Hyperpolarized 13C-pyruvate MRI detects real-time metabolic flux in prostate cancer metastases to bone and liver: a clinical feasibility study.

BackgroundHyperpolarized (HP) 13C-pyruvate MRI is a stable-isotope molecular imaging modality that provides real-time assessment of the rate of metabolism through glycolytic pathways in human prostate cancer. Heretofore this imaging modality has been successfully utilized in prostate cancer only in localized disease. This pilot clinical study investigated the feasibility and imaging performance of HP 13C-pyruvate MR metabolic imaging in prostate cancer patients with metastases to the bone and/or viscera.MethodsSix patients who had metastatic castration-resistant prostate cancer were recruited. Carbon-13 MR examination were conducted on a clinical 3T MRI following injection of 250 mM hyperpolarized 13C-pyruvate, where pyruvate-to-lactate conversion rate (kPL) was calculated. Paired metastatic tumor biopsy was performed with histopathological and RNA-seq analyses.ResultsWe observed a high rate of glycolytic metabolism in prostate cancer metastases, with a mean kPL value of 0.020 ± 0.006 (s-1) and 0.026 ± 0.000 (s-1) in bone (N = 4) and liver (N = 2) metastases, respectively. Overall, high kPL showed concordance with biopsy-confirmed high-grade prostate cancer including neuroendocrine differentiation in one case. Interval decrease of kPL from 0.026 at baseline to 0.015 (s-1) was observed in a liver metastasis 2 months after the initiation of taxane plus platinum chemotherapy. RNA-seq found higher levels of the lactate dehydrogenase isoform A (Ldha,15.7 ± 0.7) expression relative to the dominant isoform of pyruvate dehydrogenase (Pdha1, 12.8 ± 0.9).ConclusionsHP 13C-pyruvate MRI can detect real-time glycolytic metabolism within prostate cancer metastases, and can measure changes in quantitative kPL values following treatment response at early time points. This first feasibility study supports future clinical studies of HP 13C-pyruvate MRI in the setting of advanced prostate cancer

Elevated Tumor Lactate and Efflux in High-grade Prostate Cancer demonstrated by Hyperpolarized 13C Magnetic Resonance Spectroscopy of Prostate Tissue Slice Cultures.

Non-invasive assessment of the biological aggressiveness of prostate cancer (PCa) is needed for men with localized disease. Hyperpolarized (HP) 13C magnetic resonance (MR) spectroscopy is a powerful approach to image metabolism, specifically the conversion of HP [1-13C]pyruvate to [1-13C]lactate, catalyzed by lactate dehydrogenase (LDH). Significant increase in tumor lactate was measured in high-grade PCa relative to benign and low-grade cancer, suggesting that HP 13C MR could distinguish low-risk (Gleason score ≤3 + 4) from high-risk (Gleason score ≥4 + 3) PCa. To test this and the ability of HP 13C MR to detect these metabolic changes, we cultured prostate tissues in an MR-compatible bioreactor under continuous perfusion. 31P spectra demonstrated good viability and dynamic HP 13C-pyruvate MR demonstrated that high-grade PCa had significantly increased lactate efflux compared to low-grade PCa and benign prostate tissue. These metabolic differences are attributed to significantly increased LDHA expression and LDH activity, as well as significantly increased monocarboxylate transporter 4 (MCT4) expression in high- versus low- grade PCa. Moreover, lactate efflux, LDH activity, and MCT4 expression were not different between low-grade PCa and benign prostate tissues, indicating that these metabolic alterations are specific for high-grade disease. These distinctive metabolic alterations can be used to differentiate high-grade PCa from low-grade PCa and benign prostate tissues using clinically translatable HP [1-13C]pyruvate MR

In vivo metabolic imaging of Traumatic Brain Injury.

Complex alterations in cerebral energetic metabolism arise after traumatic brain injury (TBI). To date, methods allowing for metabolic evaluation are highly invasive, limiting our understanding of metabolic impairments associated with TBI pathogenesis. We investigated whether 13C MRSI of hyperpolarized (HP) [1-13C] pyruvate, a non-invasive metabolic imaging method, could detect metabolic changes in controlled cortical injury (CCI) mice (n = 57). Our results show that HP [1-13C] lactate-to-pyruvate ratios were increased in the injured cortex at acute (12/24 hours) and sub-acute (7 days) time points after injury, in line with decreased pyruvate dehydrogenase (PDH) activity, suggesting impairment of the oxidative phosphorylation pathway. We then used the colony-stimulating factor-1 receptor inhibitor PLX5622 to deplete brain resident microglia prior to and after CCI, in order to confirm that modulations of HP [1-13C] lactate-to-pyruvate ratios were linked to microglial activation. Despite CCI, the HP [1-13C] lactate-to-pyruvate ratio at the injury cortex of microglia-depleted animals at 7 days post-injury remained unchanged compared to contralateral hemisphere, and PDH activity was not affected. Altogether, our results demonstrate that HP [1-13C] pyruvate has great potential for in vivo non-invasive detection of cerebral metabolism post-TBI, providing a new tool to monitor the effect of therapies targeting microglia/macrophages activation after TBI

Rapidly signal‐enhanced metabolites for atomic scale monitoring of living cells with magnetic resonance

Nuclear magnetic resonance (NMR) is widely applied from analytics to biomedicine although it is an inherently insensitive phenomenon. Overcoming sensitivity challenges is key to further broaden the applicability of NMR and, for example, improve medical diagnostics. Here, we present a rapid strategy to enhance the signals of 13C-labelled metabolites with para-hydrogen and, in particular, 13C-pyruvate, an important molecule for the energy metabolism. We succeeded to obtain an average of 27 % 13C polarization of 1-13C-pyruvate in water which allowed us to introduce two applications for studying cellular metabolism. Firstly, we demonstrate that the metabolism of 1-13C-pyruvate can serve as a biomarker in cellular models of Parkinson's disease and, secondly, we introduce the opportunity to combine real-time metabolic analysis with protein structure determination in the same cells. Based on the here presented results, we envision the use of our approach for future biomedical studies to detect diseases

Cryogen-Free dissolution Dynamic Nuclear Polarization polarizer operating at 3.35 T, 6.70 T and 10.1 T

Purpose: A novel dissolution dynamic nuclear polarization (dDNP) polarizer platform is presented. The polarizer meets a number of key requirements for in vitro, pre-clinical and clinical applications. Method: It uses no liquid cryogens, operates in continuous mode, accommodates a wide range of sample sizes up to and including those required for human studies, and is fully automated. Results: It offers a wide operational window both in terms of magnetic field, up to 10.1 T, and temperature, from room temperature down to 1.3 K. The polarizer delivers a 13C liquid state polarization for [1-13C]pyruvate of 70%. The build-up time constant in the solid state is approx. 1200 s (20 min), allowing a sample throughput of at least one sample per hour including sample loading and dissolution. Conclusion: We confirm the previously reported strong field dependence in the range 3.35 to 6.7 T, but see no further increase in polarization when increasing the magnetic field strength to 10.1 T for [1-13C]pyruvate and trityl. Using a custom dry magnet, cold head and recondensing, closed-cycle cooling system, combined with a modular DNP probe, automation and fluid handling systems; we have designed a unique dDNP system with unrivalled flexibility and performance.Comment: 16 pages, 8 figure

Magn Reson Med

Purpose:Noninvasive imaging with hyperpolarized pyruvate can capture in vivo cardiac metabolism. For proper quantification of the metabolites and optimization of imaging parameters, understanding MR characteristics such as T2*s of the hyperpolarized signals is critical. This study is to measure in vivo cardiac T2*s of hyperpolarized [1-13C]pyruvate and the products in rodents and humans.Methods:A dynamic 13C multi-echo spiral imaging sequence that acquires [13C]bicarbonate, [1-13C]lactate, and [1-13C]pyruvate images in an interleaved manner was implemented for a clinical 3T system. T2* of each metabolite was calculated from the multi-echo images by fitting the signal decay of each region of interest mono-exponentially. The performance of measuring T2* using the sequence was validated using a 13C phantom, then with rodents following a bolus injection of hyperpolarized [1-13C]pyruvate. In humans, T2* of each metabolite was calculated for left ventricle (LV), right ventricle (RV) and myocardium.Results:Cardiac T2*s of hyperpolarized [1-13C]pyruvate, [1-13C]lactate and [13C]bicarbonate in rodents were measured as 24.9 \ub1 5.0, 16.4 \ub1 4.7, and 16.9 \ub1 3.4 ms, respectively. In humans, T2* of [1-13C]pyruvate was 108.7 \ub1 22.6 ms in LV and 129.4 \ub1 8.9 ms in RV. T2* of [1-13C]lactate was 40.9 \ub1 8.3, 44.2 \ub1 5.5, and 43.7 \ub1 9.0 ms in LV, RV and myocardium, respectively. T2* of [13C]bicarbonate in myocardium was 64.4 \ub1 2.5 ms. The measurements were reproducible and consistent over time after the pyruvate injection.Conclusions:The proposed metabolite-selective multi-echo spiral imaging sequence reliably measures in vivo cardiac T2*s of hyperpolarized [1-13C]pyruvate and products.RP180404/Cancer Prevention and Research Institute of Texas/S10 RR029119/RR/NCRR NIH HHSUnited States/UTD 1907789/UT Dallas Collaborative Biomedical Research Award/S10 OD018468/OD/NIH HHSUnited States/P41 EB015908/EB/NIBIB NIH HHSUnited States/The Texas Institute for Brain Injury and Repair/R01 NS107409/NS/NINDS NIH HHSUnited States/S10 OD018468/CD/ODCDC CDC HHSUnited States/I-2009-20190330/The Welch Foundation/P41 EB015908/EB/NIBIB NIH HHSUnited States/R01 NS107409/NS/NINDS NIH HHSUnited States/S10 OD018468/CD/ODCDC CDC HHSUnited States/S10 RR029119/RR/NCRR NIH HHSUnited States/2022-09-01T00:00:00Z33821504PMC82124211188

Magnetic Resonance Imaging Is More Sensitive Than PET for Detecting Treatment-Induced Cell Death-Dependent Changes in Glycolysis.

Metabolic imaging has been widely used to measure the early responses of tumors to treatment. Here, we assess the abilities of PET measurement of [18F]FDG uptake and MRI measurement of hyperpolarized [1-13C]pyruvate metabolism to detect early changes in glycolysis following treatment-induced cell death in human colorectal (Colo205) and breast adenocarcinoma (MDA-MB-231) xenografts in mice. A TRAIL agonist that binds to human but not mouse cells induced tumor-selective cell death. Tumor glycolysis was assessed by injecting [1,6-13C2]glucose and measuring 13C-labeled metabolites in tumor extracts. Injection of hyperpolarized [1-13C]pyruvate induced rapid reduction in lactate labeling. This decrease, which correlated with an increase in histologic markers of cell death and preceded decrease in tumor volume, reflected reduced flux from glucose to lactate and decreased lactate concentration. However, [18F]FDG uptake and phosphorylation were maintained following treatment, which has been attributed previously to increased [18F]FDG uptake by infiltrating immune cells. Quantification of [18F]FDG uptake in flow-sorted tumor and immune cells from disaggregated tumors identified CD11b+/CD45+ macrophages as the most [18F]FDG-avid cell type present, yet they represented <5% of the cells present in the tumors and could not explain the failure of [18F]FDG-PET to detect treatment response. MRI measurement of hyperpolarized [1-13C]pyruvate metabolism is therefore a more sensitive marker of the early decreases in glycolytic flux that occur following cell death than PET measurements of [18F]FDG uptake. SIGNIFICANCE: These findings demonstrate superior sensitivity of MRI measurement of hyperpolarized [1-13C]pyruvate metabolism versus PET measurement of 18F-FDG uptake for detecting early changes in glycolysis following treatment-induced tumor cell death