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

• Published in: Scientific reports 2020-10, Vol.10 (1), p.18220, Article 18220
• Main Authors: Ohta, Seiichi, Kikuchi, Emi, Ishijima, Ayumu, Azuma, Takashi, Sakuma, Ichiro, Ito, Taichi
• Format: Article
• Language: English
• Subjects: 639/925/352; 639/925/352/152; Animals; Blood-brain barrier; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - radiation effects; Brain - drug effects; Brain - metabolism; Brain Diseases - drug therapy; Brain Diseases - metabolism; Brain Diseases - pathology; Cell Membrane Permeability - radiation effects; Central nervous system; Central nervous system diseases; Computational neuroscience; Drug Delivery Systems - methods; Humanities and Social Sciences; Magnetic Resonance Imaging - methods; Male; Metal Nanoparticles - administration & dosage; Metal Nanoparticles - chemistry; Mice; Mice, Inbred ICR; Microbubbles; multidisciplinary; Nanoparticles; Permeability; Science; Science (multidisciplinary); Tight junctions; Ultrasonic imaging; Ultrasonic Waves; Ultrasound
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-75253-9

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.