title: Towards Real-time Metabolic Profiling of Cancer with Hyperpolarized Succinate.
abstract: OBJECTIVE
  The energy-yielding mitochondrial Krebs cycle has been shown in many cancers and other diseases to be inhibited or mutated. In most cells, the Krebs cycle with oxidative phosphorylation generates approximately 90% of the adenosine triphosphate in the cell. We designed and hyperpolarized carbon-13 labeled succinate (SUC) and its derivative diethyl succinate (DES) to interrogate the Krebs cycle in real-time in cancer animal models.
  
  
  METHODS
  Using Parahydrogen Induced Polarization (PHIP), we generated hyperpolarized SUC and DES by hydrogenating their respective fumarate precursors. DES and SUC metabolism was studied in five cancer allograft animal models: breast (4T1), Renal Cell Carcinoma (RENCA), colon (CT26), lymphoma NSO, and lymphoma A20.
  
  
  RESULTS
  The extent of hyperpolarization was 8 ± 2% for SUC and 2.1 ± 0.6% for DES. The metabolism of DES and SUC in the Krebs cycle could be followed in animals 5 s after tail vein injection. The biodistribution of the compounds was observed using13C FISP imaging. We observed significant differences in uptake and conversion of both compounds in different cell types bothin vivoandin vitro.
  
  
  CONCLUSIONS
  With hyperpolarized DES and SUC, we are able to meet many of the requirements for a useablein vivometabolic imaging compound - high polarization, relatively long T1values, low toxicity and high water solubility. However, succinate and its derivative DES are metabolized robustly by RENCA but not by the other cancer models. Our results underscore the heterogeneity of cancer cells and the role cellular uptake plays in hyperpolarized metabolic spectroscopy.
authors.affiliation: Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, USA; Department of Bioengineering, Rice University, 6100 Main Street, Houston, USA.
authors.forename: Niki M
authors.initials: NM
authors.lastname: Zacharias
authors.affiliation: Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: McCullough
authors.affiliation: Department of Biomedical Sciences, Cedars-Sinai, Los Angeles, USA.
authors.forename: Shawn
authors.initials: S
authors.lastname: Wagner
authors.affiliation: Enhanced Magnetic Resonance Laboratories, Huntington Medical Research Institutes, Pasadena, USA.
authors.forename: Napapon
authors.initials: N
authors.lastname: Sailasuta
authors.affiliation: Enhanced Magnetic Resonance Laboratories, Huntington Medical Research Institutes, Pasadena, USA.
authors.forename: Henry R
authors.initials: HR
authors.lastname: Chan
authors.affiliation: Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, USA; Department of Applied Chemistry, Hanyang University, Ansan, Korea.
authors.forename: Youngbok
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, USA; Department of Bioengineering, Rice University, 6100 Main Street, Houston, USA.
authors.forename: Jingzhe
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Radiology, School of Medicine Saint Louis University, St. Louis, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Perman
authors.affiliation: Enhanced Magnetic Resonance Laboratories, Huntington Medical Research Institutes, Pasadena, USA.
authors.forename: Cameron
authors.initials: C
authors.lastname: Henneberg
authors.affiliation: Enhanced Magnetic Resonance Laboratories, Huntington Medical Research Institutes, Pasadena, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Ross
authors.affiliation: Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: Pratip
authors.initials: P
authors.lastname: Bhattacharya
keywords: hyperpolarization; krebs cycle; magnetic resonance spectroscopy; metabolic imaging; succinate