nCP:Fe-A Biomineral Magnetic Nanocontrast Agent for Tracking Implanted Stem Cells in Brain Using MRI

In vivo tracking of transplanted stem cells to monitor their migration, biodistribution, and engraftment in the host tissue is important for assessing the efficacy of stem cell therapeutics. Here, we report a biomineral nanocontrast agent, iron doped calcium phosphate nanoparticles (nCP:Fe), for the in vivo tracking of stem cells in brain using magnetic resonance imaging (MRI). We have synthesized similar to 100 nm sized nCP nanoparticles doped with 9.81 wt % Fe3+. In vitro studies using mesenchymal stem cells (MSCs) showed excellent biocompatibility for nCP:Fe with similar to 87% labeling efficiency under optimized conditions (100 mu g/mL, 6 h). Most importantly, the labeling was not found to affect the neurogenic differentiation potential of MSCs. MRI of labeled cells (similar to 22.34 pg Fe/cell) showed significant reduction in T2 relaxation time from 195 to 89 ms, rendering dark contrast. In vivo transplantation of labeled cells (1 x 10(6) cells) in external capsule of healthy rat brain showed a clearly distinguishable hypointense (dark) region in T2 weighted MR images, which remained visible up to 30 days. Subsequently, MRI tracking of labeled MSCs transplanted intracerebrally, 3 mm near to the LPS induced inflammatory site in brain, showed successful migration of labeled MSCs toward the site of inflammation. The cell migration was confirmed ex vivo by Prussian-blue (Fe3+) and Alizarin-red (Ca2+) staining of tissue sections, where individual cells were found migrated to the site of inflammation over a period of 30 days. In summary, our results clearly show that, as a biocompatible mineral composition, nCP:Fe is a promising magnetic nanocontrast agent for MRI based cell tracking in vivo.