Focused ultrasound combined with microbubble-mediated intranasal delivery of gold nanoclusters to the brain.
Authors: Ye D, Zhang X, Yue Y, Raliya R, Biswas P, Taylor S, Tai YC, Rubin JB, Liu Y, Chen H
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 <sup>64</sup>Cu-alloyed AuNCs (<sup>64</sup>Cu-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 <sup>64</sup>Cu-AuNCs. Second, <sup>64</sup>Cu-AuNCs and Texas red-labeled AuNCs (TR-AuNCs) were used separately to evaluate FUSIN delivery outcome in the brain. <sup>64</sup>Cu-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 <sup>64</sup>Cu-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 <sup>64</sup>Cu-AuNCs accumulation in the blood, lungs, liver, spleen, kidney, and heart compared with IV injection. FUSIN enhanced the delivery of <sup>64</sup>Cu-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.
Introduction
Purpose
Drug delivery WITHOUT BBB opening
Study Objective
To evaluate the biodistribution of intranasally administered gold nanoclusters and assess the feasibility and short-term safety of focused ultrasound combined with microbubble-mediated intranasal delivery (FUSIN) for targeting the brainstem.
Animal model / Human subject
mice, C57BL/6, not reported, female
Disease model
healthy
Targeted brain region(s)
Brainstem
Cargo name and characteristics
nanoparticle
Route of administration
intranasal
Outcomes and Safety
Summary of Outcomes
FUSIN significantly enhanced gold nanocluster delivery to the FUS-targeted brainstem compared with intranasal delivery alone.
Duration of biological effect
not reported
Safety-related matter
No histological damage detected in the nose, trigeminal nerve, or brain.
Brain Region
Ultrasound Parameters
Ultrasound instrument
focused ultrasound transducer
FUS Frequency
not reported
FUS Intensity
not reported
FUS Pressure
not reported
FUS Mode
not reported
Pulse duration
not reported
Duration of a single FUS session
not reported
Treatment frequency
single
We are open to feedback. If you see a mistake or have a suggestion, please contact us.
← Back to Search