Pharmacodynamics and pharmacokinetics of hyperpolarized [1‐¹³C]‐pyruvate in a translational oncologic model

Abstract

This study investigates the in vivo pharmacokinetics and pharmacodynamics of hyperpolarized [1-13 C]-pyruvate in a translational cancer model in order to inform the application of dynamic nuclear polarization (DNP)-enhanced magnetic resonance spectroscopic imaging (MRSI) as a tool for imaging liver cancer. Intratumoral metabolism within autochthonous hepatocellular carcinomas in male Wistar rats was analyzed by MRSI following hyperpolarized [1-13 C]-pyruvate injections with 80 mM (low dose [LD]) or 160 mM (high dose [HD]) pyruvate. Rats received (i) LD followed by HD injection, (ii) sequential LD injections with or without an interposed lactate dehydrogenase inhibitor (LDHi) injection, or (iii) a single LD injection. A subset of rats in (ii) were sacrificed immediately after imaging, permitting measurement of active LDH concentrations in tumor extracts. Urine and serum were collected before and after injections for rats in (iii). Comparison of LD and HD injections confirmed concentration-dependent variation of intratumoral metabolite fractions and intermetabolite ratios. In addition, quantification of the lactate-to-pyruvate ratio was sensitive to pharmacologic inhibition with intermetabolite ratios correlating with active LDH concentrations in tumor extracts. Finally, comparison of pre-and post-DNP urine collections revealed that pyruvate and the radical source are renally excreted after injection. These data demonstrate that DNP-MRSI facilitates real-time quantification of intratumoral metabolism that is repeatable and reflective of intracellular processes. A translational model system confirmed that interpretation requires consideration of probe dose, administration frequency and excretion.

Efficient Parahydrogen Induced 13C Hyperpolarization on a Microfluidic Device

“…Hyperpolarized metabolites have great potential as contrast agents for magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging (MRSI), providing real-time and quantitative information on active metabolic pathways in healthy and diseased tissues. 20,21 This approach has been used in vivo for metabolic profiling of tumours such glioma, 22,23 hepatocellular carcinoma, lymphoma, 24,25 pancreatic 26 and breast cancers. 27,28 In this modality, relatively large amounts (several g) of hyperpolarized material (most commonly pyruvate) are prepared and injected intravenously into the patient.…”

Efficient Parahydrogen Induced 13C Hyperpolarization on a Microfluidic Device

“…This allows provision of real-time and quantitative information on the kinetics of downstream metabolites in healthy and diseased systems. The method has been used in vivo for metabolic profiling of tumours such glioma, 12,13 hepatocellular carcinoma, lymphoma, 14,15 pancreatic 16 and breast cancers. 17,18 More generally, high-resolution NMR spectroscopy is an ideal technique to follow chemical reactions and monitor biological systems in LoC and OoC due to its non-invasive nature, chemical specificity and the ability to quantify metabolites.…”

Efficient Parahydrogen-Induced 13C Hyperpolarization on a Microfluidic Device

“…Hyperpolarized metabolites have great potential as contrast agents for magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging (MRSI), providing real-time and quantitative information on active metabolic pathways in healthy and diseased tissues. 20,21 This approach has been used in vivo for metabolic profiling of tumors such glioma, 22,23 hepatocellular carcinoma, lymphoma, 24,25 pancreatic 26 and breast cancers. 27,28 In this modality, relatively large amounts (several g) of hyperpolarized material (most commonly pyruvate) are prepared and injected intravenously into the patient.…”

“…Hyperpolarized metabolites have great potential as contrast agents for magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging (MRSI), providing real-time and quantitative information on active metabolic pathways in healthy and diseased tissues. , This approach has been used in vivo for metabolic profiling of tumors such glioma, , hepatocellular carcinoma, lymphoma, , pancreatic and breast cancers. , In this modality, relatively large amounts (several g) of hyperpolarized material (most commonly pyruvate) are prepared and injected intravenously into the patient. Preparation relies on either dissolution dynamic nuclear polarization , or on low-field polarization transfer based on parahydrogen-induced polarization (PHIP). , The batch mode of operation of these methods does not lend itself to LoC culture devices, where a steady supply of much smaller amounts of hyperpolarized metabolites is needed.…”