Brain tumor acidification using drugs simultaneously targeting multiple pH regulatory mechanisms

Area of Science:

• Biomedical Imaging
• Oncology
• Biochemistry

Background:

• Distinguishing aggressive brain tumors non-invasively is a clinical challenge.
• Cancer cells exhibit reversed intracellular pH gradients, maintained by distinct regulatory mechanisms.
• Previous studies showed acute pH modulation in glioblastoma using MRI after blocking individual pH regulators.

Purpose of the Study:

• To simultaneously block five pH regulatory mechanisms and provide glucose in glioblastoma.
• To investigate if this approach enhances acute pH modulation for aggressive cancer identification.

Main Methods:

• Utilized a 9.4 T MRI scanner to acquire pH-sensitive CEST spectra (AACID).
• Injected a combination of five drugs (quercetin, cariporide, dichloroacetate, acetazolamide, pantoprazole) with and without glucose in mice with U87 glioblastoma.
• Scanned mice before and after drug/glucose administration.

Main Results:

• Combination drug injection increased tumor AACID by 0.1 ± 0.03, decreasing intracellular pH (pHi) by 0.4.
• Drug combination with glucose increased AACID by 0.18 ± 0.03, decreasing pHi by 0.72.
• Slight AACID increases were observed in contralateral tissue.

Conclusions:

• Combined drug treatment with glucose induced significant acute CEST MRI contrast, indicating tumor acidification.
• This method can help localize brain cancer and monitor chemotherapy response.
• The findings suggest potential for improved non-invasive brain tumor characterization.