Enzyme activities are important biomarkers for cancer diagnoses and assessing chemotherapies. We have developed MRI contrast agents that are detected via Chemical Exchange Saturation Transfer (CEST) and that are responsive to enzyme activity. We have also developed CEST MRI methods that can detect these agents within in vivo tumor tissues in mouse models of human cancers. Importantly, we can selectively detect an enzyme-responsive agent and an unresponsive "control" agent during the same study in the same tissue location, which improves our evaluation of enzyme activity within the mouse model. Just as multiple fluorophores have revolutionized the evaluation of enzyme activities during in vitro and ex vivo studies, CEST agents and CEST MRI has potential to revolutionize the evaluation of enzyme activities in vivo. We propose to build on our recent research successes by linking enzyme-responsive and control agents to create a dimeric agent, by comparing paramagnetic and diamagnetic CEST agents, and by optimizing the saturation period of the CEST MRI acquisition protocol in order to improve the detection sensitivity of CEST MRI. We also propose to develop enzyme-responsive CEST agents that semi-quantitatively detect the activities of urokinase Plasminogen Activator (uPA) in mouse models of pancreatic cancer, Prostate Specific Membrane Antigen (PSMA) in mouse models of prostate cancer, and transglutaminase (TG2) in mouse models of breast cancer. We propose to use these CEST agents and our in vivo CEST MRI methodology to investigate three biomedical aims: A) to predict the effect of chemotherapies before they are administered to mouse models;B) to evaluate early response to chemotherapies;C) to investigate our hypothesis that enzyme activity is a more accurate biomarker than enzyme expression for predicting and evaluating therapeutic effects. Together, these studies address our overarching goal of eventually using CEST agents and CEST MRI to tailor the choice of chemotherapy and treatment regimen for each individual patient, in order to support the paradigm of personalized medicine.
We propose to continue to develop CEST agents and CEST MRI methods that detect enzyme activities within in vivo mouse models of cancer. We propose to use our CEST agents and CEST MRI methods to evaluate chemotherapies and to assess whether enzyme activity is a better biomarker than enzyme expression.
|Hingorani, Dina V; Montano, Luis A; Randtke, Edward A et al. (2016) A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals. Contrast Media Mol Imaging 11:130-8|
|Sinharay, Sanhita; FernÃ¡ndez-Cuervo, Gabriela; Acfalle, Jasmine P et al. (2016) Detection of Sulfatase Enzyme Activity with a CatalyCEST MRI Contrast Agent. Chemistry 22:6491-5|
|Sinharay, Sanhita; Pagel, Mark D (2016) Advances in Magnetic Resonance Imaging Contrast Agents for Biomarker Detection. Annu Rev Anal Chem (Palo Alto Calif) 9:95-115|
|Sinharay, Sanhita; Randtke, Edward A; Jones, Kyle M et al. (2016) Noninvasive detection of enzyme activity in tumor models of human ovarian cancer using catalyCEST MRI. Magn Reson Med :|
|FernÃ¡ndez-Cuervo, Gabriela; Sinharay, Sanhita; Pagel, Mark D (2016) A CatalyCEST MRI Contrast Agent that Can Simultaneously Detect Two Enzyme Activities. Chembiochem 17:383-7|
|Daryaei, Iman; Randtke, Edward A; Pagel, Mark D (2016) A biomarker-responsive T2ex MRI contrast agent. Magn Reson Med :|
|Yoshimaru, Eriko S; Randtke, Edward A; Pagel, Mark D et al. (2016) Design and optimization of pulsed Chemical Exchange Saturation Transfer MRI using a multiobjective genetic algorithm. J Magn Reson 263:184-92|
|Hingorani, Dina V; Bernstein, Adam S; Pagel, Mark D (2015) A review of responsive MRI contrast agents: 2005-2014. Contrast Media Mol Imaging 10:245-65|
|Randtke, Edward A; Chen, Liu Qi; Pagel, Mark D (2014) The reciprocal linear QUEST analysis method facilitates the measurements of chemical exchange rates with CEST MRI. Contrast Media Mol Imaging 9:252-8|
|Randtke, Edward A; Chen, Liu Qi; Corrales, L Rene et al. (2014) The Hanes-Woolf linear QUESP method improves the measurements of fast chemical exchange rates with CEST MRI. Magn Reson Med 71:1603-12|
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