Investigating the optimum size of nanoparticles for their delivery into the brain assisted by focused ultrasound-induced blood-brain barrier opening.

The blood-brain barrier (BBB) has hampered the efficiency of nanoparticle delivery into the brain via conventional strategies. The widening of BBB tight junctions via focused ultrasound (FUS) offers a promising approach for enhancing the delivery of nanoparticles into the brain. However, there is currently an insufficient understanding of how nanoparticles pass through the opened BBB gaps. Here we investigated the size-dependence of nanoparticle delivery into the brain assisted by FUS-induced BBB opening, using gold nanoparticles (AuNPs) of 3, 15, and 120 nm diameter. For 3- and 15-nm AuNPs, FUS exposure significantly increased permeation across an in vitro BBB model by up to 9.5 times, and the permeability was higher with smaller diameter. However, in vivo transcranial FUS exposure in mice demonstrated that smaller particles were not necessarily better for delivery into the brain. Medium-sized (15 nm) AuNPs showed the highest delivery efficiency (0.22% ID), compared with 3- and 120-nm particles. A computational model suggested that this optimum size was determined by the competition between their permeation through opened BBB gaps and their excretion from blood. Our results would greatly contribute to designing nanoparticles for their delivery into the brain for the treatment of central nervous system diseases.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To determine how nanoparticle size affects delivery into the brain via focused ultrasound-induced blood–brain barrier opening using PEG-coated gold nanoparticles (3–120 nm) in vitro and in vivo.

Animal model / Human subject Mouse (Mus musculus), strain None, age None, sex None

Cargo name and characteristics Gold nanoparticles (AuNPs), inorganic metallic nanoparticles; spherical gold particles of diameters 3 nm, 15 nm, and 120 nm used to evaluate size-dependent blood–brain barrier delivery

Outcomes and Safety

Summary of Outcomes Focused ultrasound (FUS) with microbubbles transiently opened the blood–brain barrier and enhanced brain delivery of gold nanoparticles with an optimal delivery for 15 nm particles (~0.22% ID), and successful FUS parameters included in vitro 1 MHz, 88 kPa peak-positive pressure, 10 ms bursts at 1 Hz for 40 s with Sonazoid microbubbles, and in vivo transcranial exposures at ~0.6–0.7 MPa (using ~8.0×10^7–8.0×10^8 MBs/mouse); pressures >0.8 MPa induced hemorrhage.

Duration of biological effect 4 h

Safety-related matter The authors report safety concerns with FUS: higher acoustic pressures (e.g., PPP = 320 kPa without microbubbles or >0.8 MPa in vivo) increase the risk of cellular damage and can cause severe brain bleeding, so appropriate FUS conditions must be chosen to avoid large defects and adverse effects. They also state that the PEGylated AuNPs showed no significant cytotoxicity in HUVEC assays, suggesting good biocompatibility.

Brain Region

Visualization unavailable

Ultrasound Parameters

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

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