Comparison of Focused Ultrasound-Mediated Intranasal Delivery and Focused Ultrasound-Induced Blood-Brain Barrier Disruption in the Delivery of Gold Nanoclusters to the Brainstem

Focused ultrasound-enabled intranasal brain drug delivery (FUSIN)utilizes the nose-to-brain pathway for drug administration and FUS in combination with microbubbles for enhancing the accumulation of the administered drugs at the FUS-targeted brain location. FUSIN is different from the established FUS-induced BBB disruption (FUS-BBBD)technique. The objective of this study was to compare the delivery efficiency, systemic exposure, and delivery pathways of FUSIN and FUS-BBBD. Taxes red-labeled gold nanoclusters (TR-AuNCs)were used as the model agent and FUS was targeted at the brainstem. Mice were divided into four groups: FUSIN, FUS-BBBD, IN only, and IV only. The delivery efficiency of TR-AuNCs to the mouse brain and exposure to other major organs, as well as the blood, nasal tissue, and trigeminal nerve, were quantified using inductively coupled plasma-mass spectrometry (ICP-MS)analysis of Au concentration. It was found that FUSIN achieved one order of magnitude higher delivery efficiency and one order of magnitude lower systemic exposure in major organs except stomach and intestines than FUS-BBBD. It also verified that FUSIN delivered the AuNCs through the nose-to-brain pathway, while FUS-BBBD utilized the blood-to-brain pathway. These findings suggested that FUSIN is a promising technique for noninvasive and localized brain drug delivery with minimized systemic exposure.