Monitoring the Effect of Cariporide On Intracellular PH in Brain Tumors by Chemical Exchange Saturation Transfer MRI
Presentations
TU-D930-IePD-F9-3 (Tuesday, 7/12/2022) 9:30 AM - 10:00 AM [Eastern Time (GMT-4)]
Exhibit Hall | Forum 9
Purpose: Intracellular pH (pHᵢ) is a hallmark feature of the tumor microenvironment that can be altered by drug treatment. NHE1, an acid-extruding membrane transport protein, is involved in pHᵢ regulation. Blockage of NHE1 by cariporide as a therapeutic strategy produces tumor acidification.¹ We have shown that cariporide selectively acidifies U87MG gliomas in mice.² However, the effect of cariporide on different tumor models is unknown. Tumor pHᵢ can be monitored in vivo using a chemical exchange saturation transfer (CEST) MRI technique called AACID.³ The measured AACID value is inversely related to pHᵢ. The goal of this study was to determine whether cariporide could selectively acidify C6 glioblastoma tumors in rats monitored by AACID-CEST-MRI.
Methods: C6 glioma cells were injected into the brain of six rats. Rats were scanned on day 7 and day 14 following implantation. On day 14, rats received cariporide (6 mg/kg) inside a 9.4T MRI scanner, and eight AACID-CEST images were acquired through the tumor prior to injection and for 160 minutes afterwards.
Results: Twenty minutes after cariporide injection, the average AACID value in the tumor significantly increased. It was 6.4% higher compared to pre-injection, corresponding to a drop of 0.31 pHᵢ units. A second maximum occurred 100 minutes post-injection but the AACID value in tumor was not significantly increased. Although the average AACID value in contralateral tissue also increased, the immediate effect of cariporide in tumors was more pronounced.
Conclusion: Selective tumor acidification was not observed following cariporide injection. Rather, acidification occurred in the tumor and in contralateral tissues. The reason for this discrepancy in comparison to the U87MG tumor model in mice may be related to differences in brain or tumor vasculature impacting the ability of cariporide to infiltrate the tissue or tumor.⁴ Future work will examine the impact of cariporide on healthy rat brain tissue.
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