MRI is the imaging modality of choice for soft tissue imaging but in general lacks sufficient sensitivity for molecular imaging of biological processes associated with cancer. Although Gd-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 molecular imaging modalities. Paramagnetic complexes based on chemical exchange saturation transfer (PARACEST) offer a new mechanism for MRI contrast that could potentially improve sensitivity substantially and at the same time offer the unique ability to modulate imaging contrast (on/off) plus reflect specific tissue environments or physiology (pH, redox state, glucose levels).
The first aim i s to develop bifunctional ligands based on PARACEST for attachment to protein surface residues. These will be attached to model proteins and the water exchange characteristics of the resulting products will be evaluated and the lower detection limit of these systems evaluated by MRI. Two specific targeting systems will be evaluated, a phosphatidyl serine antibody and adenovirus particles with modified knob domain proteins, with the goal of creating activatible PARACEST systems that are completely """"""""off"""""""" unless bound to their intended targets in vivo. A PARACEST agent will be developed that is trapped only in hypoxic tumor cells. The overriding goal of this project is to develop a new paradigm of molecular imaging agents for anatomical MR imaging of cancer based upon high sensitivity PARACEST agents.
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|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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