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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 111 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. [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. [ABSTRACT FROM AUTHOR]

Drug delivery to the central nervous system remains a major problem due to biological barriers. The blood-brain-barrier can be bypassed by administering drugs intrathecally directly to the cerebrospinal fluid (CSF). The glymphatic system, a network of perivascular spaces promoting fluid exchange between CSF and interstitial space, could be utilized to enhance convective drug delivery from the CSF to the parenchyma. Glymphatic flow is highest during sleep and anesthesia regimens that induce a slow-wave sleep-like state. Here, using mass spectrometry and fluorescent imaging techniques, we show that the clinically used α 2 -adrenergic agonist dexmedetomidine that enhances EEG slow-wave activity, increases brain and spinal cord drug exposure of intrathecally administered drugs in mice and rats. Using oxycodone, naloxone, and an IgG-sized antibody as relevant model drugs we demonstrate that modulation of glymphatic flow has a distinct impact on the distribution of intrathecally administered therapeutics. These findings can be exploited in the clinic to improve the efficacy and safety of intrathecally administered therapeutics. Unlabelled Image • The glymphatic system drives cerebrospinal fluid influx into brain tissue. • Glymphatic flow is increased by drugs that decrease brain noradrenergic tone. • Dexmedetomidine is a clinically used α 2 -adrenergic agonist sedative. • Dexmedetomidine increases the brain delivery of intrathecally administered drugs. • Glymphatic flow can be manipulated to enhance the CNS delivery of intrathecal therapeutics. [ABSTRACT FROM AUTHOR]