Focused Ultrasound-Facilitated Brain Drug Delivery Using Optimized Nanodroplets

Focused ultrasound with nanodroplets could facilitate localized drug delivery after vaporization with potentially improved in vivo stability, drug payload, and minimal interference outside of the focal zone compared with microbubbles. While the feasibility of blood-brain barrier (BBB) opening using nanodroplets has been previously reported, characterization of the associated delivery has not been achieved. It was hypothesized that the outcome of drug delivery was associated with the droplet sensitivity to acoustic energy, and can be modulated with the boiling point of the liquid core. Therefore, in this study, highly-efficient octafluoropropane (OFP) and less-efficient decafluorobutane (DFB) nanodroplets were used in vivo for delivering molecules with a size relevant to proteins (40-kDa dextran) to the murine brain. It was found that successful delivery was achieved with OFP droplets at 300 kPa or higher safely using 1/4 dosage compared to DFB droplets at 900 kPa where inertial cavitation caused damage. As a result, the OFP droplets due to the higher vaporization efficiency served as better acoustic agents to deliver large molecules safely and efficiently to the brain compared with the DFB droplets.