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

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.