Monitor Tumor pHe and Response Longitudinally during Treatment Using CEST MRI-Detectable Alginate Microbeads

[Image: see text] Imaging pHe of the tumor microenvironment has paramount importance for characterizing aggressive, invasive tumors, as well as therapeutic responses. Here, a robust approach to image pH changes in the tumor microenvironment longitudinally and during sodium bicarbonate treatment was reported. The pH-sensing microbeads were designed and prepared based on materials approved for clinical use, i.e., alginate microbead-containing computed tomography (CT) contrast-agent (iopamidol)-loaded liposomes (Iop-lipobeads). This Iop-lipobead prepared using a customized microfluidic device generated a CEST contrast of 10.6% at 4.2 ppm at pH 7.0, which was stable for 20 days in vitro. The CEST contrast decreased by 11.8% when the pH decreased from 7.0 to 6.5 in vitro. Optimized Iop-lipobeads next to tumors showed a significant increase of 19.7 ± 6.1% (p < 0.01) in CEST contrast at 4.2 ppm during the first 3 days of treatment and decreased to 15.2 ± 4.8% when treatment stopped. Notably, percentage changes in Iop-lipobeads were higher than that of amide CEST (11.7% and 9.1%) in tumors during and after treatment. These findings demonstrated that the Iop-lipobead could provide an independent and sensitive assessment of the pHe changes for a noninvasive and longitudinal monitoring of the treatment effects using multiple CEST contrast.