Magnetic resonance imaging (MRI), the most widely used imaging modality for soft tissues, in general lacks sufficient sensitivity for molecular imaging of biological processes associated with cancer. Although Gd3+based contrast agents are widely used in clinical MRI as non-specific extracellular agents, new approaches need to be developed to bring MRI into competition with optical and nuclear methods for molecular imaging of cancer. A new class of responsive paramagnetic chemical exchange saturation transfer (PARACEST) agent has been designed as highly specific reporters of tumor physiology and metabolism. Although several groups have recognized their potential importance as molecular imaging agents, their practical application to tumor imaging has not been realized at this point largely because of background interference from the inherent magnetization transfer (MT) signal from all tissues. In this project, we propose a practical solution to eliminate this background MT signal so the inherent molecular specificity of these reporter molecules can be fully realized in vivo. A novel molecular design is proposed that will yield a platform of responsive MRI agents for discriminating regions of low pH, hypoxia and reactive oxygen species (ROS) in tumors using standard clinical MRI scanners. These three indices, pH, hypoxia and excess ROS, are all hallmarks of rapidly proliferating cells so having a stable of responsive agents capable of sensing these tissue biomarkers would be extremely valuable for monitoring tumor metabolism. Our objective is to implement all three responsive agents in vivo in animal tumors using agent concentrations that would be considered acceptable for human use and without interference from tissue MT signals by the end of this 5 year project. A second newer class of probes called T2exch agents will be tested and evaluated as reporters of cancer-related protease activities by MRI. If successful, the agents developed in this project will make MRI competitive as an effective molecular imaging tool for cancer diagnosis.
Magnetic resonance imaging (MRI) is widely used to detect tumors but provides little or no information about tumor biology, tumor metabolism or tumor microenvironment. This project involves developing a new class of responsive imaging agents to act as highly specific reporters of tumor physiology and metabolism. A low extracellular pH, hypoxia (low oxygen), and the presence of reactive oxygen species (ROS) are all hallmarks of rapidly proliferating cells so having a stable of responsive MRI agents capable of sensing these tissue biomarkers would be extremely valuable for monitoring tumor biology.
|Kikuchi, Kazufumi; Ishimatsu, Keisuke; Zhang, Shanrong et al. (2018) Presaturation Power Adjusted Pulsed CEST: A Method to Increase Independence of Target CEST Signals. Contrast Media Mol Imaging 2018:3141789|
|Dharmarwardana, Madushani; Martins, André F; Chen, Zhuo et al. (2018) Nitroxyl Modified Tobacco Mosaic Virus as a Metal-Free High-Relaxivity MRI and EPR Active Superoxide Sensor. Mol Pharm 15:2973-2983|
|Burnett, Marianne E; Adebesin, Bukola; Ratnakar, S James et al. (2018) Crystallographic Characterization and Non-Innocent Redox Activity of the Glycine Modified DOTA Scaffold and Its Impact on EuIII Electrochemistry. Eur J Inorg Chem 2018:1556-1562|
|Zhang, Lei; Evbuomwan, Osasere M; Tieu, Michael et al. (2017) Protonation of carboxyl groups in EuDOTA-tetraamide complexes results in catalytic prototropic exchange and quenching of the CEST signal. Philos Trans A Math Phys Eng Sci 375:|
|Zhang, Lei; Martins, André F; Mai, Yuyan et al. (2017) Imaging Extracellular Lactate In Vitro and In Vivo Using CEST MRI and a Paramagnetic Shift Reagent. Chemistry 23:1752-1756|
|Farashishiko, Annah; Plush, Sally E; Maier, Karley B et al. (2017) Crosslinked shells for nano-assembled capsules: a new encapsulation method for smaller Gd3+-loaded capsules with exceedingly high relaxivities. Chem Commun (Camb) 53:6355-6358|
|Singh, Jaspal; Rustagi, Vineeta; Zhang, Shanrong et al. (2017) On-bead combinatorial synthesis and imaging of europium(III)-based paraCEST agents aids in identification of chemical features that enhance CEST sensitivity. Magn Reson Chem 55:747-753|
|Zhang, Lei; Martins, André F; Zhao, Piyu et al. (2017) Enantiomeric Recognition of d- and l-Lactate by CEST with the Aid of a Paramagnetic Shift Reagent. J Am Chem Soc 139:17431-17437|
|Burnett, Marianne E; Adebesin, Bokola; Funk, Alexander M et al. (2017) Electrochemical investigation of the Eu3+/2+ redox couple in complexes with variable numbers of glycinamide and acetate pendant arms. Eur J Inorg Chem 2017:5001-5005|
|Zhang, Lei; Martins, André F; Zhao, Piyu et al. (2017) Lanthanide-Based T2ex and CEST Complexes Provide Insights into the Design of pH Sensitive MRI Agents. Angew Chem Int Ed Engl 56:16626-16630|
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