Evaluating pH in the Extracellular Tumor Microenvironment Using CEST MRI and Other Imaging Methods

Chen, Liu Qi; Pagel, Mark

doi:10.1155/2015/206405

Cited by 105 publications

(90 citation statements)

References 106 publications

(141 reference statements)

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“…Overall, these results showed that stronger CEST signals can be detected under mildly acidic or neutral physiological conditions, relative to strongly acidic physiological conditions. Solid tumors are often mildly acidic, because tumor cells often have enhanced aerobic glycolysis that produces excess lactic acid, known as the Warburg effect . Therefore, the CEST effect of GR‐4Am‐SA has a dependence on pH that is well suited for the study of solid tumors.…”

Section: Resultsmentioning

confidence: 99%

Detecting in vivo urokinase plasminogen activator activity with a catalyCEST MRI contrast agent

et al. 2017

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Urokinase plasmogen activator (uPA) promotes tumor invasion and metastasis. The monitoring of uPA activity using molecular imaging may have prognostic value and be predictive for response to anti-cancer therapies. However, the detection of in vivo enzyme activity with molecular imaging remains a challenge. To address this problem, we designed a nonmetallic contrast agent, GR-4Am-SA, that can be detected with Chemical Exchange Saturation Transfer Magnetic Resonance Imaging (CEST MRI). This agent has a peptide that is cleaved by uPA which causes a CEST signal at 5.0 ppm to decrease, and also has a salicylic acid moiety that can produce a CEST signal at 9.5 ppm which is largely unresponsive to enzyme activity. The two CEST signals were used to determine a reaction coordinate, representing the extent of enzyme-catalyzed cleavage of the GR-4Am-SA agent during an experimental study. Initial biochemical studies showed that GR-4Am-SA could detect uPA activity in reducing conditions. Subsequently, we used our catalyCEST MRI protocol with the agent to detect the uPA catalysis of GR-4Am-SA in a flank xenograft model of Capan-2 pancreatic cancer. The results showed an average reaction coordinate of 80% ± 8%, which was strongly dependent on the CEST signal at 5.0 ppm. The relative independence of the reaction coordinate on the CEST signal at 9.5 ppm showed that the detection of enzyme activity was largely independent of the concentration of GR-4Am-SA within the tumor tissue. These results demonstrated the advantages of a single CEST agent with biomarker-responsive and unresponsive signals for reliably assessing enzyme activity during in vivo cancer studies.

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Section: Resultsmentioning

confidence: 99%

Detecting in vivo urokinase plasminogen activator activity with a catalyCEST MRI contrast agent

et al. 2017

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“…A lower saturation power during CEST MRI studies can cause the reaction coordinate to be underestimated, which may be addressed by performing additional MRI scans that map the variability in saturation power applied in vivo , known as a B 1 map [26]. Also, a lower pH causes the reaction coordinate to be underestimated, which should be addressed during in vivo studies of tumors with high metabolic acidosis [27]. For example, we estimated that the shKLK6 model would need to be ≥0.9 pH units lower than the HCT116 model to account for our in vivo catalyCEST MRI results described below, which is unrealistic for these similar tumor cell lines.…”

Section: Discussionmentioning

confidence: 99%

Detection of Enzyme Activity and Inhibition during Studies in Solution, In Vitro and In Vivo with CatalyCEST MRI

et al. 2017

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Purpose The detection of enzyme activities and evaluation of enzyme inhibitors have been challenging with magnetic resonance imaging (MRI). To address this need, we have developed a diamagnetic, nonmetallic contrast agent and a protocol known as catalyCEST MRI that uses chemical exchange saturation transfer (CEST) to detect enzyme activity as well as enzyme inhibition. Procedures We synthesized a diamagnetic MRI contrast agent that has enzyme responsive and enzyme unresponsive CEST signals. We tested the ability of this agent to detect the activity of kallikrein 6 (KLK6) in biochemical solutions, in vitro and in vivo, with and without a KLK6 inhibitor. Results The agent detected KLK6 activity in solution and also detected KLK6 inhibition by antithrombin III. KLK6 activity was detected during in vitro studies with HCT116 colon cancer cells, relative to the detection of almost no activity in a KLK6-knockdown HCT116 cell line and HCT116 cells treated with antithrombin III inhibitor. Finally, strong enzyme activity was detected within an in vivo HCT116 tumor model, while lower enzyme activity was detected in a KLK6 knockdown tumor model and in the HCT116 tumor model treated with antithrombin III inhibitor. In all cases, comparisons of the enzyme responsive and enzyme unresponsive CEST signals were critical for the detection of enzyme activity. Conclusions This study has established that catalyCEST MRI with an exogenous diaCEST agent can evaluate enzyme activity and inhibition in solution, in vitro and in vivo.

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“…The first five repetitions of the post-injection scans of the patient with metastatic ovarian cancer had CEST contrast greater than 2*sqrt (2)*noise, which was approximately 2 %. Contrast greater than this threshold has a 95 % probability of arising from the agent [2]. The remaining 10 repetitions had CEST contrast less than 2*sqrt (2)*noise so those repetitions were discarded from data analysis and we only averaged the first five repetitions of the post-injection scans for our average post-injection image.…”

Section: Methodsmentioning

confidence: 99%

“…An increased glycolysis leads to increased production of lactic acid, which causes the extracellular pH (pHe) to become lower in the tumor microenvironment [2]. Aggressive tumors are often more metabolically active, and therefore, the tumor pHe may be used to evaluate tumor aggressiveness [3, 4].…”

Section: Introductionmentioning

confidence: 99%

Clinical Translation of Tumor Acidosis Measurements with AcidoCEST MRI

et al. 2016

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Purpose We optimized acido-chemical exchange saturation transfer (acidoCEST) magnetic resonance imaging (MRI), a method that measures extracellular pH (pHe), and translated this method to the radiology clinic to evaluate tumor acidosis. Procedures A CEST-FISP MRI protocol was used to image a flank SKOV3 tumor model. Bloch fitting modified to include the direct estimation of pH was developed to generate parametric maps of tumor pHe in the SKOV3 tumor model, a patient with high-grade invasive ductal carcinoma, and a patient with metastatic ovarian cancer. The acidoCEST MRI results of the patient with metastatic ovarian cancer were compared with DCE MRI and histopathology. Results The pHe maps of a flank model showed pHe measurements between 6.4 and 7.4, which matched with the expected tumor pHe range from past acidoCEST MRI studies in flank tumors. In the patient with metastatic ovarian cancer, the average pHe value of three adjacent tumors was 6.58, and the most reliable pHe measurements were obtained from the right posterior tumor, which favorably compared with DCE MRI and histopathological results. The average pHe of the kidney showed an average pHe of 6.73 units. The patient with high-grade invasive ductal carcinoma failed to accumulate sufficient agent to generate pHe measurements. Conclusions Optimized acidoCEST MRI generated pHe measurements in a flank tumor model and could be translated to the clinic to assess a patient with metastatic ovarian cancer.

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Evaluating pH in the Extracellular Tumor Microenvironment Using CEST MRI and Other Imaging Methods

Cited by 105 publications

References 106 publications

Detecting in vivo urokinase plasminogen activator activity with a catalyCEST MRI contrast agent

Detecting in vivo urokinase plasminogen activator activity with a catalyCEST MRI contrast agent

Detection of Enzyme Activity and Inhibition during Studies in Solution, In Vitro and In Vivo with CatalyCEST MRI

Clinical Translation of Tumor Acidosis Measurements with AcidoCEST MRI

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