Intracellular Acidification in a Rat C6 Glioma Model Following Cariporide Injection Monitored by Chemical Exchange Saturation Transfer Magnetic Resonance Imaging

Abstract

Gliomas are the most common primary brain tumors. Selective acidification of cancerous tissue induced pharmacologically may slow tumor growth and can be detected using magnetic resonance imaging (MRI). The sodium proton exchanger inhibitor cariporide can selectively acidify U87MG gliomas in mice. This study aimed to determine whether cariporide could selectively acidify C6 glioma tumors in rats with an intact immune system. C6 glioma cells were implanted in the right brain hemisphere of ten male Wistar rats. Chemical exchange saturation transfer (CEST) MRI (9.4T) was acquired on days 7–8 (N= 10) and 14–15 (N= 10) after implantation to measure in vivo tissue intracellular pH (pHi) within the tumors and on the contralateral side. Intracellular pH was basic relative to contralateral tissue at both time points (p < 0.05) assessed using the amine and amide concentration-independent detection (AACID) value. On day 14–15, measurements were made before and up to 160 minutes after cariporide injection (N= 6, dose: 6 mg/kg in 2 mL with 10% DMSO). Twenty minutes after drug injection, the average AACID value in the tumor significantly increased by ∼6.4% compared to pre-injection, corresponding to 0.31 ± 0.20 lower pHi, while in contralateral tissue, AACID value increases significantly by ∼4.3% compared to pre-injection, corresponding to 0.22 ± 0.19 lower pHi. Then the average AACID value returned to the baseline level in both tissues about an hour after the injection before trending back up in contralateral tissue 80 minutes and 100 minutes after injection. Control rats without tumors showed no changes following injection of cariporide in 10% or 1% DMSO. This study demonstrates the sensitivity of CEST-based pH-weighted imaging for monitoring the response of tumors to pharmacologically induced acidification. Although cariporide did induce intracellular acidification in the C6 glioma, this acidification was not tumor selective in this model.