Physico-chemical properties of the microbubble lipid shell [ultrasound contrast agents]

Targeted microbubbles stabilized by a lipid monolayer are currently being developed in conjunction with ultrasound for diagnostic and therapeutic applications. Targeted microbubbles utilize specific receptor-ligand interactions to adhere to the site of interest - a process which can be enhanced by using ultrasonic radiation force. The monolayer shell is composed of a main phospholipid component and an emulsifier comprising a poly(ethylene glycol) (PEG) headgroup. The targeting ligand is tethered to a lipid in the monolayer via a PEG spacer. Using epi-fluorescence microscopic techniques, we show here for the first time that the targeting ligand is not uniformly distributed over the microbubble surface, but instead clusters into the expanded phase interdomain region. We also demonstrate for the first time the relationships between composition, microstructure and lipid shedding properties during ultrasonic insonation of the microbubble. These results have implications for the rational design of lipid-coated microbubbles as targeted ultrasound contrast agents.