Early detection is key to eradicating most diseases, especially cancers. Magnetic Resonance Imaging (MRI) is a powerful, noninvasive method to detect aberrant tissues within the body. Current clinically approved contrast agents, however, lack specificity for cancer cells, undergo inefficient relaxivity, and can be cytotoxic. We propose a new class of "smart" MRI agents that become activated selectively at cancer sites. For this proposal, the MRI agents will be turned "on" through selective enzymatic hydrolysis via cathepsin B, an enzyme that is overexpressed by many cancer cells. Not only will this method greatly enhance the intensity of the signal at cancerous over healthy cells and tissues, but the proposed agents should be less toxic and demonstrate greater relaxivity as compared to traditional Gd3+ based MRI agents. Furthermore, the proposed agents could enter cells in an energy independent process to give smart MRI agents that operate within cells. Future applications include equipping the MRI agents with targeting agents for greater cell/tissue selectivity. To detect cancers that do not overexpress suitable enzymes, different types of switches will be attached that will respond to redox chemistry or changes in pH.
The specific aims of this proposal are to create MRI agents, which can be optimized in the "off" and "on" modes, test their response to cathepsin B, measure their relaxivity values, and to determine their toxicities in cells and mice. The long-term goal is to provide researchers and the medical community tailor made smart MRI agents to advance the study of cellular functions and provide early detection of diseases, such as cancer.

Public Health Relevance

MRI is a widely used imaging tool to detect cancers at early stages within the body. Combining "smart" MRI agents that light up selectively at diseased tissues would greatly advance MRI, saving lives, reducing costs, and reducing debilitation. Presented in this proposal is a new class of smart MRI agents that turn on at sites that over express cathepsin B, a biomarker of several cancers. The long-term goal is to construct smart MRI agents that detect the unique features of cancers, such as enzyme expression, hypoxia, and acidic pH.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21EB012122-01A1
Application #
8302566
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Liu, Christina
Project Start
2012-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$157,000
Indirect Cost
$57,000
Name
University of Cincinnati
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Smithrud, David B; Wang, Xiaoyang; Tarapore, Pheruza et al. (2013) Crown Ether Host-Rotaxanes as Cytotoxic Agents. ACS Med Chem Lett 4:27-31