Glucose Infusion Induced Change in Intracellular pH and Its Relationship with Tumor Glycolysis in a C6 Rat Model of Glioblastoma

Introduction The reliance on glycolytic metabolism is a hallmark of tumor metabolism. Excess acid and protons are produced, leading to an acidic tumor environment. Therefore, we explored the relationship between the tumor glycolytic metabolism and tissue pH by comparing 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) and hyperpolarized [1- 13 C]pyruvate MR spectroscopy imaging (MRSI) to chemical exchange saturation transfer (CEST) MRI measurements of tumor pH. Methods 10 6 C6 glioma cells were implanted in the brains of male Wistar rats ( N = 11) using stereotactic surgery. A 60-min PET acquisition after a bolus of FDG was performed at 11–13 days post implantation, and standardized uptake value (SUV) was calculated. CEST measurements were acquired the following day before and during constant infusion of glucose solution. Tumor intracellular pH (pHi) was evaluated using amine and amide concentration-independent detection (AACID) CEST MRI. The change of pH i (∆pH i ) was calculated as the difference between pH i pre- and during glucose infusion. Rats were imaged immediately with hyperpolarized [1- 13 C]pyruvate MRSI. Regional maps of the ratio of Lac:Pyr were acquired. The correlations between SUV, Lac:Pyr ratio, and ∆pH i were evaluated using Pearson’s correlation. Results A decrease of 0.14 in pH i was found after glucose infusion in tumor region. Significant correlations between tumor glycolysis measurements of Lac:Pyr and ∆pH i within the tumor ( ρ = 0.83, P = 0.01) and peritumoral region ( ρ = 0.76, P = 0.028) were observed. No significant correlations were found between tumor SUV and ∆pH i within the tumor ( ρ = − 0.45, P = 0.17) and peritumor regions ( ρ = − 0.6, P = 0.051). Conclusion AACID detected the changes in pH i induced by glucose infusion. Significant correlations between tumor glycolytic measurement of Lac:Pyr and tumoral and peritumoral pH i and ∆pH i suggest the intrinsic relationship between tumor glycolytic metabolism and the tumor pH environment as well as the peritumor pH environment.