Focused Ultrasound as a Plasma Protein Binding-targeted Strategy to Enhance Brain Uptake of Donepezil
6 affiliations
- 1Department of Pharmacy, Yonsei University, Incheon 21983 Chuncheon 24252 Korea
- 2Bionics Research Center, Biomedical Research Division, Korea Institute of Science and Technology, Seoul 02792 Chuncheon 24252 Korea
- 3Advanced Analysis and Data Center, Korea Institute of Science and Technology, Seoul 02792 Chuncheon 24252 Korea
- 4School of Mathematics and Computing (Computational Science and Engineering), Yonsei University, Seoul 03722 Chuncheon 24252 Korea
- 5Department of Neurology, Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong 18450 Chuncheon 24252 Korea
- 6Research Institute for Complementary and Alternative Medicine, Hallym University Chuncheon 24252 Korea
Abstract
Donepezil, a reversible acetylcholinesterase inhibitor, is widely used for the symptomatic treatment of Alzheimer’s disease (AD). Although higher-dose donepezil has been shown to provide additional clinical benefit, dose escalation is often limited by cholinergic adverse effects. Given that approximately 96% of circulating donepezil is bound to plasma proteins, especially albumin, we hypothesized that increasing its unbound fraction from albumin may improve brain delivery without increasing the administered dose. To achieve this goal, herein we examined whether the donepezil-albumin complex can be dissociated by low-intensity focused ultrasound (FUS) in vitro. Then brain uptake of donepezil was evaluated in mice receiving intravenous donepezil followed by targeted brain FUS stimulation. As a result, FUS significantly increased unbound fraction of donepezil at the targeted region in vitro, resulting in a 41.1% increase of donepezil diffusion into dialysis cassettes compared with non-sonicated controls. In mice receiving intravenous donepezil, targeted brain FUS stimulation increased brain donepezil concentrations by 52.7% at 15-min post-administration time. These findings suggest that low-intensity FUS enhances brain uptake of donepezil, potentially through modulation of donepezil-albumin binding, and support further investigation of plasma protein binding-targeted brain drug delivery.
Related
- Functional brain imaging and targeted lesion studies using manganese-enhanced MRI and focused ultrasound in non-conventional model species
- A practical prioritization strategy for vegetation‐focused restoration of anthropogenic wastelands
- Focused Ultrasound Neuromodulation of the Central Lateral Thalamus in a Non-Human Primate Model of Disorders of Consciousness
- Dose-Dependent Effects of Low-Intensity Focused Ultrasound on Human Deep White Matter Tracts
- High-Frequency Focused Ultrasound targeting the midbrain in the Guinea Pig Induces Activation and Plasticity of the Efferent System, and Protection Against Noise-Induced Hearing Loss
BibTeX
@article{lee2026focused,
title = {{Focused Ultrasound as a Plasma Protein Binding-targeted Strategy to Enhance Brain Uptake of Donepezil}},
author = {Songmin Lee and Kyeonghwan Kim and Hyungmin Kim and Min-Seok Oh and Kyungho Yoon and Subin Kwak and JiMin Kim and Gwan-Ho Lee and YoungSoo Kim and Jaeho Kim},
journal = {Experimental Neurobiology},
year = {2026},
month = oct,
doi = {10.5607/en26028},
url = {https://doi.org/10.5607/en26028},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Focused Ultrasound as a Plasma Protein Binding-targeted Strategy to Enhance Brain Uptake of Donepezil
AU - Songmin Lee
AU - Kyeonghwan Kim
AU - Hyungmin Kim
AU - Min-Seok Oh
AU - Kyungho Yoon
AU - Subin Kwak
AU - JiMin Kim
AU - Gwan-Ho Lee
AU - YoungSoo Kim
AU - Jaeho Kim
PY - 2026
DA - 2026/10/31
JO - Experimental Neurobiology
DO - 10.5607/en26028
UR - https://doi.org/10.5607/en26028
AB - Donepezil, a reversible acetylcholinesterase inhibitor, is widely used for the symptomatic treatment of Alzheimer’s disease (AD). Although higher-dose donepezil has been shown to provide additional clinical benefit, dose escalation is often limited by cholinergic adverse effects. Given that approximately 96% of circulating donepezil is bound to plasma proteins, especially albumin, we hypothesized that increasing its unbound fraction from albumin may improve brain delivery without increasing the administered dose. To achieve this goal, herein we examined whether the donepezil-albumin complex can be dissociated by low-intensity focused ultrasound (FUS) in vitro. Then brain uptake of donepezil was evaluated in mice receiving intravenous donepezil followed by targeted brain FUS stimulation. As a result, FUS significantly increased unbound fraction of donepezil at the targeted region in vitro, resulting in a 41.1% increase of donepezil diffusion into dialysis cassettes compared with non-sonicated controls. In mice receiving intravenous donepezil, targeted brain FUS stimulation increased brain donepezil concentrations by 52.7% at 15-min post-administration time. These findings suggest that low-intensity FUS enhances brain uptake of donepezil, potentially through modulation of donepezil-albumin binding, and support further investigation of plasma protein binding-targeted brain drug delivery.
SN - 1226-2560
SN - 2093-8144
ER -