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Liposome delivery to the brain with rapid short-pulses of focused ultrasound and microbubbles

Research output: Contribution to journalArticlepeer-review

Sophie V Morse, Aishwarya Mishra, Tiffany G Chan, Rafael T M de Rosales, James J Choi

Original languageEnglish
Pages (from-to)605-615
Number of pages11
JournalJournal of controlled release : official journal of the Controlled Release Society
Volume341
Early online date10 Dec 2021
DOIs
E-pub ahead of print10 Dec 2021
PublishedJan 2022

Bibliographical note

Funding Information: This study was funded by the Alzheimer's Research UK ( ARUK-IRG2017A-7 ) and the PhD studentships of S.V.M., A.M. and T.G.C. funded by the King's College London and Imperial College London EPSRC Centre for Doctoral Training in Medical Imaging ( EP/L015226/1 ) and the EPSRC Centre for Neurotechnology ( EP/L016737/1 ). A.M and R.T.M.R also acknowledge support from EPSRC programme grants EP/S032789/1 and EP/R045046/1 . This study used equipment from the Facility for Imaging by Light Microscopy (FILM) at Imperial College London, supported by funding from the Wellcome Trust (grant 104931/ZS/14/Z ) and BBSRC (grant BB/L015129/1 ), and a Wellcome Trust Multiuser Equipment Grant at King's College London [ 212885/Z/18/Z ]. We also acknowledge support from the Wellcome/EPSRC Centre for Medical Engineering [ WT/203148/Z/16/Z ] and the KCL and UCL Comprehensive Cancer Imaging Centre funded by CRUK and EPSRC in association with the MRC and DoH (England). The authors finally acknowledge support from the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and KCL [grant number IS-BRC-1215-20006 ]. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The authors would also like to thank Hee Seok Jung and Javier Cudeiro Blanco for their help. Publisher Copyright: © 2021 The Authors

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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.

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