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

Abstract

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-co-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.

Photoacoustic Imaging Quantifies Drug Release from Nanocarriers via Redox Chemistry of Dye‐Labeled Cargo

“…For PTX‐MB, the depth of imaging is currently limited by the penetration of 680 nm light in tissue, but photoacoustics can be coupled with other modalities such as ultrasound or magnetic resonance to locate the drug delivery site . This is a powerful tool to monitor the location and concentration of drugs and determine whether they remain encapsulated in nanocarriers.…”

Superparamagnetic iron oxides as MPI tracers: A primer and review of early applications

“…Since these studies have used very small FOV’s for brain or liver (not whole mouse FOV), with each cell containing >100-fold iron content, these MRI studies do not allow a proper comparison for its sensitivity of MPI. Multi-modal MPI cell tracking agents are now also being developed, although at the cost of a lower sensitivity in the order of 1 million cells [29]. …”

Magnetic particle imaging for radiation-free, sensitive and high-contrast vascular imaging and cell tracking

“…Moreover, the neural implant work imaged stem cells over 87 days, a study which would not be possible with the clinical tracer modalities today due to the need for radioactively decaying tracers. These early studies on stem cell lines have sparked further interest in the field of MPI stem cell tracking, leading to work demonstrating that MPI can be used to image pancreatic islet transplants in mice and work developing new nanoparticle agents for multimodal imaging of stem cells, including via MPI 29,30 . These studies demonstrated up to 200-cell sensitivity, which is far more sensitive than other medical imaging modalities 31 .…”