Liposome delivery to the brain with rapid short-pulses of focused ultrasound and microbubbles.
File(s)8. Morse et al - 2021 - J Controlled Release.pdf (3.12 MB)
Published version
Author(s)
Morse, Sophie V
Mishra, Aishwarya
Chan, Tiffany G
T M de Rosales, Rafael
Choi, James J
Type
Journal Article
Abstract
Liposomes are clinically used drug carriers designed to improve the delivery of drugs to specific tissues while minimising systemic distribution. However, liposomes are unable to cross the blood-brain barrier (BBB) and enter the brain, mostly due to their large size (ca. 100 nm). A noninvasive and localised method of delivering liposomes across the BBB is to intravenously inject microbubbles and apply long pulses of ultrasound (pulse length: >1 ms) to a targeted brain region. Recently, we have shown that applying rapid short pulses (RaSP) (pulse length: 5 μs) can deliver drugs with an improved efficacy and safety profile. However, this was tested with a relatively smaller 3-kDa molecule (dextran). In this study, we examine whether RaSP can deliver liposomes to the murine brain in vivo. Fluorescent DiD-PEGylated liposomes were synthesized and injected intravenously alongside microbubbles. The left hippocampus of mice was then sonicated with either a RaSP sequence (5 μs at 1.25 kHz in groups of 10 ms at 0.5 Hz) or a long pulse sequence (10 ms at 0.5 Hz), with each pulse having a 1-MHz centre frequency (0.35 and 0.53 MPa). The delivery and distribution of the fluorescently-labelled liposomes were assessed by fluorescence imaging of the brain sections. The safety profile of the sonicated brains was assessed by histological staining. RaSP was shown to locally deliver liposomes across the BBB at 0.53 MPa with a more diffused and safer profile compared to the long pulse ultrasound sequence. Cellular uptake of liposomes was observed in neurons and microglia, while no uptake within astrocytes was observed in both RaSP and long pulse-treated brains. This study shows that RaSP allows a targeted and safe delivery of liposomal drugs into the murine brain with potential to deliver drugs into neuronal and glial targets.
Date Issued
2021-12-10
Date Acceptance
2021-12-04
Citation
Journal of Controlled Release, 2021, 341, pp.605-615
ISSN
0168-3659
Publisher
Elsevier
Start Page
605
End Page
615
Journal / Book Title
Journal of Controlled Release
Volume
341
Copyright Statement
© 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Sponsor
Alzheimer's Research UK (ARUK)
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/34896448
PII: S0168-3659(21)00656-8
Grant Number
ARUK-NC2020-IMP
Subjects
Blood-brain barrier
Brain drug delivery
Focused ultrasound
Liposomes
Microbubbles
Neurons
Publication Status
Published
Coverage Spatial
Netherlands
Date Publish Online
2021-12-10