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

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.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To assess whether PEGylated PLGA-based perfluoropentane phase-shift nanodroplets can serve as an effective alternative to microbubbles for focused ultrasound–induced, controllable opening of the blood–brain barrier.

Disease model Healthy

Cargo name and characteristics PEGylated PLGA-based phase-shift nanodroplets (nanoscale nanoparticles) consisting of a liquid perfluoropentane core encapsulated by PEG-PLGA (poly(ethyleneglycol)-poly(lactide-co-glycolide)) shells; ultrasound-activatable liquid-to-gas phase-change nanodroplets.

Outcomes and Safety

Summary of Outcomes FUS combined with PEG‑PLGA‑PFP phase‑shift nanodroplets produced localized, reversible BBB opening (Evans Blue extravasation) with an acoustic pressure threshold of 1.0 MPa (in vitro/echogenic and in vivo opening strongest at 1.0 MPa, 3 min); 0.5 MPa was ineffective while 1.5 MPa increased opening but caused intracerebral hemorrhage and erythrocyte extravasation. Prolonging sonication from 3 to 5 min enhanced the magnitude of BBB opening and extended the time window (3 min recovery ≈1 h; 5 min recovery ≈4 h).

Duration of biological effect 3 min

Safety-related matter At 1.5 MPa FUS combined with PEG-PLGA-PFP nanodroplets caused intracerebral hemorrhages and sporadic erythrocyte extravasations (severe brain injury attributed to inertial cavitation). No hemorrhages or erythrocyte extravasation were observed at 0.5 MPa and 1.0 MPa, and 1.0 MPa was considered a practicable, biosecure threshold producing transient BBB opening (re-established by ~1 h after 3 min sonication; up to ~4 h after 5 min).

Brain Region

Visualization unavailable

Ultrasound Parameters

FUS Pressure 1.0 MPa, 1.5 MPa

Focal Characteristics Focal depth: None; Focal length: None; Aperture size: None

Treatment frequency Single session

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