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Perfluorocarbon nanoparticles consisting essentially of liquid perfluoro-octyl bromide (PFOB) core surrounded by a lipid monolayer can serve as highly specific site-targeted contrast and therapeutic agents after binding to cellular biomarkers. Based on previous findings that ultrasound applied at 2 MHz and 1.9 mechanical index (MI) for a 5-min duration dramatically enhances the cellular interaction of targeted PFOB nanoparticles with melanoma cells in vitro without inducing apoptosis or other harmful effects to cells that are targeted, we sought to define mechanisms of interaction and the safety profile of ultrasound used in conjunction with liquid perfluorocarbon nanoparticles for targeted drug delivery, as compared with conventional microbubble ultrasound contrast agents under identical insonification conditions. Cell-culture inserts were used to grow a confluent monolayer of human umbilical vein endothelial cells. Definity in conjunction with continuous wave ultrasound (2.25 MHz for 1 and 5 min) increased the permeability of monolayer by four to six times above the normal, decreased transendothelial electrical resistance (a sign of reduced membrane integrity), and decreased cell viability by ∼50%. Histological evaluation demonstrated extensive disruptions of cell monolayers. Nanoparticles (both nontargeted and targeted) elicited no changes in these different measures under similar insonification conditions and did not disrupt cell monolayers. We hypothesize that ultrasound facilitates drug transport from the perfluorocarbon nanoparticles not by cavitation-induced effects on cell membrane but rather by direct interaction with the nanoparticles that stimulate lipid exchange and drug delivery.