Focused ultrasound-enhanced intranasal brain delivery of brain-derived neurotrophic factor.

The objective of this study was to unveil the potential mechanism of focused ultrasound (FUS)-enhanced intranasal (IN) brain drug delivery and assess its feasibility in the delivery of therapeutic molecules. Delivery outcomes of fluorescently-labeled dextrans to mouse brains by IN administration either before or after FUS sonication were compared to evaluate whether FUS enhances IN delivery by active pumping or passive diffusion. Fluorescence imaging of brain slices found that IN administration followed by FUS sonication achieved significantly higher delivery than IN administration only, while pre-treatment by FUS sonication followed by IN administration was not significantly different from IN administration only. Brain-derived neurotrophic factor (BDNF), a promising neurotrophic factor for the treatment of many central nervous system diseases, was delivered by IN followed by FUS to demonstrate the feasibility of this technique and compared with the established FUS technique where drugs are injected intravenously. Immunohistochemistry staining of BDNF revealed that FUS-enhanced IN delivery achieved similar locally enhanced delivery as the established FUS technique. This study suggested that FUS enhances IN brain drug delivery by FUS-induced active pumping of the drug and demonstrated that FUS-enhanced IN delivery is a promising technique for noninvasive and localized delivery of therapeutic molecules to the brain.

Introduction

Purpose Drug delivery WITHOUT BBB opening

Study Objective To determine whether focused ultrasound enhances intranasal brain drug delivery via active pumping versus passive diffusion and to assess the feasibility of using this method to deliver therapeutic molecules.

Animal model / Human subject Mouse (Mus musculus), strain: not specified, age: not specified, sex: not specified

Disease model Healthy

Cargo name and characteristics Fluorescently-labeled dextrans (fluorescent macromolecular polysaccharide tracers) and Brain-derived neurotrophic factor (BDNF) (protein neurotrophic factor)

Route of administration Intranasal (IN); Intravenous (IV)

Outcomes and Safety

Summary of Outcomes Intranasal (IN) administration followed immediately by focused ultrasound (FUS) with microbubbles significantly enhanced localized brain delivery of 40 kDa dextrans and enabled targeted delivery of BDNF comparable to intravenous+FUS, with no histological tissue damage observed. The successful FUS conditions were sonication applied after IN dosing (IN+FUS) with microbubbles targeting the caudate putamen and a reduced pulse length of 1,000 cycles; pretreatment FUS followed by IN (FUS+IN) did not significantly enhance delivery.

Duration of biological effect 1 hr

Safety-related matter Histological analysis found no edema, vascular damage, or other tissue damage in FUS-treated mouse brains, and the FUS pulse length was reduced to ensure safe delivery. However, known systemic side effects of IV delivery are noted, the olfactory mucosa was not evaluated, and the authors state the complete safety profile still needs to be established.

Brain Region

Visualization unavailable

Ultrasound Parameters

Focal Characteristics Focal depth: None; Focal length: None; Aperture size: None

Treatment frequency Single session

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