Electron Paramagnetic Resonance Implemented with Multiple Harmonic Detections Successfully Maps Extracellular pH In Vivo.
Ririko NakaokaKazuhiro KatoKumiko YamamotoHironobu YasuiShingo MatsumotoIgor A KirilyukValery V KhramtsovOsamu InanamiHiroshi HirataPublished in: Analytical chemistry (2023)
Extracellular acidification indicates a metabolic shift in cancer cells and is, along with tissue hypoxia, a hallmark of tumor malignancy. Thus, non-invasive mapping of extracellular pH (pHe) is essential for researchers to understand the tumor microenvironment and to monitor tumor response to metabolism-targeting drugs. While electron paramagnetic resonance (EPR) has been successfully used to map pHe in mouse xenograft models, this method is not sensitive enough to map pHe with a moderate amount of exogenous pH-sensitive probes. Here, we show that a modified EPR system achieves twofold higher sensitivity by using the multiple harmonic detection (MHD) method and improves the robustness of pHe mapping in mouse xenograft models. Our results demonstrate that treatment of a mouse xenograft model of human-derived pancreatic ductal adenocarcinoma cells with the carbonic anhydrase IX (CAIX) inhibitor U-104 delays tumor growth with a concurrent tendency toward further extracellular acidification. We anticipate that EPR-based pHe mapping can be expanded to monitor the response of other metabolism-targeting drugs. Furthermore, pHe monitoring can also be used for the development of improved metabolism-targeting cancer treatments.
Keyphrases
- high density
- high resolution
- cancer therapy
- endothelial cells
- induced apoptosis
- energy transfer
- small molecule
- oxidative stress
- drug delivery
- radiation therapy
- signaling pathway
- high intensity
- induced pluripotent stem cells
- locally advanced
- cell proliferation
- mass spectrometry
- quantum dots
- photodynamic therapy
- electron transfer
- loop mediated isothermal amplification
- pluripotent stem cells
- nucleic acid