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

Dezhuang Ye, Xiaohui Zhang, Yimei Yue, Ramesh Raliya, Pratim Biswas, Sara Taylor, Yuan chuan Tai, Joshua B. Rubin, Yongjian Liu, Hong Chen

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

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

Original languageEnglish (US)
Pages (from-to)145-153
Number of pages9
JournalJournal of Controlled Release
Volume286
DOIs
StatePublished - Sep 28 2018
Externally publishedYes

Keywords

  • Blood-brain barrier
  • Brain drug delivery
  • Brainstem
  • Focused ultrasound
  • Intranasal delivery
  • Nanoparticle
  • Positron emission tomography

ASJC Scopus subject areas

  • Pharmaceutical Science

Fingerprint

Dive into the research topics of 'Focused ultrasound combined with microbubble-mediated intranasal delivery of gold nanoclusters to the brain'. Together they form a unique fingerprint.

Cite this