Selective brain entry of lipid nanoparticles in haemorrhagic stroke is linked to biphasic blood-brain barrier disruption
Al-Ahmady, Zahraa S. (The University of Manchester. Nanomedicine Lab, Division of Pharmacy and Optometry)
Dickie, Ben R. (University of Manchester. Geoffrey Jefferson Brain Research Centre)
Aldred, Isabelle (The University of Manchester. Nanomedicine Lab, Division of Pharmacy and Optometry)
Jasim, Dhifaf A. (The University of Manchester. Nanomedicine Lab, Division of Pharmacy and Optometry)
Barrington, Jack (University of Manchester. Division of Neuroscience and Experimental Psychology)
Haley, Michael J (University of Manchester. Division of Neuroscience and Experimental Psychology)
Lemarchand, Eloise (University of Manchester. Division of Neuroscience and Experimental Psychology)
Coutts, Graham (University of Manchester. Division of Neuroscience and Experimental Psychology)
Kaur, Satinderdeep (Nottingham Trent University. Pharmacology Department)
Bates, Jessica (Nottingham Trent University. Pharmacology Department)
Curran, Sarah (Nottingham Trent University. Pharmacology Department)
Goddard, Ruth (Nottingham Trent University. Pharmacology Department)
Walker, Megan (Nottingham Trent University. Pharmacology Department)
Parry-jones, Adrian (University of Manchester. Geoffrey Jefferson Brain Research Centre)
Kostarelos, Kostas (Institut Català de Nanociència i Nanotecnologia)
Allan, Stuart M. (University of Manchester. Geoffrey Jefferson Brain Research Centre)

Data:	2022
Resum:	Haemorrhagic stroke represents a significant public health burden, yet our knowledge and ability to treat this type of stroke are lacking. Previously we showed that we can target ischaemic-stroke lesions by selective translocation of lipid nanoparticles through the site of blood-brain barrier (BBB) disruption. The data we presented in this study provide compelling evidence that haemorrhagic stroke in mice induces BBB injury that mimics key features of the human pathology and, more importantly, provides a gate for entry of lipid nanoparticles-based therapeutics selectively to the bleeding site. Methods: Haemorrhagic stroke was induced in mice by intra-striatal collagenase injection. lipid nanoparticles were injected intravenously at 3 h, 24 h & 48 h post-haemorrhagic stroke and accumulation in the brain studied using in-vivo optical imaging and histology. BBB integrity, brain water content and iron accumulation were characterised using dynamic contrast-enhanced MRI, quantitative T mapping, and gradient echo MRI. Results: Using in-vivo SPECT/CT imaging and optical imaging revealed biphasic lipid nanoparticles entry into the bleeding site, with an early phase of increased uptake at 3-24 h post-haemorrhagic stroke, followed by a second phase at 48-72 h. Lipid nanoparticles entry into the brain post-haemorrhage showed an identical entry pattern to the trans-BBB leakage rate (K trans [min -1 ]) of Gd-DOTA, a biomarker for BBB disruption, measured using dynamic contrast-enhanced MRI. Discussion: Our findings suggest that selective accumulation of liposomes into the lesion site is linked to a biphasic pattern of BBB hyper-permeability. This approach provides a unique opportunity to selectively and efficiently deliver therapeutic molecules across the BBB, an approach that has not been utilised for haemorrhagic stroke therapy and is not achievable using free small drug molecules.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Liposomes ; Blood-brain barrier ; Drug delivery ; Haemorrhagic stroke ; Lipid nanoparticles
Publicat a:	Theranostics, Vol. 12, Issue 10 (May 2022) , p. 4477-4497, ISSN 1838-7640

DOI: 10.7150/thno.72167
PMID: 35832077

21 p, 2.4 MB

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