Perfluorocarbon Nanodroplets as Potential Nanocarriers for Brain Delivery Assisted by Focused Ultrasound-Mediated Blood-Brain Barrier Disruption.

The management of brain diseases remains a challenge, particularly because of the difficulty for drugs to cross the blood-brain barrier. Among strategies developed to improve drug delivery, nano-sized emulsions (i.e., nanoemulsions), employed as nanocarriers, have been described. Moreover, focused ultrasound-mediated blood-brain barrier disruption using microbubbles is an attractive method to overcome this barrier, showing promising results in clinical trials. Therefore, nanoemulsions combined with this technology represent a real opportunity to bypass the constraints imposed by the blood-brain barrier and improve the treatment of brain diseases. In this work, a stable freeze-dried emulsion of perfluorooctyl bromide nanodroplets stabilized with home-made fluorinated surfactants able to carry hydrophobic agents is developed. This formulation is biocompatible and droplets composing the emulsion are internalized in multiple cell lines. After intravenous administration in mice, droplets are eliminated from the bloodstream in 24 h (blood half-life (t<sub>1/2</sub>) = 3.11 h) and no long-term toxicity is expected since they are completely excreted from mice' bodies after 72 h. In addition, intracerebral accumulation of tagged droplets is safely and significantly increased after focused ultrasound-mediated blood-brain barrier disruption. Thus, the proposed nanoemulsion appears as a promising nanocarrier for a successful focused ultrasound-mediated brain delivery of hydrophobic agents.

Introduction

Purpose Drug delivery with BBB opening

Study Objective Develop and evaluate a stable freeze-dried perfluorooctyl bromide nanoemulsion capable of delivering hydrophobic agents to the brain via focused ultrasound-mediated blood–brain barrier disruption.

Animal model / Human subject Mice (species: Mus musculus; strain: None; age: None; sex: None)

Disease model Brain diseases (general; focused ultrasound-mediated blood–brain barrier disruption in mice)

Cargo name and characteristics Nanoemulsion nanoparticle: perfluorooctyl bromide (PFOB) nanodroplets stabilized with home-made fluorinated surfactants (stable freeze-dried formulation). Designed as a biocompatible nanocarrier for hydrophobic small-molecule agents; droplets are internalized by cell lines, have a blood half-life ~3.11 h, are cleared from bloodstream within 24 h and fully excreted by 72 h, and show enhanced intracerebral accumulation after focused ultrasound-mediated BBB disruption.

Route of administration intravenous

Outcomes and Safety

Summary of Outcomes A biocompatible freeze-dried perfluorooctyl bromide nanoemulsion carrying hydrophobic agents is internalized by multiple cell lines, cleared from mouse blood with a 3.11 h half-life and complete excretion by 72 h, and shows significantly increased intracerebral accumulation after focused ultrasound–mediated blood–brain barrier disruption.

Duration of biological effect 24 h

Safety-related matter The authors report the nanoemulsion is biocompatible, shows no expected long-term toxicity (complete excretion by 72 h; blood t1/2 = 3.11 h), and intracerebral accumulation after focused ultrasound was increased safely.

Brain Region

Visualization unavailable

Ultrasound Parameters

Ultrasound instrument None.

Duration of a single FUS session None.

Focal Characteristics None.

Treatment frequency single session

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