Temperature-Dependent Biphasic Shrinkage of Lipid-Coated Bubbles in Ultrasound

Abstract

Lipid-coated microbubbles and emulsions are of interest as possible ultrasound-mediated drug delivery vehicles and for their interesting behaviors and fundamental properties. We and others have noted that bubbles coated with the long chain saturated phospholipid distearoylphosphatidylcholine (DSPC) rapidly shrink to a quasistable size when repeatedly insonated with short ultrasound pulses; such stability may adversely affect the bubble's subsequent ability to deliver its pharmacological cargo. Bubbles coated with the unsaturated lipid dioleoylphosphatidylcholine (DOPC) did not show stability but did undergo an abrupt change from rapid initial shrinkage to a slow persistent shrinkage, leading ultimately to dissolution or dispersion. As DOPC and DSPC differ not only in chain saturation but also phase behavior, we performed additional studies using dimyristoyl PC (DMPC) as a coat lipid and controlled the solution temperature to study bubble behavior on exposure to repeated ultrasound pulses for the same coat, in both fluid and gel phases. We find, first, that essentially all bubbles show an initially rapid shrinkage, in which gas loss exceeds the limit imposed by gas diffusion into the surrounding medium; this rapid shrinkage may be evidence of nanoscopic bubble fragmentation. Second, upon reaching a fraction of their initial size, bubbles begin a slower shrinkage with a shrinkage rate that depends on the resting phase state of the coat lipid: fluid DMPC monolayers give a more rapid shrinkage than gel phase. DOPC-coated bubbles showed no temperature-dependent responses in the same temperature range. The results are especially interesting in that bubble compression during the pulse is likely to adiabatically heat the bubble and fluidize the coat, regardless of its initial phase state; thus, some structural feature of the resting coat, such as defect lines in the gel phase, may be important in the subsequent response to the ~3 μs ultrasound pulse.