Dataset Information

Direct arterial injection of hyperpolarized ¹³ C-labeled substrates into rat tumors for rapid MR detection of metabolism with minimal substrate dilution.

ABSTRACT:

Purpose

A rat model was developed to enable direct administration of hyperpolarized ¹³ C-labeled molecules into a tumor-supplying artery for magnetic resonance spectroscopy (MRS) studies of tumor metabolism.

Methods

Rat P22 sarcomas were implanted into the right inguinal fat pad of BDIX rats such that the developing tumors received their principle blood supply directly from the right superior epigastric artery. Hyperpolarized ¹³ C-molecules were either infused directly to the tumor through the epigastric artery or systemically through the contralateral femoral vein. Spectroscopic data were obtained on a 7 Tesla preclinical scanner.

Results

Intra-arterial infusion of hyperpolarized ¹³ C-pyruvate increased the pyruvate tumor signal by a factor of 4.6, compared with intravenous infusion, despite an approximately 7 times smaller total dose to the rat. Hyperpolarized glucose signal was detected at near-physiological systemic blood concentration. Pyruvate to lactate but not glucose to lactate metabolism was detected in the tumor. Hyperpolarized ¹³ C-labeled combretastatin A1 diphosphate, a tumor vascular disrupting agent, showed an in vivo signal in the tumor.

Conclusions

The model maximizes tumor substrate/drug delivery and minimizes T₁ relaxation signal losses in addition to systemic toxicity. Therefore, it permits metabolic studies of hyperpolarized substrates with relatively short T₁ and opens up the possibility for preclinical studies of hyperpolarized drug molecules. Magn Reson Med 78:2116-2126, 2017. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

SUBMITTER: Reynolds S

PROVIDER: S-EPMC5697693 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Publications

Direct arterial injection of hyperpolarized <sup>13</sup> C-labeled substrates into rat tumors for rapid MR detection of metabolism with minimal substrate dilution.

Reynolds Steven S Metcalf Stephen S Cochrane Edward J EJ Collins Rebecca C RC Jones Simon S Paley Martyn N J MNJ Tozer Gillian M GM

Magnetic resonance in medicine 20170212 6

<h4>Purpose</h4>A rat model was developed to enable direct administration of hyperpolarized <sup>13</sup> C-labeled molecules into a tumor-supplying artery for magnetic resonance spectroscopy (MRS) studies of tumor metabolism.<h4>Methods</h4>Rat P22 sarcomas were implanted into the right inguinal fat pad of BDIX rats such that the developing tumors received their principle blood supply directly from the right superior epigastric artery. Hyperpolarized <sup>13</sup> C-molecules were either infuse ...[more]

PMID: 28191664

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Project description:IntroductionThe normal heart has remarkable metabolic flexibility that permits rapid switching between mitochondrial glucose oxidation and fatty acid (FA) oxidation to generate ATP. Loss of metabolic flexibility has been implicated in the genesis of contractile dysfunction seen in cardiomyopathy. Metabolic flexibility has been imaged in experimental models, using hyperpolarized (HP) [2-13C]pyruvate MRI, which enables interrogation of metabolites that reflect tricarboxylic acid (TCA) cycle flux in cardiac myocytes. This study aimed to develop methods, demonstrate feasibility for [2-13C]pyruvate MRI in the human heart for the first time, and assess cardiac metabolic flexibility.MethodsGood Manufacturing Practice [2-13C]pyruvic acid was polarized in a 5T polarizer for 2.5-3 hours. Following dissolution, QC parameters of HP pyruvate met all safety and sterility criteria for pharmacy release, prior to administration to study subjects. Three healthy subjects each received two HP injections and MR scans, first under fasting conditions, followed by oral glucose load. A 5cm axial slab-selective spectroscopy approach was prescribed over the left ventricle and acquired at 3s intervals on a 3T clinical MRI scanner.ResultsThe study protocol which included HP substrate injection, MR scanning and oral glucose load, was performed safely without adverse events. Key downstream metabolites of [2-13C]pyruvate metabolism in cardiac myocytes include the glycolytic derivative [2-13C]lactate, TCA-associated metabolite [5-13C]glutamate, and [1-13C]acetylcarnitine, catalyzed by carnitine acetyltransferase (CAT). After glucose load, 13C-labeling of lactate, glutamate, and acetylcarnitine from 13C-pyruvate increased by 39.3%, 29.5%, and 114%, respectively in the three subjects, that could result from increases in lactate dehydrogenase (LDH), pyruvate dehydrogenase (PDH), and CAT enzyme activity as well as TCA cycle flux (glucose oxidation).ConclusionsHP [2-13C]pyruvate imaging is safe and permits non-invasive assessment of TCA cycle intermediates and the acetyl buffer, acetylcarnitine, which is not possible using HP [1-13C]pyruvate. Cardiac metabolite measurement in the fasting/fed states provides information on cardiac metabolic flexibility and the acetylcarnitine pool.

Dataset Information

Direct arterial injection of hyperpolarized ¹³ C-labeled substrates into rat tumors for rapid MR detection of metabolism with minimal substrate dilution.

Purpose

Methods

Results

Conclusions

Publications

Direct arterial injection of hyperpolarized <sup>13</sup> C-labeled substrates into rat tumors for rapid MR detection of metabolism with minimal substrate dilution.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Direct arterial injection of hyperpolarized 13 C-labeled substrates into rat tumors for rapid MR detection of metabolism with minimal substrate dilution.

Purpose

Methods

Results

Conclusions

Publications

Direct arterial injection of hyperpolarized <sup>13</sup> C-labeled substrates into rat tumors for rapid MR detection of metabolism with minimal substrate dilution.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Direct arterial injection of hyperpolarized ¹³ C-labeled substrates into rat tumors for rapid MR detection of metabolism with minimal substrate dilution.