Loading Intracranial Drug-Eluting Reservoirs Across the Blood-Brain Barrier With Focused Ultrasound.

Abstract

Efficient, sustained and long-term delivery of therapeutics to the brain remains an important challenge to treatment of diseases such as brain cancer, stroke and neurodegenerative disease. Focused ultrasound can assist movement of drugs into the brain, but frequent and long-term use has remained impractical. Single-use intracranial drug-eluting depots show promise but are limited for the treatment of chronic diseases as they cannot be refilled non-invasively. Refillable drug-eluting depots could serve as a long-term solution, but refilling is hindered by the blood-brain barrier (BBB), which prevents drug refills from accessing the brain. In this article, we describe how focused ultrasound enables non-invasive loading of intracranial drug depots in mice. Female CD-1 mice (n=6) were intracranially injected with click-reactive and fluorescent molecules that are capable of anchoring in the brain. After healing, animals were treated with high-intensity focused ultrasound and microbubbles to temporarily increase the permeability of the blood-brain barrier and deliver dibenzocyclooctyne (DBCO)-Cy7. The mice were perfused, and the brains were imaged via ex vivo fluorescence imaging. Fluorescence imaging indicated small molecule refills are captured by intracranial depots as long as 4 wk after administration and are retained for up to 4 wk based on fluorescence imaging. Efficient loading was dependent on both focused ultrasound and the presence of refillable depots in the brain as absence of either prevented intracranial loading. The ability to target and retain small molecules at predetermined intracranial sites with pinpoint accuracy provides opportunities to continuously deliver drugs to the brain over weeks and months without excessive BBB opening and with minimal off-target side effects.