Longitudinal Measurements of Intra- and Extracellular pH Gradient in a Rat Model of Glioma

This study presents the first longitudinal measurement of the intracellular/extracellular pH gradient in a rat glioma model using noninvasive magnetic resonance imaging. The acid–base balance in the brain is tightly controlled by endogenous buffers. Tumors often express a positive pH gradient (pH(i) – pH(e)) compared with normal tissue that expresses a negative gradient. Alkaline pH(i) in tumor cells increases activity of several enzymes that drive cellular proliferation. In contrast, acidic pH(e) is established because of increased lactic acid production and subsequent active transport of protons out of the cell. pH(i) was mapped using chemical exchange saturation transfer, whereas regional pH(e) was determined using hyperpolarized (13)C bicarbonate magnetic resonance spectroscopic imaging. pH(i) and pH(e) were measured at days 8, 12, and 15 postimplantation of C6 glioma cells into rat brains. Measurements were made in tumors and compared to brain tissue without tumor. Overall, average pH gradient in the tumor changed from −0.02 ± 0.12 to 0.10 ± 0.21 and then 0.19 ± 0.16. Conversely, the pH gradient of contralateral brain tissue changed from −0.45 ± 0.16 to −0.25 ± 0.21 and then −0.34 ± 0.25 (average pH ± 1 SD) Spatial heterogeneity of tumor pH gradient was apparent at later time points and may be useful to predict local areas of treatment resistance. Overall, the intracellular/extracellular pH gradients in this rat glioma model were noninvasively measured to a precision of ∼0.1 pH units at 3 time points. Because most therapeutic agents are weak acids or bases, a priori knowledge of the pH gradient may help guide choice of therapeutic agent for precision medicine.