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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA115531-09
Application #
8610140
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Menkens, Anne E
Project Start
2005-08-15
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
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
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
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
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
Wu, Yunkou; Zhang, Shanrong; Soesbe, Todd C et al. (2016) pH imaging of mouse kidneys in vivo using a frequency-dependent paraCEST agent. Magn Reson Med 75:2432-41
Kumas, Cemile; Fernando, W Shirangi; Zhao, Piyu et al. (2016) Unexpected Changes in the Population of Coordination Isomers for the Lanthanide Ion Complexes of DOTMA-Tetraglycinate. Inorg Chem 55:9297-305
Xing, Yixun; Jindal, Ashish K; Regueiro-Figueroa, Martín et al. (2016) The Relationship between NMR Chemical Shifts of Thermally Polarized and Hyperpolarized 89 Y Complexes and Their Solution Structures. Chemistry 22:16657-16667
Funk, Alexander M; Clavijo Jordan, Veronica; Sherry, A Dean et al. (2016) Oxidative Conversion of a Europium(II)-Based T1 Agent into a Europium(III)-Based paraCEST Agent that can be Detected In Vivo by Magnetic Resonance Imaging. Angew Chem Int Ed Engl 55:5024-7
Fernando, W Shirangi; Martins, André F; Zhao, Piyu et al. (2016) Breaking the Barrier to Slow Water Exchange Rates for Optimal Magnetic Resonance Detection of paraCEST Agents. Inorg Chem 55:3007-14

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