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Science to Practice |
ImaRx Therapeutics, 1635 E 18th St, Tucson, AZ 85719 eunger@imarx.com
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The ability to image cellular migration in vivo could be very useful for studying inflammation, tumors, the immune response, and the effects of stem cell therapy. In the current issue of Radiology, Arbab et al (1) show that cells can be labeled with a commercially available iron oxide product, that they can be imaged for weeks after such labeling with magnetic resonance (MR), and that the label does not damage the cells. Their work helps pave the way for human studies.
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Iron oxide nanoparticles provide MR contrast at very low concentrations, in the nanomolar range (2). Under certain conditions, cells will be labeled with these nanoparticles (3). Labeled cells can thus be imaged and detected with MR imaging (4).
The authors performed studies with a U.S. Food and Drug Administration (FDA)-approved MR contrast agent, Feridex (iron oxide nanoparticles; Berlex Laboratories, Wayne, NJ) (5), to label human cancer and stem cells. They used a cationic (positively charged) amino acid polymer, poly-L-lysine, to form a complex with the iron oxide nanoparticles. Since both the cell membrane and the iron oxide nanoparticles have a net negative charge, cells do not normally take up the nanoparticles. The positively charged poly-L-lysine, however, forms a complex with the iron oxide nanoparticles, changing the electrostatic properties of the surfaces of the particles and causing cell uptake. The iron oxide nanoparticles are then sequestered within endosomes in the cells, and the cells retain their biologic properties. Labeled cells will migrate throughout the body as they normally would.
Other investigators have also shown that cells can be labeled with iron oxide nanoparticles (3,4,6,7), but several of the findings by Arbab et al (1) are particularly noteworthy. Since they used a commercially available FDA-approved MR contrast agent, the potential for clinical trials is expedited. The technique of labeling that the authors developed shows very high efficiency for cell labeling. Moreover, the authors showed that uptake of iron oxides by the cells is not toxic to the cells and that low concentrations of cells (only several thousand cells) can be seen on MR images.
Compared with other techniques for following cellular migration in vivo, MR imaging can be performed for a longer period of time than, for example, imaging with indium 111–oxine labels. Dynamic migration of cells can thus be studied during clinically useful time periods. In stem cell therapy, it would be useful to be able to see where the cells go after they are administered to a patient. In their study, Arbab et al also showed that the gradual disappearance of contrast agent (iron) from the cells occurs with cell division, owing to dilution. Therefore, reduction in contrast over time might be used to assess the rate of cell division.
The Practice
Clinical use.—The authors plan to begin clinical studies with labeled peripheral blood mononuclear leukocytes and CD34+ cells in patients for imaging of cancer and multiple sclerosis. The cells can be obtained from patients by means of apharesis, labeled ex vivo, and then readministered. Clinical applications for cancer imaging may improve tumor detection but should also improve our understanding of trafficking of immune cells in cancer and in immunotherapy. With regard to multiple sclerosis, the ability to study migration of immune cells into plaques may improve our understanding of the disease process and assessment of the response to therapy for multiple sclerosis.
Other applications include detection of inflammation but with the improved spatial, contrast, and temporal resolutions of MR imaging, compared with those of scintigraphy. Clinical applications are presently under investigation in which autologous stem cells derived from the patient’s own marrow and peripheral blood are used, such as stem cell therapy for treatment of myocardial infarction. Patients are treated with granulocyte macrophage colony stimulating factor, and stem cells are then harvested from the peripheral blood by using apharesis (8).
Future opportunities and challenges.—Before conducting clinical trials, it may be necessary to have the poly-L-lysine manufactured according to good manufacturing practice guidelines and to submit an investigational new drug application to the FDA. Depending on their review, the FDA may require additional studies prior to the initiation of human trials.
Another challenge will be to apply MR imaging technology to different clinical settings with magnetically labeled cells. For cardiac applications, this will involve compensating for cardiac pulsation and blood flow.
The contrast effect of the labeled cells increases as the field strength of the magnet increases. The authors have shown us that it is feasible to image low concentrations of cells at 1.5 T. The increasing clinical use of even higher field strength magnets—for example, 3.0 T—will make the contrast even more robust.
Summary
Iron oxide–labeled cell imaging with MR is emerging as a powerful new technique. The authors’ work moves this technology closer to clinical application and provides a new tool to researchers studying in vivo cell biology.
FOOTNOTES
See also the article by Arbab et al in this issue.
REFERENCES
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