Selective liposomal transport through blood brain barrier disruption in ischaemic stroke reveals two distinct therapeutic opportunities

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Al-Ahmady, ZS ORCID: https://orcid.org/0000-0001-7681-3735, Jasim, D, Ahmad, SS, Wong, R, Haley, M, Coutts, G, Schiessl, I, Allan, SM and Kostarelos, K, 2019. Selective liposomal transport through blood brain barrier disruption in ischaemic stroke reveals two distinct therapeutic opportunities. ACS Nano, 13 (11), pp. 12470-12486. ISSN 1936-0851

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Official URL: https://doi.org/10.1021/acsnano.9b01808

Abstract

The development of effective therapies for stroke continues to face repeated translational failures. Brain endothelial cells form paracellular and transcellular barriers to many blood-borne therapies and the development of efficient delivery strategies is highly warranted. Here, in a mouse model of stroke, we show selective recruitment of clinically used liposomes into the ischaemic brain that correlates with biphasic blood brain barrier (BBB) breakdown. Intravenous administration of liposomes into mice exposed to transient middle cerebral artery occlusion took place at early (0.5h and 4h) and delayed (24h and 48h) timepoints, covering different phases of BBB disruption after stroke. Using a combination of in vivo real-time imaging and histological analysis we show that selective liposomal brain accumulation coincides with biphasic enhancement in transcellular transport followed by a delayed impairment to the paracellular barrier. This process precedes neurological damage in the acute phase and maintains long-term liposomal co-localisation within the neurovascular unit, which could have great potential for neuroprotection. Levels of liposomal uptake by glial cells are similarly selectively enhanced in the ischaemic region late after experimental stroke (2-3 days), highlighting their potential for blocking delayed inflammatory responses or shifting the polarization of microglia/macrophages towards brain repair. These findings demonstrate the capability of liposomes to maximise selective translocation into the brain after stroke and identify two windows for therapeutic manipulation. This emphasizes the benefits of selective drug delivery for efficient tailoring of stroke treatments.

Item Type:	Journal article
Publication Title:	ACS Nano
Creators:	Al-Ahmady, Z.S., Jasim, D., Ahmad, S.S., Wong, R., Haley, M., Coutts, G., Schiessl, I., Allan, S.M. and Kostarelos, K.
Publisher:	ACS Publications
Date:	26 November 2019
Volume:	13
Number:	11
ISSN:	1936-0851
Identifiers:	Number Type 10.1021/acsnano.9b01808 DOI 1111392 Other
Divisions:	Schools > School of Science and Technology
Record created by:	Jill Tomkinson
Date Added:	03 Oct 2019 09:51
Last Modified:	31 May 2021 15:07
URI:	https://irep.ntu.ac.uk/id/eprint/37898