Study of Cariporide Effect On Tumor Intracellular PH (pHi) Using Chemical Exchange Saturation Transfer (CEST) MRI
M Mozaffari*, N Nystrom, A Li, M Bellyou, T Scholl, R Bartha, Robarts Research Institute, Western University, London, ON, CA,
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PO-GePV-I-22 (Sunday, 7/25/2021) [Eastern Time (GMT-4)]
Purpose: pHᵢ is a hallmark of tumor microenvironment response to therapies. NHE1 is an acid-extruding membrane transport protein in cells.¹ In CEST-MRI contrast is produced by exciting exchangeable tissue protons at their specific absorption frequency and observing the transfer of magnetization to bulk tissue water. Amine and amide concentration-independent detection (AACID) is an approach that uses the sensitivity of amine and amide proton to CETS contrast.² The AACID value inversely relates to pHᵢ. One way to achieve tumor acidification as a therapeutic strategy is by blocking the NHE1 transporter. Cariporide is a potent inhibitor of NHE1. We have shown that cariporide can selectively acidify U87MG glioma in mice.³ Our goal was to determine whether it also selectively acidifies a rat C6 glioma tumor model following injection by mapping tumor pHᵢ.
Methods: Cells were injected into the brain of six rats. To evaluate the effect of cariporide on tumor pHᵢ, rats received an IP injection of the drug two weeks after implantation while inside a 9.4T scanner to measure the change in pHᵢ following injection.
Results: Five minutes after injection, CEST-MRI was collected for three hours. For data analysis, we compared the first maximum change in AACID value post-injection with the pre-injection. After one hour, the average AACID value in the tumor significantly increased. The average AACID value in tumor post-injection was 5.4% higher compared to pre-injection. The average AACID value in contralateral tissue also increased in a similar way.
Conclusion: We did not observe selective tumor acidification following injection as was observed in the previous study. The reason for this discrepancy is currently unknown but may be related to potential differences in tumor vasculature that may limit the ability of cariporide to infiltrate the tumor.⁴ Future work includes increasing cariporide dose and modifying our quantification method of the AACID measurement.
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