Aducanumab delivery via focused ultrasound-induced transient blood–brain barrier opening in vivo

Abstract

Focused ultrasound (FUS) with magnetic resonance imaging (MRI) guidance (MRgFUS) has emerged as a promising technique for enhancing drug delivery to the brain. Through the controlled oscillation of gas-encased microbubbles, FUS temporarily modulates the integrity of tight junctions, inducing localized blood-brain barrier disruption (BBBD) and allowing targeted drug passage. Aducanumab (ADU) has demonstrated efficacy in reducing amyloid pathology, yet its clinical application remains limited by the restrictive nature of the blood-brain barrier (BBB). This in vivo study aimed to evaluate the efficiency of ADU delivery facilitated by FUS-induced BBBD in the normal Institute of Cancer Research (ICR) mouse brain under two pressure conditions: 0.25 and 0.42 MPa. Following FUS sonication with MRI guidance, ADU concentrations in brain tissues and serum were measured via enzyme-linked immunosorbent assay (ELISA) at multiple time points. Histological analysis at 24 h post-FUS-BBBD was performed to assess ADU distribution, and tissue integrity was evaluated through hematoxylin and eosin (H&E) and Nissl staining to detect potential damage in the target regions. The results demonstrated that MRgFUS significantly increased ADU concentrations within the target areas without inducing substantial tissue damage. ADU delivery efficiency was directly correlated with the degree of BBBD, exhibiting a 7-fold increase at 0.25 MPa and a 60-fold increase at 0.42 MPa compared to sham controls, with distinct kinetic profiles observed for each condition. These findings highlight the potential of FUS-BBBD as a therapeutic strategy to enhance ADU delivery to the brain, reduce required infusion doses, and mitigate side effects associated with high-dose administration.