https://www.ncbi.nlm.nih.gov/pubmed/30009893
Abstract
Focused
ultrasound combined with microbubble-mediated intranasal delivery
(FUSIN) is a new brain drug delivery technique. FUSIN utilizes the nasal
route for direct nose-to-brain drug administration, thereby bypassing
the blood-brain barrier (BBB) and minimizing systemic exposure. It also
uses FUS-induced microbubble cavitation to enhance transport of
intranasally (IN) administered agents to the FUS-targeted brain
location. Previous studies have provided proof-of-concept data showing
the feasibility of FUSIN to deliver dextran and the brain-derived
neurotrophic factor to the caudate putamen of mouse brains. The
objective of this study was to evaluate the biodistribution of IN
administered gold nanoclusters (AuNCs) and assess the feasibility and
short-term safety of FUSIN for the delivery of AuNCs to the brainstem.
Three experiments were performed. First, the whole-body biodistribution
of IN administered 64Cu-alloyed AuNCs (64Cu-AuNCs)
was assessed using in vivo positron emission tomography/computed
tomography (PET/CT) and verified with ex vivo gamma counting. Control
mice were intravenously (IV) injected with the 64Cu-AuNCs. Second, 64Cu-AuNCs and Texas red-labeled AuNCs (TR-AuNCs) were used separately to evaluate FUSIN delivery outcome in the brain. 64Cu-AuNCs
or TR-AuNCs were administered to mice through the nasal route, followed
by FUS sonication at the brainstem in the presence of systemically
injected microbubbles. The spatial distribution of 64Cu-AuNCs
and TR-AuNCs were examined by autoradiography and fluorescence
microscopy of ex vivo brain slices, respectively. Third, histological
analysis was performed to evaluate any potential histological damage to
the nose and brain after FUSIN treatment. The experimental results
revealed that IN administration induced significantly lower 64Cu-AuNCs
accumulation in the blood, lungs, liver, spleen, kidney, and heart
compared with IV injection. FUSIN enhanced the delivery of 64Cu-AuNCs
and TR-AuNCs at the FUS-targeted brain region compared with IN delivery
alone. No histological-level tissue damage was detected in the nose,
trigeminal nerve, and brain. These results suggest that FUSIN is a
promising technique for noninvasive, spatially targeted, and safe
delivery of nanoparticles to the brain with minimal systemic exposure.
KEYWORDS:
Blood-brain barrier; Brain drug delivery; Brainstem; Focused ultrasound; Intranasal delivery; Nanoparticle; Positron emission tomography- PMID:
- 30009893
- DOI:
- 10.1016/j.jconrel.2018.07.020
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