Application of low-intensity ultrasound by opening blood–brain barrier for enhanced brain-targeted drug delivery

Abstract

Brain-targeted drug delivery has been a research hotspot, and substantial amount of related studies were already translated into standard therapy and put into clinical use. However, low effective rate retains a huge challenge for brain disease. Because, the blood–brain barrier (BBB) protects brain from pathogenic molecules and tightly controls the process of molecular transportation, which gives rise to poor-liposoluble drugs or molecules with high molecular weight cannot permeate the barrier to exert treating effect. There is an ongoing process to dig out more methods for efficient brain-targeted drug delivery. Besides modified chemical methods such as prodrugs design and brain-targeted nanotechnology, physical methods as a novel initiative could enhance the treatment effect for brain disease. In our study, the influence of low-intensity ultrasound on transient opening BBB and the related applications were explored. A medical ultrasound therapeutic device (1 MHz) was used on heads of mice at different intensities and for different treating time. Evans blue was used as a model to exhibit the permeability of the BBB after subcutaneous injection. Three types of intensities (0.6, 0.8, and 1.0 W/cm2) and duration times (1, 3, and 5 min) of ultrasound were respectively investigated. It was found that the combinations of 0.6 W/cm2/1 min, 0.6 W/cm2/3 min, 0.6 W/cm2/5 min, 0.8 W/cm2/1 min, and 1.0 W/cm2/1 min could open the BBB sufficiently with significant Evans blue staining in the brain. Brain pathological analysis showed structural change on moderate degree was found on cerebral cortex after ultrasound and could recovered rapidly. There are no obvious changes in the behavior of mice after ultrasound processing. More importantly, the BBB recovered quickly at 12 h after ultrasound application with complete BBB structure and unbroken tight junction, suggesting that ultrasound was safe to apply for brain-targeted drug delivery. Proper use of local ultrasound on the brain is a promising technique to open the BBB and enhance brain-targeted delivery.