Ultrasound microbubble contrast agents for diagnostic and therapeutic applications: current status and future design

Ultrasound contrast agents are highly echogenic microbubbles with many unique properties. Microbubbles can basically improve the sensitivity of conventional ultrasound imaging to the microcirculation. The resonance of microbubbles in response to an incident ultrasound pulse results in nonlinear harmonic emission that serves as the signature of microbubbles in microbubble-specific imaging. Inertial cavitation and destruction of microbubbles can produce a strong mechanical stress enhancing the permeability of the surrounding tissues, and can further increase the extravasation of drugs from the blood into the cytoplasm or interstitium. Stable cavitation by high-frequency ultrasound can also mildly increase tissue permeability without causing any damage even at a high acoustic pressure. Microbubbles can carry drugs, release them upon ultrasound-mediated microbubble destruction, and simultaneously enhance vascular permeability to increase drug deposition in tissues. Various targeting ligands can be conjugated to the surface of microbubbles to attain ligand-directed and site-specific accumulation for targeted imaging. In addition to current developments in microbubble technology, this review introduces our studies of the applications of microbubble- specific imaging, ultrasound-aided drug delivery, and targeted imaging. These applications are promising but may require further improvement for clinical use.