Lau, A. Z. | Search bioRxiv

bioRxiv2021

Deuterium Magnetic Resonance Spectroscopy of Early Treatment-Induced Changes in Tumour Lactate in vitro

Elevated production of lactate is a key characteristic of aberrant tumour cell metabolism and can be non-invasively measured as an early marker of tumour response using deuterium (2H) magnetic resonance spectroscopy (MRS). Following treatment, changes in the 2H-labeled lactate signal could identify tumour cell death or impaired metabolic function, which precede morphological changes conventionally used to assess tumour response. In this work, the association between apoptotic cell death, extracellular lactate concentration, and early treatment-induced changes in the 2H-labeled lactate signal was established in an in vitro tumour model. Experiments were conducted at 7 T on acute myeloid leukemia cells which had been treated with 10 {micro}g/mL of the chemotherapeutic agent cisplatin. At 24 and 48 hours after cisplatin treatment, the cells were injected with 20 mM of [6,6-2H2]glucose and scanned over two hours using a two-dimensional 2H MR spectroscopic imaging sequence. The resulting signals from 2H-labeled glucose, lactate, and water were quantified using a spectral fitting algorithm implemented on the OXford Spectroscopy Analysis (OXSA) MATLAB toolbox. After scanning, the cells were processed for histological stains (TUNEL [terminal deoxynucleotidyl transferase UTP nick end labeling] and H&E [hematoxylin and eosin]) to assess apoptotic area fraction and cell morphology respectively, while a colorimetric assay was used to measure extracellular lactate concentrations in the supernatant. Significantly lower levels of 2H-labeled lactate were observed in the 48-hour treated cells compared to the untreated and 24-hour treated cells, and these changes were significantly correlated with an increase in apoptotic fraction and a decrease in extracellular lactate. By establishing the biological processes associated with treatment-induced changes in the 2H-labeled lactate signal, these findings suggest that 2H MRS of lactate may be valuable in evaluating early tumour response.

biophysics↗

bioRxiv2020

Cardiac metabolic imaging using hyperpolarized lactate as a substrate

Hyperpolarized [1-13C]lactate is an attractive alternative to [1-13C]pyruvate as a substrate to investigate cardiac metabolism in vivo; it can be administered safely at a higher dose and can be polarized to a similar degree as pyruvate via dynamic nuclear polarization. While 13C cardiac experiments using HP lactate have been performed in small animal models, it has not been demonstrated in large animal models or humans. Utilizing the same hardware and data acquisition methods used in the first human HP 13C cardiac study, 13C metabolic images were acquired following injections of HP [1-13C]lactate in porcine hearts. Data were also acquired using HP [1-13C]pyruvate for comparison. The 13C bicarbonate signal was localized to the myocardium and had a similar appearance with both substrates for all animals. No 13C pyruvate signal was detected in the experiments following injection of hyperpolarized 13C lactate. The SNR of injected lactate was 88 +/-14% of the SNR of injected pyruvate, and the SNR of bicarbonate in the experiments using lactate as the substrate was 52+/-19% of the SNR in the experiments using pyruvate as the substrate. The lower SNR was likely due to the shorter T1 of [1-13C]lactate as compared to [1-13C]pyruvate and the additional enzyme-catalyzed metabolic conversion step before the 13C nuclei from [1-13C]lactate were detected as 13C bicarbonate. While challenges remain, the potential of HP lactate as a substrate for clinical metabolic imaging of human heart was demonstrated.

biophysics↗