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 #
5R01CA115531-07
Application #
8231390
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Menkens, Anne E
Project Start
2005-08-15
Project End
2016-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
7
Fiscal Year
2012
Total Cost
$267,556
Indirect Cost
$99,017
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Evbuomwan, Osasere M; Lee, Joohwan; Woods, Mark et al. (2014) The presence of fast-exchanging proton species in aqueous solutions of paraCEST agents can impact rate constants measured for slower exchanging species when fitting CEST spectra to the Bloch equations. Inorg Chem 53:10012-4
Gulaka, Praveen K; Rojas-Quijano, Federico; Kovacs, Zoltan et al. (2014) GdDO3NI, a nitroimidazole-based T1 MRI contrast agent for imaging tumor hypoxia in vivo. J Biol Inorg Chem 19:271-9
Sagiyama, Koji; Mashimo, Tomoyuki; Togao, Osamu et al. (2014) In vivo chemical exchange saturation transfer imaging allows early detection of a therapeutic response in glioblastoma. Proc Natl Acad Sci U S A 111:4542-7
Lin, Chien-Yuan; Yadav, Nirbhay N; Ratnakar, James et al. (2014) In vivo imaging of paraCEST agents using frequency labeled exchange transfer MRI. Magn Reson Med 71:286-93
Soesbe, Todd C; Ratnakar, S James; Milne, Mark et al. (2014) Maximizing T2-exchange in Dy(3+)DOTA-(amide)X chelates: fine-tuning the water molecule exchange rate for enhanced T2 contrast in MRI. Magn Reson Med 71:1179-85
Do, Quyen N; Ratnakar, James S; Kovács, Zoltán et al. (2014) Redox- and hypoxia-responsive MRI contrast agents. ChemMedChem 9:1116-29
Mani, Tomoyasu; Opina, Ana Christina L; Zhao, Piyu et al. (2014) The stereochemistry of amide side chains containing carboxyl groups influences water exchange rates in EuDOTA-tetraamide complexes. J Biol Inorg Chem 19:161-71
Song, Bo; Wu, Yunkou; Yu, Mengxiao et al. (2013) A europium(III)-based PARACEST agent for sensing singlet oxygen by MRI. Dalton Trans 42:8066-9
Vinogradov, Elena; Sherry, A Dean; Lenkinski, Robert E (2013) CEST: from basic principles to applications, challenges and opportunities. J Magn Reson 229:155-72
Zhang, Shanrong; Zhou, Kejin; Huang, Gang et al. (2013) A novel class of polymeric pH-responsive MRI CEST agents. Chem Commun (Camb) 49:6418-20

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