Abstract
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.
Highlights
The blood–brain barrier (BBB) has hampered the efficiency of nanoparticle delivery into the brain via conventional strategies
We constructed an in vitro BBB model capable of focused ultrasound (FUS) exposure under the existence of MBs (Figs. 2a and S1). bEND.[3] mouse brain endothelial cells were chosen as model BBB cells in this study
Compared with the control group without FUS, no obvious difference in ZO-1 expression following FUS exposure was observed within the resolution range of a confocal laser microscope. These results suggested that the small gaps at less than the sub-micron scale were created by FUS exposure in the BBB model, but not the large, micron-scale defects
Summary
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. We investigated the size-dependence of nanoparticle delivery into the brain assisted by FUSinduced BBB opening, using gold nanoparticles (AuNPs) of 3, 15, and 120 nm diameter. Clinical trials are being conducted into the FUS-assisted delivery of small molecular drugs into gliomas[27,28] This technology could provide a promising strategy for improving the efficiency of nanoparticle delivery to the brain, there are still only a limited number of reports on its application for nanoparticles[29,30,31,32,33,34]
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