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

Abstract

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 (t1/2) = 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.

Synchronous Intravital Imaging and Cavitation Monitoring of Antivascular Focused Ultrasound in Tumor Microvasculature Using Monodisperse Low Boiling Point Nanodroplets

“…However, a smaller mean diameter and lower PDI were achieved here with a simpler and more cost-effective approach, with a low-boiling-point (C 4 F 10 ) core. Importantly, the additional size-isolation step of the parent MBs appears to lower the resultant ND polydispersity index (values of 0.1–0.4 have been reported ,, ) and eliminates the formation of droplets larger than 0.5 μm in diameter that have been reported with the conventional condensation approach of polydisperse precursor MBs . Achieving a small size and narrow size distribution of NDs is important, as these factors strongly influence ND behavior in vivo , including circulation time, organ retention, extravasation, as well as vaporization threshold and conversion efficiency. ,,− The importance extends beyond vaporization, as the acoustic response of the resultant MB population after conversion similarly depends on size and size distribution, and a more narrow MB distribution can be expected to have a more homogeneous response to the incident ultrasound. ,, …”

Glycerol-weighted chemical exchange saturation transfer nanoprobes allow 19F/1H dual-modality magnetic resonance imaging-guided cancer radiotherapy

“…In this context, PFCs are inert organic compounds used as “artificial blood” that improve tissue oxygenation and have been widely used in the clinic for various purposes, including artificial blood substitution, organ preservation, ultrasound, and 19 F magnetic resonance imaging 27 , 28 . Perfluorooctylbromide (PFOB) used in this study stands out among PFCs for medical use as it is non-toxic, high stability, inertness, and an acceptable excretion profile 30 . Therefore, the PFC-based Gly-PFOBs nanoplatform presented in this study has desirable biocompatibility and holds great potential in clinical translation.…”

“…Consequently, PFC nano-emulsions hold promise for being harnessed as a versatile magnetic resonance (MR) contrast agent. PFOB used in this study stands out among PFCs for medical use as it, non-toxic, high stability, inertness, possesses the unique property of being both hydrophobic and lipophobic, and has an acceptable excretion profile 30 .…”

Modulation of engineered nanomaterial interactions with organ barriers for enhanced drug transport

“…Bérard et al developed perfluorooctyl bromide (PFOB) nanodroplets loaded with a hydrophobic molecule of interest (dye or drug) and administered them in healthy mice, combined with FUS-mediated BBB disruption using microbubbles. 414 Their results showed BBB permeabilization and delivery of nanodroplets to the FUS exposed hemisphere only (Fig. 19).…”