Early detection of ultra-small cancer is important, particularly early metastatic cancer detection, and can save the lives of breast cancer patients with existing therapies. The three core issues in developing a clinically feasible imaging technique are clinical suitability, safety, and sensitivity. We propose to develop a novel cellular MRI technique that combines the MRI phase blooming effect, the property of ferritin, and the tropism effect of certain cells towards tumors to address these three core issues simultaneously. MRI is a favorable imaging modality in clinical settings. However, to be imaged by MRI, cells need to be labeled with MRI detectable tags first. Ferritin is an ideal MRI tag because of its unique biological and MRI properties. Unlike superparamagnetic iron oxide (SPIO) nanoparticles which can only be internalized natively by phagocytic cells, cells in almost all living organisms have their natural ways to interact with ferritin, and ferritin has its natural wa to deal with irons. Like SPIO, ferritin can store a large amount of Fe3+ (up to 4500) and offers stronger contrast effects on MRI than conventional contrast agents. To detect an ultra-small object that is two to three orders of magnitude smaller than those currently detected with conventional MRI, we propose to use the susceptibility related blooming effect of MR phase. Unlike MR magnitude information, MR phase information had been largely discarded due to its high sensitivity to susceptibility, and recent studies have been focused on how to minimize/remove phase blooming effects or to correct them for T2*-magnitude imaging. We propose to do just the opposite: enhancing blooming effects in phase to detect ultra-small objects. The underlying assumption is that the MR phase blooming effect can spatially extend to two to three orders of the original size of the object. To detect tumors using phase blooming effect, we need to induce a susceptibility change specifically within tumor. Preliminary study indicates the capability of 4T1-piPSCs (protein induced pluripotent stem cells reprogrammed from breast cancer line 4T1) to migrate to not only primary but also metastatic tumors without migrating to the normal tissues. To that end, we hypothesize that by injecting QQ-ferritin labeled 4T1-piPSCs the susceptibility in tumors can be selectively enhanced, creating blooming effects that can be utilized to detect tumors that are two to three orders of magnitude smaller than those currently detected with MRI.
Our specific aims are: 1) to demonstrate the phase blooming effect is of two to three orders of the original object in in vitro models, and 2) to demonstrate te feasibility of imaging an ultra-small object that is two to three orders smaller than those currenty detected in a 4T1 mouse model in vivo. Although exclusively using 4T1-piPSC as the testing cell in this project, the proposed blooming effect and QQ ferritin based novel cellular MRI technique is developed for imaging all types of cells in the future, including research based or clinically proved therapeutic cells with tropism effects.

Public Health Relevance

This project is to determine the feasibility of a novel cellular MRI technique that utilize the property of ferritin, the phase blooming effect, and the tropism effect to address PQC5 in RFA-CA-12-020 and pave the way for its routine clinical usage in the future.

National Institute of Health (NIH)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZCA1)
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Zhang, Huiming
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Wayne State University
Schools of Medicine
United States
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