Nanoparticles are attracting considerable interest as contrast agents in medical imaging. Their small size makes them ideally suited to targeting cells outside the capillary vasculature, such as cancer cells. Nanoparticles are also likely to circulate within the human body for a reasonable length of time, providing a greater time window for imaging. This offers an advantage over contrast agents made from larger particles (>1 μm diameter), which are cleared rapidly by the body's reticuloendothelial system following injection into the bloodstream.
To date, the development of nanoparticulate contrast agents has concentrated mainly on MRI. Efforts to boost ultrasound signals have focused on gas-filled bubbles that enhance acoustic reflectivity. But solid nano-sized particles could, in theory, be a better ultrasound contrast material than microbubbles, the Ohio State researchers suggest. Not only should the solid particles remain stable during insonication, but they should also generate good enhancement, owing to the acoustic-impedance mismatch between solids and soft tissue.
"The feasibility of using nanoparticles for ultrasound imaging is not well understood," Jun Liu, lead author of the paper, told medicalphysicsweb. "We hope to capitalize on the recent development of nanoparticle technologies for ultrasound imaging because nanoparticles have many advantages for specific targeting."
Liu and colleagues tested their hypothesis in vitro on tissue-phantom samples by suspending varying concentrations of silica (100 nm) and polystyrene (500-3000 nm) particles in agarose gels. Samples were imaged using a high-frequency ultrasound system with a 30 MHz transducer. The pure agarose gel remained translucent to the sound waves, while the silica and polystyrene particles created visible signals at low volume concentrations. Image brightness increased as the concentration of particles increased, and as particle size increased.
The ability of solid particles to enhance ultrasound contrast was also tested in vivo. A solution of 50 μl silica nanoparticles suspended in saline was injected into the tail vein of three anaesthetized mice. Ultrasound images of the mouse livers, acquired with the same system as before, were acquired at 0, 1, 2, 3, 4, 5 and 10 min, and then every 5 min up to 1.5 h after injection.
The grey scale of liver parenchyma increased quickly over the first 15 min then remained constant. Transmission electron micrographs of liver tissue acquired 2 h after nanoparticle administration showed that the silica particles had aggregated in the lyosomes of liver Kupffer cells. The livers of control mice, injected with saline alone, maintained the same grey scale on ultrasound images throughout.
The results show the feasibility of using solid nanoparticles as contrast agents, claim the authors. "Ultrasound is a readily available, safe and cost-effective imaging modality," they write. "Effective imaging agents that will improve its specificity for disease detection and diagnosis are highly desirable."
Even so, much work remains to be done before nanoparticle-based ultrasound contrast agents reach the medical market-place. The next step will be to direct the nanoparticles towards target tissues, Liu says. This requires modifying the particles' surface in some way - for instance, by attaching antibodies that will home in on specific cells. "Accumulation of sufficient nanoparticles at a particular tissue site to generate significant ultrasound enhancement could be a challenge," Liu admitted.
Toxicity and biocompatibility issues will also need to be considered if nanoparticles are to be considered for clinical imaging applications. "Biodegradable nanoparticles will be ideal," Liu concluded.