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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA115531-02
Application #
7110193
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Menkens, Anne E
Project Start
2005-08-15
Project End
2010-04-30
Budget Start
2006-06-01
Budget End
2007-04-30
Support Year
2
Fiscal Year
2006
Total Cost
$270,774
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
800771545
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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