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 journalArticle

52 Citations (Scopus)

Abstract

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
Volume24
Issue number10
DOIs
StatePublished - Dec 2011

Fingerprint

Magnetic resonance imaging
Contrast Media
Tumors
Imaging techniques
Injections
Gadolinium
Echo-Planar Imaging
Neoplasms
Acids
Dysprosium
Brain models
Calibration
Glioma
Pharmacokinetics
Phase measurement
Linewidth
Rats
Rate constants
Pixels
Capillary Permeability

Keywords

  • Cocktail
  • Contrast agent
  • PH
  • Susceptibility

ASJC Scopus subject areas

  • Spectroscopy
  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging

Cite this

Martinez, G. V., Zhang, X., García-Martín, M. L., Morse, D. L., Woods, M., Sherry, A. D., & Gillies, R. J. (2011). Imaging the extracellular pH of tumors by MRI after injection of a single cocktail of T 1 and T 2 contrast agents. NMR in Biomedicine, 24(10), 1380-1391. https://doi.org/10.1002/nbm.1701

Imaging the extracellular pH of tumors by MRI after injection of a single cocktail of T 1 and T 2 contrast agents. / Martinez, Gary V.; Zhang, Xiaomeng; García-Martín, María L.; Morse, David L.; Woods, Mark; Sherry, A. Dean; Gillies, Robert J.

In: NMR in Biomedicine, Vol. 24, No. 10, 12.2011, p. 1380-1391.

Research output: Contribution to journalArticle

Martinez, GV, Zhang, X, García-Martín, ML, Morse, DL, Woods, M, Sherry, AD & Gillies, RJ 2011, 'Imaging the extracellular pH of tumors by MRI after injection of a single cocktail of T 1 and T 2 contrast agents', NMR in Biomedicine, vol. 24, no. 10, pp. 1380-1391. https://doi.org/10.1002/nbm.1701
Martinez, Gary V. ; Zhang, Xiaomeng ; García-Martín, María L. ; Morse, David L. ; Woods, Mark ; Sherry, A. Dean ; Gillies, Robert J. / Imaging the extracellular pH of tumors by MRI after injection of a single cocktail of T 1 and T 2 contrast agents. In: NMR in Biomedicine. 2011 ; Vol. 24, No. 10. pp. 1380-1391.
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