PEGylated PLGA-based phase shift nanodroplets combined with focused ultrasound for blood brain barrier opening in rats

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.

Ultrasound-responsive droplets for therapy: A review

“…Haemorrhaging in the rat renal tubules was observed at an MI of 1.9. Similarly, in the application of increasing BBB permeability in rats, the use of PFC droplets and associated bio-effects were recorded by Zhang et al [36], where the extravasation of Evans Blue was used to illustrate successful delivery at 1.0 MPa with 1 MHz, but haemorrhage at 1.5 MPa. The mechanism for damage has been attributed to the onset of inertial cavitation [32].…”

“…Thus far cancer therapy has been the avenue explored most extensively for therapeutic droplets. However, alongside substantial recent developments in clinical applications of trans-cranial focused ultrasound [33,34] applications of droplets for drug delivery to the brain are coming to the fore [35,32,36]. When using droplets for drug delivery to the brain, exploitation of the vaporisation threshold for safe, efficient drug release is often sought without inducing inertial cavitation, since violent bubble collapse has been associated with damage of cerebral tissue [37].…”

Recent Advances on Ultrasound Contrast Agents for Blood-Brain Barrier Opening with Focused Ultrasound

“…PCCA presents a significantly longer circulation time in vivo than microbubbles since the liquid core prevents gas dissolution [ 128 ]: depending on the choice of PFC, droplets may persist stably for hours in vivo [ 133 ]. Due to their smaller size, PCCA can also potentially extravasate in the leaky vasculature within tumors, unlike microbubbles [ 31 , 80 , 133 ].…”

“…In our literature search, the BBB disruption with PCCA has been achieved only three times [ 33 , 80 , 133 ]. Chen et al firstly demonstrated BBB disruption with lipid-shelled and C 4 F 10 core PCCA and successfully delivered 3 kDa dextran to C57BL/6 mice brain without damages.…”

“…Interestingly, they showed that PCCA had a higher BBB opening pressure threshold (0.450 MPa vs. 0.225 MPa) than the same material microbubbles [ 133 ]. In the first study using polymeric PCCA (PEGylated-PLGA shell and C 5 F 12 core) for BBB opening, Zhang et al demonstrated that their PCCA has better-focusing abilities than lipid shelled microbubbles (distribution pattern of Evans Blue extravasation on Figure 5 ) [ 80 ], thus reducing side effects outside the focal zone [ 32 , 80 ]. More recently, Wu et al successfully delivered 40 kDa dextran to the C57BL/6 mice brain without damage with lipid shelled PCCA [ 33 ].…”