Microfluctuations in a pH gradient create a harsh microenvironment in tumors, leaving behind the most aggressive, invasive, and drug-resistant tumor cells. Directly visualizing the spatiotemporal distribution of pH variations and accurately quantifying the dynamic acid-base changes during cancer treatment are critical to estimate prognosis and to evaluate therapeutic efficacy. However, the quantification of subtle pH variations dynamically and noninvasively remains challenging. The purpose of this study is to determine and visualize dynamic acid-base changes in solid tumors during anti-acid treatments by magnetic resonance imaging (MRI) using pH-sensitive nanoparticles. We report the development of pH-sensitive nanoparticles, MnO₂@BSA, that rapidly and strongly amplify the MR contrast signal in response to the extracellular acidic environment of solid tumors. The spatiotemporal distribution and dynamic fluctuations of pH heterogeneity in NCI-H460 lung tumors were observed with MnO₂@BSA at different time points after an anti-acid treatment with esomeprazole, which directly interferes with the acidic microenvironment of the tumor. Imaging results were validated using a pH microsensor. MRI of pH-sensitive MnO₂@BSA nanoparticles provided direct readouts of the kinetics of pH gradient fluctuations during esomeprazole treatment. A significant MR signal reduction was observed at the 48 h time point after treatment. The manipulated extracellular pH changes detected noninvasively by MRI coincided with the extracellular pH fluctuations measured with a pH microsensor (pH 6.12-6.63). Immunofluorescence and Western blot analyses confirmed the expression of V-ATPase in NCI-H460 lung cancer cells, which could be inhibited by esomeprazole, as detected by ELISA assay. Overall, these results demonstrate that MnO₂@BSA MRI has great potential as a noninvasive tool to accurately monitor pH fluctuations, thereby paving the way for the dynamic detection of acidic microenvironments in vivo without the need for pH microsensors.

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