Intracellular Acidification in a Rat C6 Glioma Model following Cariporide Injection Investigated by CEST-MRI
Abstract
Acidification of cancerous tissue induced pharmacologically may slow tumor growth and can be detected using magnetic resonance imaging. Numerous studies have shown that pharmacologically inhibiting specific transporters, such as the Na⁺/H⁺ exchanger 1 (NHE1), can alter glycolitic metabolism and affect tumor acidosis. The sodium proton exchanger inhibitor Cariporide can acidify U87MG gliomas in mice. This study aimed to determine whether Cariporide could acidify C6 glioma tumors in rats with an intact immune system. C6 glioma cells were implanted in the right brain hemisphere of ten rats. Chemical exchange saturation transfer (CEST) MRI (9.4T) was acquired on days 7–8 and 14–15 after implantation to measure in vivo tissue intracellular pH (pHᵢ) within the tumors and on the contralateral side. pHᵢ was basic relative to contralateral tissue at both time points assessed using the amine and amide concentration-independent detection (AACID) value. On day 14–15, measurements were made before and up to 160 min after Cariporide injection (N = 6). 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 increased significantly by ∼4.3% compared to pre-injection, corresponding to 0.22 ± 0.19 lower pHᵢ. Control rats without tumors showed no changes following injection of Cariporide dissolved in 10% or 1% DMSO and diluted in PBS. This study demonstrates the sensitivity of CEST-based pH-weighted imaging for monitoring the response of tumors to pharmacologically induced acidification.
Copyright and License
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Funding
This research was funded by the Canadian Institutes of Health Research (CIHR-375870), Canada First Research Excellence Fund (BrainsCAN), and Brain Canada Platform Support Grant.
Contributions
M.M. conceived the study, performed experiments (animal handling, technical validation, data acquisition), developed the data analysis tool, data analysis, and wrote the manuscript. N.N.N. cultured and prepared the cells for tumor implantation. A.L. developed MRI protocols, conducted experiments, and contributed to developing the data analysis tool. M.B. submitted animal ethics, animal handling, and provided technical advice. T.J.S. oversaw the animal model and provided technical advice. R.B. conceived the study and oversaw all aspects of the work. All authors have read and agreed to the published version of the manuscript.
Ethics
All applicable national and institutional guidelines for the care and use of animals were followed. All procedures performed in animal studies followed the ethical standards of the institution or practice at which the studies were conducted.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Conflict of Interest
The authors declare that they have no competing interests.
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Additional details
Identifiers
- PMCID
- PMC10386045
Funding
- Canadian Institutes of Health Research
- CIHR-375870
- Brain Canada Foundation
Dates
- Accepted
-
2023-07-05published online