title: Direct arterial injection of hyperpolarized13C-labeled substrates into rat tumors for rapid MR detection of metabolism with minimal substrate dilution.
abstract: OBJECTIVE
  A rat model was developed to enable direct administration of hyperpolarized13C-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. Hyperpolarized13C-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 hyperpolarized13C-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. Hyperpolarized13C-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 T1relaxation signal losses in addition to systemic toxicity. Therefore, it permits metabolic studies of hyperpolarized substrates with relatively short T1and 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.
authors.affiliation: Academic Unit of Radiology, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Steven
authors.initials: S
authors.lastname: Reynolds
authors.affiliation: Tumour Microcirculation Group, Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Metcalf
authors.affiliation: Department of Chemistry, Dainton Building, University of Sheffield, Brook Hill, Sheffield, United Kingdom.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Cochrane
authors.affiliation: Department of Chemistry, Dainton Building, University of Sheffield, Brook Hill, Sheffield, United Kingdom.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Collins
authors.affiliation: Department of Chemistry, Dainton Building, University of Sheffield, Brook Hill, Sheffield, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Jones
authors.affiliation: Academic Unit of Radiology, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Martyn N J
authors.initials: MNJ
authors.lastname: Paley
authors.affiliation: Tumour Microcirculation Group, Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Tozer
mesh_terms: D000818:Animals; D001158:Arteries / Q000000981:diagnostic imaging; D002247:Carbon Isotopes / Q000737:chemistry*; D016503:Drug Delivery Systems; D019074:Epigastric Arteries / Q000000981:diagnostic imaging; D005260:Female; D005268:Femoral Vein / Q000000981:diagnostic imaging; D005682:Gadolinium / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D061848:Optical Imaging; D010477:Perfusion; D010766:Phosphorylation; D019289:Pyruvic Acid / Q000737:chemistry; D051381:Rats; D013053:Spectrophotometry; D013267:Stilbenes / Q000737:chemistry
chemical_list: D002247:Carbon Isotopes; D013267:Stilbenes; C063690:combretastatin A-1; D019289:Pyruvic Acid; D005682:Gadolinium
keywords: 13C-glucose; 13C-pyruvate; P22 tumor; combretastatin; hyperpolarization; intra-arterial