Glymphatic-assisted perivascular brain delivery of intrathecal small gold nanoparticles

Nanoparticles are ultrafine particulate matter having considerable potential for treatment of central nervous system (CNS) disorders. Despite their tiny size, the blood-brain barrier (BBB) restricts their access to the CNS. Their direct cerebrospinal fluid (CSF) administration bypasses the BBB endot...

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Published in	Journal of controlled release Vol. 355; pp. 135 - 148
Main Authors	Lilius, Tuomas O., Mortensen, Kristian Nygaard, Deville, Claire, Lohela, Terhi J., Stæger, Frederik Filip, Sigurdsson, Björn, Fiordaliso, Elisabetta M., Rosenholm, Marko, Kamphuis, Chris, Beekman, Freek J., Jensen, Andreas I., Nedergaard, Maiken
Format	Journal Article
Language	English
Published	Netherlands Elsevier B.V 01.03.2023
Subjects	Biological Transport blood-brain barrier Blood-Brain Barrier - metabolism brain Brain - metabolism Central nervous system drug delivery cerebrospinal fluid endothelium Glymphatic system Gold - metabolism Hypertonic solution Metal Nanoparticles nanogold Nanoparticles particulates Single-photon emission tomography Nanoparticles Glymphatic system Hypertonic solution Central nervous system drug delivery Single-photon emission tomography
Online Access	Get full text
ISSN	0168-3659 1873-4995 1873-4995
DOI	10.1016/j.jconrel.2023.01.054

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Abstract	Nanoparticles are ultrafine particulate matter having considerable potential for treatment of central nervous system (CNS) disorders. Despite their tiny size, the blood-brain barrier (BBB) restricts their access to the CNS. Their direct cerebrospinal fluid (CSF) administration bypasses the BBB endothelium, but still fails to give adequate brain uptake. We present a novel approach for efficient CNS delivery of 111In-radiolabelled gold nanoparticles (AuNPs; 10–15 nm) via intra-cisterna magna administration, with tracking by SPECT imaging. To accelerate CSF brain influx, we administered AuNPs intracisternally in conjunction with systemic hypertonic saline, which dramatically increased the parenchymal AuNP uptake, especially in deep brain regions. AuNPs entered the CNS along periarterial spaces as visualized by MRI of gadolinium-labelled AuNPs and were cleared from brain within 24 h and excreted through the kidneys. Thus, the glymphatic-assisted perivascular network augment by systemic hypertonic saline is a pathway for highly efficient brain-wide distribution of small AuNPs. [Display omitted] •Brain access of intrathecally administered nanoparticles has been considered sparse.•Glymphatic-assisted CNS drug delivery has emerged as a new CNS drug delivery system.•We studied the brain distribution of 111In-labelled small gold nanoparticles (AuNPs).•Systemic hypertonic solution markedly increased brainwide AuNP delivery.•MRI of Gd-AuNPs visualizes their periarterial flow towards deep brain structures.
AbstractList	Nanoparticles are ultrafine particulate matter having considerable potential for treatment of central nervous system (CNS) disorders. Despite their tiny size, the blood-brain barrier (BBB) restricts their access to the CNS. Their direct cerebrospinal fluid (CSF) administration bypasses the BBB endothelium, but still fails to give adequate brain uptake. We present a novel approach for efficient CNS delivery of 111In-radiolabelled gold nanoparticles (AuNPs; 10–15 nm) via intra-cisterna magna administration, with tracking by SPECT imaging. To accelerate CSF brain influx, we administered AuNPs intracisternally in conjunction with systemic hypertonic saline, which dramatically increased the parenchymal AuNP uptake, especially in deep brain regions. AuNPs entered the CNS along periarterial spaces as visualized by MRI of gadolinium-labelled AuNPs and were cleared from brain within 24 h and excreted through the kidneys. Thus, the glymphatic-assisted perivascular network augment by systemic hypertonic saline is a pathway for highly efficient brain-wide distribution of small AuNPs. [Display omitted] •Brain access of intrathecally administered nanoparticles has been considered sparse.•Glymphatic-assisted CNS drug delivery has emerged as a new CNS drug delivery system.•We studied the brain distribution of 111In-labelled small gold nanoparticles (AuNPs).•Systemic hypertonic solution markedly increased brainwide AuNP delivery.•MRI of Gd-AuNPs visualizes their periarterial flow towards deep brain structures. Nanoparticles are ultrafine particulate matter having considerable potential for treatment of central nervous system (CNS) disorders. Despite their tiny size, the blood-brain barrier (BBB) restricts their access to the CNS. Their direct cerebrospinal fluid (CSF) administration bypasses the BBB endothelium, but still fails to give adequate brain uptake. We present a novel approach for efficient CNS delivery of 111In-radiolabelled gold nanoparticles (AuNPs; 10-15 nm) via intra-cisterna magna administration, with tracking by SPECT imaging. To accelerate CSF brain influx, we administered AuNPs intracisternally in conjunction with systemic hypertonic saline, which dramatically increased the parenchymal AuNP uptake, especially in deep brain regions. AuNPs entered the CNS along periarterial spaces as visualized by MRI of gadolinium-labelled AuNPs and were cleared from brain within 24 h and excreted through the kidneys. Thus, the glymphatic-assisted perivascular network augment by systemic hypertonic saline is a pathway for highly efficient brain-wide distribution of small AuNPs.Nanoparticles are ultrafine particulate matter having considerable potential for treatment of central nervous system (CNS) disorders. Despite their tiny size, the blood-brain barrier (BBB) restricts their access to the CNS. Their direct cerebrospinal fluid (CSF) administration bypasses the BBB endothelium, but still fails to give adequate brain uptake. We present a novel approach for efficient CNS delivery of 111In-radiolabelled gold nanoparticles (AuNPs; 10-15 nm) via intra-cisterna magna administration, with tracking by SPECT imaging. To accelerate CSF brain influx, we administered AuNPs intracisternally in conjunction with systemic hypertonic saline, which dramatically increased the parenchymal AuNP uptake, especially in deep brain regions. AuNPs entered the CNS along periarterial spaces as visualized by MRI of gadolinium-labelled AuNPs and were cleared from brain within 24 h and excreted through the kidneys. Thus, the glymphatic-assisted perivascular network augment by systemic hypertonic saline is a pathway for highly efficient brain-wide distribution of small AuNPs. Nanoparticles are ultrafine particulate matter having considerable potential for treatment of central nervous system (CNS) disorders. Despite their tiny size, the blood-brain barrier (BBB) restricts their access to the CNS. Their direct cerebrospinal fluid (CSF) administration bypasses the BBB endothelium, but still fails to give adequate brain uptake. We present a novel approach for efficient CNS delivery of ¹¹¹In-radiolabelled gold nanoparticles (AuNPs; 10–15 nm) via intra-cisterna magna administration, with tracking by SPECT imaging. To accelerate CSF brain influx, we administered AuNPs intracisternally in conjunction with systemic hypertonic saline, which dramatically increased the parenchymal AuNP uptake, especially in deep brain regions. AuNPs entered the CNS along periarterial spaces as visualized by MRI of gadolinium-labelled AuNPs and were cleared from brain within 24 h and excreted through the kidneys. Thus, the glymphatic-assisted perivascular network augment by systemic hypertonic saline is a pathway for highly efficient brain-wide distribution of small AuNPs. Nanoparticles are ultrafine particulate matter having considerable potential for treatment of central nervous system (CNS) disorders. Despite their tiny size, the blood-brain barrier (BBB) restricts their access to the CNS. Their direct cerebrospinal fluid (CSF) administration bypasses the BBB endothelium, but still fails to give adequate brain uptake. We present a novel approach for efficient CNS delivery of In-radiolabelled gold nanoparticles (AuNPs; 10-15 nm) via intra-cisterna magna administration, with tracking by SPECT imaging. To accelerate CSF brain influx, we administered AuNPs intracisternally in conjunction with systemic hypertonic saline, which dramatically increased the parenchymal AuNP uptake, especially in deep brain regions. AuNPs entered the CNS along periarterial spaces as visualized by MRI of gadolinium-labelled AuNPs and were cleared from brain within 24 h and excreted through the kidneys. Thus, the glymphatic-assisted perivascular network augment by systemic hypertonic saline is a pathway for highly efficient brain-wide distribution of small AuNPs.
Author	Fiordaliso, Elisabetta M. Beekman, Freek J. Sigurdsson, Björn Lilius, Tuomas O. Lohela, Terhi J. Stæger, Frederik Filip Kamphuis, Chris Mortensen, Kristian Nygaard Deville, Claire Rosenholm, Marko Nedergaard, Maiken Jensen, Andreas I.
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Keywords	Nanoparticles Glymphatic system Hypertonic solution Central nervous system drug delivery Single-photon emission tomography
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Snippet	Nanoparticles are ultrafine particulate matter having considerable potential for treatment of central nervous system (CNS) disorders. Despite their tiny size,...
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SubjectTerms	Biological Transport blood-brain barrier Blood-Brain Barrier - metabolism brain Brain - metabolism Central nervous system drug delivery cerebrospinal fluid endothelium Glymphatic system Gold - metabolism Hypertonic solution Metal Nanoparticles nanogold Nanoparticles particulates Single-photon emission tomography
Title	Glymphatic-assisted perivascular brain delivery of intrathecal small gold nanoparticles
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