Development of a Trimodal Contrast Agent for Acoustic and Magnetic Particle Imaging of Stem Cells.

Stem cell therapy has the potential to improve tissue remodeling and repair. For cardiac stem cell therapy, methods to improve the injection and tracking of stem cells may help to increase patient outcomes. Here we describe a multimodal approach that combines ultrasound imaging, photoacoustic imaging, and magnetic particle imaging (MPI). Ultrasound imaging offers real-time guidance, photoacoustic imaging offers enhanced contrast, and MPI offers high-contrast, deep-tissue imaging. This work was facilitated by a poly(lactic--glycolic acid) (PLGA)-based iron oxide nanobubble labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR) as a trimodal contrast agent. The PLGA coating facilitated the ultrasound signal, the DiR increased the photoacoustic signal, and the iron oxide facilitated the MPI signal. We confirmed that cell metabolism, proliferation, differentiation, and migration were not adversely affected by cell treatment with nanobubbles. The nanobubble-labeled cells were injected intramyocardially into live mice for real-time imaging. Ultrasound imaging showed a 3.8-fold increase in the imaging intensity of labeled cells postinjection compared to the baseline; photoacoustic imaging showed a 10.2-fold increase in the cardiac tissue signal postinjection. The MPI intensity of the nanobubble-treated human mesenchymal stem cells injected into the hearts of mice was approximately 20-fold greater than the negative control.