Using ultrasound-targeted microbubble cavitation to open the blood–brain barrier for drug delivery in Alzheimer’s disease

Drug delivery for Alzheimer’s disease (AD) is challenging due to restricted diffusion across the blood–brain barrier (BBB). Ultrasound-targeted microbubble cavitation (UTMC) can be used to transiently open the BBB. We hypothesized that opening the BBB with UTMC would increase the brain concentration of LY2886721 (LY), an orally administered drug developed for AD, in 5XFAD mice, a model of AD. We treated the right hemisphere using an RK-50 system (FUS Instruments Inc). Definity microbubbles were injected, and ultrasound (1.45 MHz, 2 Hz pulse repetition frequency, 10 ms pulse length, 0.6 MPa for 30 s) was applied to 11 locations across the right hemisphere. Thirty minutes after UTMC, mice were administered LY (30 mg/kg p.o.). In one cohort, 45 min after dosing with LY, there was an increase in the concentration of LY in the UTMC-treated hemisphere compared to the non-UTMC treated hemisphere (p < 0.05). In a second cohort, 2.5 h after dosing with LY, there was a decrease in soluble Aβ;40 (p < 0.05), insoluble Aβ;40 (p < 0.05), and insoluble Aβ;42 (p < 0.05) in the UTMC-treated hemisphere compared to the non-UTMC treated hemisphere. UTMC can be used to open the BBB to increase the concentration of LY and decrease Aβ in a preclinical model of AD.