Imaging the extracellular pH of tumors by MRI after injection of a single cocktail of T1 and T2 contrast agents

• Published in: NMR in biomedicine Vol. 24; no. 10; pp. 1380 - 1391
• Main Authors: Martinez, Gary V., Zhang, Xiaomeng, García-Martín, María L., Morse, David L., Woods, Mark, Sherry, A. Dean, Gillies, Robert J.
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.12.2011; Wiley Subscription Services, Inc
• Subjects: Animals; Calibration; cocktail; contrast agent; Contrast Media - administration & dosage; Contrast Media - pharmacology; Extracellular Space - drug effects; Extracellular Space - metabolism; Female; Hydrogen-Ion Concentration - drug effects; Injections; Magnetic Resonance Imaging - methods; Rats; Rats, Wistar; susceptibility; Time Factors
• ISSN: 0952-3480; 1099-1492
• DOI: 10.1002/nbm.1701

The extracellular pH (pHe) of solid tumors is acidic, and there is evidence that an acidic pHe is related to invasiveness. Herein, we describe an MRI single‐infusion method to measure pHe 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 ΔR1, whereas the Dy‐CA dominated the spin–spin relaxivity ΔR2*. The ΔR2* 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 ΔR1 values to the molar relaxivity Δr1 and, hence, pHe 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 ΔR1 and ΔR2* induced by the two pH‐independent CAs, gadolinium–diethylenetriaminepentaacetic acid (GdDTPA) and DyDOTP, using echo planar spectroscopic imaging (EPSI) and T1‐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 pHe measurement phase, GdDOTA‐4AmP was infused instead of GdDTPA, and relaxivities were obtained through the combination of interleaved T1‐weighted images (R1) and EPSI for ΔR2*. The resulting r1 values yielded pHe maps with high spatial resolution. Copyright © 2011 John Wiley & Sons, Ltd. A single‐infusion protocol consisting of the slow infusion of a contrast agent cocktail yielded high‐resolution extracellular pH (pHe) maps of tumors. The current method is based on a calibration between [Gd] derived from T1‐weighted spin echo and ΔR2*. The primary advantage of this protocol over previous studies is the rapidity of generating the pHe measurement after the calibration curve has been obtained.