Abstract
Previous studies have shown that focused ultrasound (FUS) combined with systematic administration of microbubbles (MBs) can open the blood brain barrier (BBB) locally, transiently and reversibly. However, because of the micro size diameters, MBs are restricted in the intravascular space and cannot extravasate into diseased sites through the opened BBB. In this study, we fabricated one kind of nanoscale droplets which consisted of encapsulated liquid perfluoropentane cores and poly (ethyleneglycol) - poly (lactide-co-glycolic acid) shells. The nanodroplets had the capacity to realize liquid to gas phase shift under FUS. Significant extravasation of Evan's blue appeared when acoustic pressure reached 1.0 MPa. Intracerebral hemorrhages and erythrocyte extravasations were observed when the pressure was increased to 1.5 MPa. Prolonged sonication duration could enhance the level of BBB opening and broaden the time window simultaneously. Furthermore, compared with MBs, the distribution of EB extravasation was firmly confined within narrow region in the center of focal zone, suggesting the site of FUS induced BBB opening could be controlled with high precision by this procedure. Our results show the feasibility of serving PEGylated PLGA-based phase shift nanodroplet as an effective alternative mediating agent for FUS induced BBB opening.
Highlights
Blood-brain barrier (BBB) is the foremost obstacle which highly prevents effective therapeutic agents from transferring into brain parenchyma and functioning properly
Compared with MBs, the distribution of Evan’s Blue (EB) extravasation was firmly confined within narrow region in the center of focal zone, suggesting the site of focused ultrasound (FUS) induced blood brain barrier (BBB) opening could be controlled with high precision by this procedure
Our results show the feasibility of serving PEGylated PLGA-based phase shift nanodroplet as an effective alternative mediating agent for FUS induced BBB opening
Summary
Blood-brain barrier (BBB) is the foremost obstacle which highly prevents effective therapeutic agents from transferring into brain parenchyma and functioning properly. MBs oscillate regularly and the repetitive contraction and expansion of MBs create microstreamings in nearby medium This is known as stable cavitation [3, 9]. When the pressure exceeds a certain level, MBs will collapse and generate forceful shock waves and microjets (called inertial cavitation) These powerful stresses can create pores within the cell membrane, break tight junctions between the adjacent brain endothelial www.impactjournals.com/oncotarget cells, and enhance the transcellular and paracellular permeability of BBB [10]. These hypotheses are supported by convincing experimental data, the exact mechanism of FUS induced BBB opening in the presence of MBs is still unclear
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