Imaging the extracellular pH of tumors by MRI after injection of a single cocktail of T 1 and T 2 contrast agents

Gary V. Martinez, Xiaomeng Zhang, María L. García-Martín, David L. Morse, Mark Woods, A. Dean Sherry, Robert J. Gillies

Research output: Contribution to journalArticlepeer-review

70 Scopus citations


The extracellular pH (pH e) of solid tumors is acidic, and there is evidence that an acidic pH e is related to invasiveness. Herein, we describe an MRI single-infusion method to measure pH e in gliomas using a cocktail of contrast agents (CAs). The cocktail contained gadolinium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaminophosphonate (GdDOTA-4AmP) and dysprosium-1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′′-tetrakis(methylenephosphonic acid) (DyDOTP), whose effects on relaxation are sensitive and insensitive to pH, respectively. The Gd-CA dominated the spin-lattice relaxivity ΔR 1, whereas the Dy-CA dominated the spin-spin relaxivity ΔR 2*. The ΔR 2* effects were used to determine the pixel-wise concentration of [Dy] which, in turn, was used to calculate a value for [Gd] concentration. This value was used to convert ΔR 1 values to the molar relaxivity Δr 1 and, hence, pH e maps. The development of the method involved in vivo calibration and measurements in a rat brain glioma model. The calibration phase consisted of determining a quantitative relationship between ΔR 1 and ΔR 2* induced by the two pH-independent CAs, gadolinium-diethylenetriaminepentaacetic acid (GdDTPA) and DyDOTP, using echo planar spectroscopic imaging (EPSI) and T 1-weighted images. The intensities and linewidths of the water peaks in EPSI images were affected by CA and were used to follow the pharmacokinetics. These data showed a linear relationship between inner- and outer-sphere relaxation rate constants that were used for CA concentration determination. Nonlinearity in the slope of the relationship was observed and ascribed to variations in vascular permeability. In the pH e measurement phase, GdDOTA-4AmP was infused instead of GdDTPA, and relaxivities were obtained through the combination of interleaved T 1-weighted images (R 1) and EPSI for ΔR 2*. The resulting r 1 values yielded pH e maps with high spatial resolution.

Original languageEnglish (US)
Pages (from-to)1380-1391
Number of pages12
JournalNMR in biomedicine
Issue number10
StatePublished - Dec 2011
Externally publishedYes


  • Cocktail
  • Contrast agent
  • PH
  • Susceptibility

ASJC Scopus subject areas

  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging
  • Spectroscopy


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