Diverse types of probes have been employed to image cell death, in order to determine the immune mediated damage of transplanted organs, the extent of ischemia related damage in the heart or brain, and the response to cancer chemotherapy. Despite the role cell death plays in diverse pathologies, there currently is no imaging agent that meets the widespread need to image this process. Vital fluorochromes (VF's), key reagents in cell death research, bind dead but not live cells. However, light attenuation blocks the clinical use of VF's as fluorescent probes, and they lack the reactive groups needed for the conjugation of radioactive or magnetic labels. Recently, we synthesized a modified version of a commercially available VF known as TO-PRO 1 and attached a paramagnetic gadolinium ion. The resulting multimodal vital fluorochrome (MVF) was able to detect dead cells in vitro and in vivo by MRI. MVF's provide a broad approach to imaging cell death based on well-understood VF behavior. In addition the selective disposition of VF's in dead cells can be easily verified by common research techniques in cell biology (FACS, microscopy). We shall synthesize MVF's with different physical and optical properties, and demonstrate their utility in diverse models of human diseases (ischemia, cancer) by MRI and PET. A gadolinium MVF designed for imaging cell death by MRI and an 18F MVF for imaging cell death by PET can become widely used, highly general tools in diagnostic imaging.

Public Health Relevance

Despite the key role cell death plays in diverse pathologies, there currently is no imaging agent that meets the widespread need to image this process. Vital fluorochromes (VF's), key reagents in cell death research, bind dead but not live cells. However, VF's lack the reactive groups needed for the conjugation of radioactive or magnetic labels and cannot be used with clinical imaging modalities. Our recent advances in fluorochrome chemistry permit the attachment of imaging reporter groups to VF's, and their use for imaging cell death by different imaging modalities. A gadolinium MVF designed for imaging cell death by MRI and an 18F MVF for imaging cell death by PET will be developed and can become widely used, highly general tools in diagnostic imaging.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB011996-04
Application #
8461155
Study Section
Special Emphasis Panel (ZRG1-SBIB-A (50))
Program Officer
Conroy, Richard
Project Start
2010-07-15
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$359,722
Indirect Cost
$155,779
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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