Dissolution-Dynamic Nuclear Polarization (dissolution-DNP) for Magnetic Resonance (MR) Spectroscopic Imaging has recently emerged as a novel technique for non invasive studies of the metabolic fate of biomolecules in vivo. Since acetate is the most abundant extra- and intra-cellular short-chain fatty acid, we focused on [1-13C]acetate as a promising candidate for a chemical probe to study myocardial metabolism of beating heart.
Dissolution-DNP procedure of Na[1-13C]acetate for in vivo cardiac applications with 3T MR scanner was optimized in pigs during bolus injection of doses up to 3 mmoles. The Na[1-13C]acetate formulation was characterized by a liquid-state polarization of 14.2% and T1Eff in vivo of 17.6 ± 1.7 s. In vivo Na[1-13C]acetate kinetic displayed a bimodal shape: [1-13C]acetyl carnitine (AcC) was detected in a slice covering the cardiac volume, and the signal of 13C-acetate and 13C-AcC was modeled using the total Area Under the Curve (AUC) for kinetic analysis. A good correlation was found between the ratio AUC(AcC)/AUC(acetate) and the apparent kinetic constant of metabolic conversion kAcC/r1 from [1-13C]acetate to [1-13C]AcC. Our study proved the feasibility and limitations of administration of large doses of hyperpolarized [1-13C]acetate with dissolution DNP to study by MR spectroscopy the myocardial conversion of [1-13C]acetate in [1-13C]acetyl-carnitine generated by acetyltransferase in healthy pigs.
Hyperpolarization of ¹³C-labeled energy substrates enables the noninvasive detection and mapping of metabolic activity, in vivo, with magnetic resonance spectroscopy (MRS). Therefore, hyperpolarization and ¹³C MRS can potentially become a powerful tool to study the physiology of organs such as the heart, through the quantification of kinetic patterns under both normal and pathological conditions. In this study we assessed myocardial uptake and metabolism of hyperpolarized [1-¹³C]pyruvate in anesthetized pigs. Pyruvate metabolism was studied at baseline and during dobutamine-induced stimulation. We applied a numerical approach for spectral analysis and kinetic fitting (LSFIT/KIMOfit), making a comparison with a well-known jMRUI/AMARES analysis and γ-variate function, and we estimated the apparent conversion rate of hyperpolarized [1-¹³C]pyruvate into its downstream metabolites [1-¹³C]lactate, [1-¹³C]alanine and [¹³C]bicarbonate in a 3 T MR scanner. We detected an increase in the apparent kinetic constants (k(PX) ) for bicarbonate and lactate of two-fold during dobutamine infusion. These data correlate with the double product (rate-pressure product), an indirect parameter of cardiac oxygen consumption: we observed an increase in value by 46 ± 11% during inotropic stress. The proposed approach might be applied to future studies in models of cardiac disease and/or for the assessment of the pharmacokinetic properties of suitable ¹³C-enriched tracers for MRS.
Superparamagnetic Iron Oxide Nanoparticles (SPIONs) are performing contrast agents for Magnetic Resonance Imaging (MRI). A functionalization strategy for SPIONs based on hydrophobic interactions is a versatile approach easily extendable to several kinds of inorganic nanoparticles and suitable for obtaining stable and biocompatible systems. Here we report on the original preparation of functionalized SPIONs with an 8 nm radius exploiting the hydrophobic interaction between a phosphocholine and an inner amphiphilic. With respect to other similarly functionalized SPIONs, characterized by the typical nanoparticle clustering that leads to large aggregates, our phosphocholine-decorated SPIONs are demonstrated to be monodisperse. We report the in vitro and in vivo study that proves the effective applicability of phosphocholine-decorated SPIONs as MRI contrast agents. The versatility of this functionalization approach is highlighted by introducing on the SPION surface a ruthenium-based potential antitumoral drug, named ToThyCholRu. Even if in this case we observed the formation of SPION clusters, ascribable to the presence of the amphiphilic ruthenium complex, interesting and promising antiproliferative activity points at the ToThyCholRu-decorated SPIONs as potential theranostic agents.
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