A Ratiometric MRI Probe With a Tuned Crosslinked Network for Quantitative Imaging of Physiological pH

Quantitative pH imaging is important for understanding pathological tissue environments and diagnosing diseases such as tumors and inflammation. MRI-based pH quantification has been developed based on several approaches including chemical exchange saturation transfer and ratiometric probes. However, existing approaches involve trade-offs in sensitivity, probe complexity, and reversibility, and robust quantitative pH imaging remains challenging. Previously, we reported ratiometric MRI probes based on a simple core-shell architecture in which a gadolinium-loaded core and a pH-responsive hydrogel shell independently contribute to longitudinal relaxivity (r₁) and transverse relaxivity (r₂), respectively. These probes enabled pH quantification using r₂/r₁ ratiometry although their pH responses were not optimized for the physiological pH range and their usable probe concentrations were limited. Here, we optimized the crosslinked network of the shell using tetraethylene glycol dimethacrylate, achieving substantial pH-dependent changes in r₂ around physiological pH while preserving r₁ and extending the usable probe concentration range. Electron microscopy confirmed the core-shell structure and elemental distribution of the probe. The resulting probe enabled quantitative pH imaging over pH 6.0-7.5 across probe concentrations from 0.5 to 1.5 wt.%. These findings establish a practical strategy for MRI-based pH quantification, offering a step toward standardized non-invasive pH measurements.