Focused ultrasound combined with microbubble-mediated intranasal delivery of gold nanoclusters to the brain

JOURNAL OF CONTROLLED RELEASE

卷:286

Article

Ye, Dezhuang¹  Zhang, Xiaohui²  Yue, Yimei³  Raliya, Ramesh⁴  Biswas, Pratim⁴  Taylor, Sara⁵  Tai, Yuan-chuan²  Rubin, Joshua B.^5,6  Liu, Yongjian²  Chen, Hong^3,7 

[1] Washington Univ, Dept Mech Engn & Mat Sci, St Louis, MO 63130 USA

[2] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO 63110 USA

[3] Washington Univ, Dept Biomed Engn, 4511 Forest Pk Ave, St Louis, MO 63130 USA

[4] Washington Univ, Dept Energy Environm & Chem Engn, St Louis, MO 63130 USA

[5] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA

[6] Washington Univ, Sch Med, Dept Neurosci, St Louis, MO 63110 USA

[7] Washington Univ, Sch Med, Dept Radiat Oncol, St Louis, MO 63108 USA

关键词: Focused ultrasound;    Nanoparticle;    Intranasal delivery;    Blood-brain barrier;    Positron emission tomography;    Brain drug delivery;    Brainstem;   

DOI  :  10.1016/j.jconrel.2018.07.020

来源: Elsevier

【 摘 要 】

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 Cu-64-alloyed AuNCs (Cu-64-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 Cu-64-AuNCs. Second, Cu-64-AuNCs and Texas red-labeled AuNCs (TR-AuNCs) were used separately to evaluate FUSIN delivery outcome in the brain. Cu-64-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 Cu-64-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 Cu-64-AuNCs accumulation in the blood, lungs, liver, spleen, kidney, and heart compared with IV injection. FUSIN enhanced the delivery of Cu-64-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.

【 授权许可】

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