Multi-compound polarization by DNP allows simultaneous assessment of multiple enzymatic activities in vivo

Methods for the simultaneous polarization of multiple C-13-enriched metabolites were developed to probe several enzymatic pathways and other physiologic properties in vivo, using a single intravenous bolus. A new method for polarization of C-13 sodium bicarbonate suitable for use in patients was developed, and the co-polarization of C-13 sodium bicarbonate and [1-C-13] pyruvate in the same sample was achieved, resulting in high solution-state polarizations (15.7% and 17.6%, respectively) and long spin-lattice relaxation times (T-1) (46.7 s and 47.7 s respectively at 3 T). Consistent with chemical shift anisotropy dominating the Ti relaxation of carbonyls, T-1 values for C-13 bicarbonate and [1-C-13] pyruvate were even longer at 3 T (49.7 s and 67.3 s, respectively). Co-polarized C-13 bicarbonate and [1-C-13] pyruvate were injected into normal mice and a murine prostate tumor model at 3 T. Rapid equilibration of injected hyperpolarized C-13 sodium bicarbonate with C-13 CO2 allowed calculation of pH on a voxel by voxel basis, and simultaneous assessment of pyruvate metabolism with cellular uptake and conversion of [1-C-13] pyruvate to its metabolic products. Initial studies in a Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model demonstrated higher levels of hyperpolarized lactate and lower pH within tumor, relative to surrounding benign tissues and to the abdominal viscera of normal controls. There was no significant difference observed in the tumor lactateipyruvate ratio obtained after the injection of co-polarized C-13 bicarbonate and [1-C-13] pyruvate or polarized [1-C-13] pyruvate alone. The technique was extended to polarize four C-13 labelled substrates potentially providing information on pH, metabolism, necrosis and perfusion, namely [1-C-13]pyruvic acid, C-13 sodium bicarbonate, [1,4-C-13]fumaric acid, and C-13 urea with high levels of solution polarization (17.5%, 10.3%, 15.6% and 11.6%, respectively) and spin-lattice relaxation values similar to those recorded for the individual metabolites. These studies demonstrated the feasibility of simultaneously measuring in vivo pH and tumor metabolism using nontoxic, endogenous species, and the potential to extend the multi-polarization approach to include up to four hyperpolarized probes providing multiple metabolic and physiologic measures in a single MR acquisition. (C) 2010 Elsevier Inc. All rights reserved.