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

Abstract

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 microbeadcontaining 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.

Deep‐learning‐based super‐resolution for accelerating chemical exchange saturation transfer MRI

“…[1][2][3][4] By detecting these protons in an increasing library of biomolecules, which includes glucose, [5][6][7][8][9] mobile proteins and peptides, 10,11 lactate, 12 creatine, [13][14][15] glycogen, 16 and other metabolites, with high sensitivity and specificity, CEST MRI has shown promising clinical applications in disease diagnosis and guided treatment for many neurological diseases, including Alzheimer's disease (AD), 8,17 multiple sclerosis, [18][19][20][21] stroke, [22][23][24] and cancer. [25][26][27][28] For example, it has been demonstrated as a unique approach to differentiate tumor recurrence from radiation necrosis using the amide proton of proteins and peptides in cancer, which cannot be easily identify by other neuroimaging technologies. 29 To identify small regional changes in tissue environment, which is essential for its clinical applications, high-resolution CEST source images are needed.…”

“…Chemical exchange saturation transfer (CEST) MRI is a molecular imaging approach that enables the visualization of physiological environment in tissues by harnessing exchangeable protons in biomolecules as contrast agents 1–4 . By detecting these protons in an increasing library of biomolecules, which includes glucose, 5–9 mobile proteins and peptides, 10,11 lactate, 12 creatine, 13–15 glycogen, 16 and other metabolites, with high sensitivity and specificity, CEST MRI has shown promising clinical applications in disease diagnosis and guided treatment for many neurological diseases, including Alzheimer's disease (AD), 8,17 multiple sclerosis, 18–21 stroke, 22–24 and cancer 25–28 . For example, it has been demonstrated as a unique approach to differentiate tumor recurrence from radiation necrosis using the amide proton of proteins and peptides in cancer, which cannot be easily identify by other neuroimaging technologies 29 .…”

Novel Nanoprobe with Combined Ultrasonography/Chemical Exchange Saturation Transfer Magnetic Resonance Imaging for Precise Diagnosis of Tumors

“…By detecting the degree of reduction of free water signals, CEST can obtain significant physiological and biochemical information about the target tissue. CEST not only enables pH imaging but is also a type of non-invasive imaging suitable for studying tumor metabolism and the tumor microenvironment [ 23 , 24 , 25 , 26 , 27 , 28 ]. To further enhance the imaging effect, contrast agents are often employed [ 29 , 30 , 31 ].…”

“…ochemical information about the target tissue. CEST not only enables pH imaging but is also a type of non-invasive imaging suitable for studying tumor metabolism and the tumor microenvironment [23][24][25][26][27][28]. To further enhance the imaging effect, contrast agents are often employed [29][30][31].…”

Effect of Esomeprazole Treatment on Extracellular Tumor pH in a Preclinical Model of Prostate Cancer by MRI-CEST Tumor pH Imaging

“…Nevertheless, other assays are needed to complete the screening, such as biopsies and prostate-specific antigen (PSA) tests that look into specific biomarkers for achieving the best prognosis for patients [ 8 ]. An emerging MRI approach is the Chemical Exchange Saturation Transfer (CEST) imaging technique, which by exploiting pH sensitive agents can provide measurements of tissue pH [ 9 , 10 , 11 ]. In particular, the administration of Iopamidol, a pH-responsive contrast agent, allows accurate quantitative assessments of extracellular tumor pH in vivo [ 9 , 12 , 13 , 14 ].…”