Gd₂O₃ nanoparticles in hematopoietic cells for MRI contrast enhancement

Anna Hedlund^1,2, Maria Ahrén³, Håkan Gustafsson^1,2, Natalia Abrikossova³, Marcel Warntjes^2,4, Jan-Ingvar Jönsson⁵, Kajsa Uvdal³, Maria Engström^1,2
1Division of Radiology, Department of Medical and Health Sciences, ²Center for Medical Image Science and Visualization, ³Division of Molecular Surface Physics and Nanoscience, Department of Physics, Chemistry, and Biology, ⁴Division of Clinical Physiology, Department of Medicine and Health Sciences, ⁵Department of Clinical and Experimental Medicine, Experimental Hematology Unit, Linköping University, Linköping, Sweden

Abstract: As the utility of magnetic resonance imaging (MRI) broadens, the importance of having specific and efficient contrast agents increases and in recent time there has been a huge development in the fields of molecular imaging and intracellular markers. Previous studies have shown that gadolinium oxide (Gd₂O₃) nanoparticles generate higher relaxivity than currently available Gd chelates: In addition, the Gd₂O₃ nanoparticles have promising properties for MRI cell tracking. The aim of the present work was to study cell labeling with Gd₂O₃ nanoparticles in hematopoietic cells and to improve techniques for monitoring hematopoietic stem cell migration by MRI. Particle uptake was studied in two cell lines: the hematopoietic progenitor cell line Ba/F3 and the monocytic cell line THP-1. Cells were incubated with Gd₂O₃ nanoparticles and it was investigated whether the transfection agent protamine sulfate increased the particle uptake. Treated cells were examined by electron microscopy and MRI, and analyzed for particle content by inductively coupled plasma sector field mass spectrometry. Results showed that particles were intracellular, however, sparsely in Ba/F3. The relaxation times were shortened with increasing particle concentration. Relaxivities, r₁ and r₂ at 1.5 T and 21°C, for Gd₂O₃ nanoparticles in different cell samples were 3.6–5.3 s^-1 mM^-1 and 9.6–17.2 s^-1 mM^-1, respectively. Protamine sulfate treatment increased the uptake in both Ba/F3 cells and THP-1 cells. However, the increased uptake did not increase the relaxation rate for THP-1 as for Ba/F3, probably due to aggregation and/or saturation effects. Viability of treated cells was not significantly decreased and thus, it was concluded that the use of Gd₂O₃ nanoparticles is suitable for this type of cell labeling by means of detecting and monitoring hematopoietic cells. In conclusion, Gd₂O₃ nanoparticles are a promising material to achieve positive intracellular MRI contrast; however, further particle development needs to be performed.

Keywords: gadolinium oxide, magnetic resonance imaging, contrast agent, cell labeling, Ba/F3 cells, THP-1 cells