum of clinical manifestations. Currently, diagnostic strategies tend to be subjective and limited quantitative tools exist to monitor optimal treatment strategies. Pro-inflammatory M1 polarized macrophages exhibit a distinct metabolic glycolytic phenotype compared to the continuum of M2 polarization states. In the present study, the distinct metabolic phenotypes of resting and activated macrophages were successfully characterized and quantified using hyperpolarized carbon-13 (13C) labeled pyruvate and its metabolic products, i.e. lactate, as a biomarker of resting, disease and treated states. Methods: Mouse macrophage J774A.1 cells were used as a model system in an NMR compatible bioreactor to facilitate dynamic hyperpolarized 13C measurements. The glycolytic metabolism of the cells in the quiescent or resting state were compared with macrophages stimulated by lipopolysaccharide, a classical M1 activator using hyperpolarized 13C labeled pyruvate. Additionally, the activated macrophages were also treated with a non-steroidal anti-inflammatory drug to assess the changes in hyperpolarized lactate signal. The hyperpolarized lactate signals were then correlated using biochemical and molecular assays. Results: We first validated our model system of inflammatory cells by the hallmarks of M1 polarization using steady state metabolic profiling with high resolution NMR in conjunction with nitric oxide Greiss assay, enzyme activity, and mRNA expression. Subsequently, we clearly showed that the cutting edge technology of hyperpolarized 13C NMR can be used to detect elevated lactate levels in M1 polarized macrophages in comparison to control and non-steroidal anti-inflammatory drug treated M2 states. Conclusion: Hyperpolarized 13C lactate has the potential to serve as a biomarker to non-invasively detect and quantify pro-inflammatory state of immune regulatory cells and its response to therapy.

Dataset Information

Detection of metabolic change in glioblastoma cells after radiotherapy using hyperpolarized ¹³ C-MRI.

Publications

Detection of metabolic change in glioblastoma cells after radiotherapy using hyperpolarized <sup>13</sup> C-MRI.

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