Advances in Monitoring Cell-Based Therapies with Magnetic Resonance Imaging: Future Perspectives

Cell-based therapies are currently being developed for applications in both regenerative medicine and in oncology. Preclinical, translational, and clinical research on cell-based therapies will benefit tremendously from novel imaging approaches that enable the effective monitoring of the delivery, survival, migration, biodistribution, and integration of transplanted cells. Magnetic resonance imaging (MRI) offers several advantages over other imaging modalities for elucidating the fate of transplanted cells both preclinically and clinically. These advantages include the ability to image transplanted cells longitudinally at high spatial resolution without exposure to ionizing radiation, and the possibility to co-register anatomical structures with molecular processes and functional changes. However, since cellular MRI is still in its infancy, it currently faces a number of challenges, which provide avenues for future research and development. In this review, we describe the basic principle of cell-tracking with MRI; explain the different approaches currently used to monitor cell-based therapies; describe currently available MRI contrast generation mechanisms and strategies for monitoring transplanted cells; discuss some of the challenges in tracking transplanted cells; and suggest future research directions

Non-Temperature Induced Effects of Magnetized Iron Oxide Nanoparticles in Alternating Magnetic Field in Cancer Cells

<div><p>This paper reports the damaging effects of magnetic iron-oxide nanoparticles (MNP) on magnetically labeled cancer cells when subjected to oscillating gradients in a strong external magnetic field. Human breast cancer MDA-MB-231 cells were labeled with MNP, placed in the high magnetic field, and subjected to oscillating gradients generated by an imaging gradient system of a 9.4T preclinical MRI system. Changes in cell morphology and a decrease in cell viability were detected in cells treated with oscillating gradients. The cytotoxicity was determined qualitatively and quantitatively by microscopic imaging and cell viability assays. An approximately 26.6% reduction in cell viability was detected in magnetically labeled cells subjected to the combined effect of a static magnetic field and oscillating gradients. No reduction in cell viability was observed in unlabeled cells subjected to gradients, or in MNP-labeled cells in the static magnetic field. As no increase in local temperature was observed, the cell damage was not a result of hyperthermia. Currently, we consider the coherent motion of internalized and aggregated nanoparticles that produce mechanical moments as a potential mechanism of cell destruction. The formation and dynamics of the intracellular aggregates of nanoparticles were visualized by optical and transmission electron microscopy (TEM). The images revealed a rapid formation of elongated MNP aggregates in the cells, which were aligned with the external magnetic field. This strategy provides a new way to eradicate a specific population of MNP-labeled cells, potentially with magnetic resonance imaging guidance using standard MRI equipment, with minimal side effects for the host.</p></div

Effects of treatment on cancer cells assessed by LIVE/DEAD^® assay microscopy in MDA-MB-231 cells.

<p>(A) LIVE/DEAD^® cell microscopic images of MNP-labeled, treated cells after 24 h. (i) Phase contrast optical image, (ii) distribution of live cells, (iii) distribution of dead cells, and (iv) merged image. (B) LIVE/DEAD^® cell microscopic images of unlabeled, treated cells after 24 h. (i) Phase contrast optical image, (ii) distribution of live cells, (iii) distribution of dead cells, and (iv) merged image.</p

Microscopic images of MNP aggregates orientation in MDA-MB-231 cells.

<p>Optical microscopy and TEM micrographs of the orientation of MDA-MB-231 cells incubated <b>(A)</b> at B₀ = 4.7T magnetic field (i) optical image at 40x, (ii) TEM at 17,500x (scale bar, 500 nm), and (iii) TEM at 65,000x (scale bar, 100 nm), or <b>(B)</b> at a non-magnetic condition (i) optical image at 40x, (ii) TEM at 17,500x (scale bar, 500 nm), and (iii) TEM at 65,000x (scale bar, 100 nm).</p

MNP-labeling and the therapeutic effect in MDA-MB-231cells.

<p><b>(A)</b> Prussian blue staining of unlabeled (i) and MNP-labeled (ii) cells. <b>(B)</b> MNP-labeled cells before treatment (i) and immediately after the treatment (ii).</p

Specifications of the treatment and the gradient system.

<p><b>(A)</b> Schematic diagram of the therapeutic system. <b>(B)</b> Gradient pulse sequence used in the high magnetic field. <b>(C)</b> Changes in local temperatures in agarose samples prepared with (100 μg/ml) and without MNP.</p

MTS cell viability assay.

<p>The percentage of dead cells in MNP-labeled/treated, unlabeled/treated, and MNP-labeled/untreated MDA-MB-231 cells was measured with respect to the unlabeled/untreated cell population.</p