The use of hyperpolarised 13 C pyruvate for nononcological neurological applications has not been widespread so far, possibly due to delivery issues limiting the visibility of metabolites. First proof-of-concept results have indicated that metabolism can be detected in human brain, and this may supersede the results obtained in preclinical settings. One major difference between the experimental setups is that preclinical MRI/MRS routinely uses anaesthesia, which alters both haemodynamics and metabolism. Here, we used hyperpolarised [1-13 C]pyruvate to compare brain metabolism in awake rats and under isoflurane, urethane or medetomidine anaesthesia. Spectroscopic [1-13 C]pyruvate time courses measured sequentially showed that pyruvateto-bicarbonate and pyruvate-to-lactate labelling rates were lower in isoflurane animals than awake animals. An increased bicarbonate-to-lactate ratio was observed in the medetomidine group compared with other groups. The study shows that hyperpolarised [1-13 C]pyruvate experiments can be performed in awake rats, thus avoiding anaesthesia-related issues. The results suggest that haemodynamics probably dominate the observed pyruvate-to-metabolite labelling rates and area-undertime course ratios of referenced to pyruvate. On the other hand, the results obtained with medetomidine suggest that the ratios are also modulated by the underlying cerebral metabolism. However, the ratios between intracellular metabolites were unchanged in awake compared with isoflurane-anaesthetised rats.
Hyperpolarised [1‐13C]pyruvate MRI has shown promise in monitoring therapeutic efficacy in a number of cancers including glioma. In this study, we assessed the pyruvate response to the lentiviral suicide gene therapy of herpes simplex virus‐1 thymidine kinase with the prodrug ganciclovir (HSV‐TK/GCV) in C6 rat glioma and compared it with traditional MR therapy markers. Female Wistar rats were inoculated with 106 C6 glioma cells. Treated animals received intratumoural lentiviral HSV‐TK gene transfers on days 7 and 8 followed by 2‐week GCV therapy starting on day 10. Animals were repeatedly imaged during therapy using volumetric MRI, diffusion and relaxation mapping, as well as metabolic [1‐13C]pyruvate MRS imaging. Survival (measured as time before animals reached a humane endpoint and were euthanised) was assessed up to day 30 posttherapy. HSV‐TK/GCV gene therapy lengthened the median survival time from 12 to 25 days. This was accompanied by an apparent tumour growth arrest, but no changes in diffusion or relaxation parameters in treated animals. The metabolic response was more evident in the case‐by‐case analysis than in the group‐level analysis. Treated animals also showed a 37 ± 15% decrease (P < 0.05, n = 5) in lactate‐to‐pyruvate ratio between therapy weeks, whereas a 44 ± 18% increase (P < 0.05, n = 6) was observed in control animals. Hyperpolarised [1‐13C]pyruvate MRI can offer complementary metabolic information to traditional MR methods to give a more comprehensive picture of the slowly developing gene therapy response. This may benefit the detection of the successful therapy response in patients.
This paper reports the synthesis, characterization and in vivo application of water‐soluble supramolecular contrast agents (Mw: 5–5.6 kDa) for MRI obtained from β‐cyclodextrin functionalized with different kinds of nitroxide radicals, both with piperidine structure (CD2 and CD3) and with pyrrolidine structure (CD4 and CD5). As to the stability of the radicals in presence of ascorbic acid, CD4 and CD5 have low second order kinetic constants (≤0.05 M−1 s−1) compared to CD2 (3.5 M−1 s−1) and CD3 (0.73 M−1 s−1). Relaxivity (r1) measurements on compounds CD3‐CD5 were carried out at different magnetic field strength (0.7, 3, 7 and 9.4 T). At 0.7 T, r1 values comprised between 1.5 mM−1 s−1 and 1.9 mM−1 s−1 were found while a significant reduction was observed at higher fields (r1≈0.6‐0.9 mM−1 s−1 at 9.4 T). Tests in vitro on HEK293 human embryonic kidney cells, L929 mouse fibroblasts and U87 glioblastoma cells indicated that all compounds were non‐cytotoxic at concentrations below 1 μmol mL−1. MRI in vivo was carried out at 9.4 T on glioma‐bearing rats using the compounds CD3‐CD5. The experiments showed a good lowering of T1 relaxation in tumor with a retention of the contrast for at least 60 mins confirming improved stability also in vivo conditions.
Anesthesia has profound effects on overall metabolism, leading to significant signal changes in metabolic MR brain experiments using hyperpolarized [1-13C]pyruvate. In the current study, we studied the possible origins of the signals from rat liver and heart under isoflurane anesthesia and while the animals were awake. Increased metabolite signals, especially lactate, were observed from both organs in awake animals.
Porous Si nanoparticles (NPs) with different doping degree were prepared using low-load metal assisted catalytic etching and subjected to dynamic nuclear polarization at 3.4 T and 6.7 T. Thermal oxidation of Si was applied to form paramagnetic centers of dangling bond type in Si/SiO2 interface, which were used to polarize 29Si nuclei. The doping significantly affected the gained polarization and buildup times: high doping degree generally led to lower and faster polarization compared to the low doping. On the other hand, slight p-type or n-type doping was necessary to achieve the highest polarization of about 11 %.
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