An advanced focused ultrasound protocol improves the blood-brain barrier permeability and doxorubicin delivery into the rat brain.

Abstract

Despite the recent development of a focused ultrasound (FUS) technique for disrupting the blood-brain barrier (BBB) and enabling the delivery of drugs into the targeted brain region, different sonication protocols have not been fully explored. In this study, we suggest a simple and cost-effective protocol that improves the BBB permeability and drug delivery without damaging the tissue. In this protocol, called FUS\u2009+\u2009BBBD protocol , an additional FUS stimulation without microbubbles ( FUS protocol ; 0.5, 1.0, or 2.0\u2009MPa acoustic pressure, 10\u2009ms tone burst, 1\u2009Hz pulse repetition frequency, 120\u2009s total duration) is applied prior to the conventional BBB disruption with microbubbles ( BBBD protocol ; 0.6∼0.72\u2009MPa acoustic pressure, 10\u2009ms tone burst, 1\u2009Hz pulse repetition frequency, 120\u2009s total duration). With the FUS\u2009+\u2009BBBD protocol , the magnetic resonance signal intensity and doxorubicin delivery at the targeted brain region were increased by 1.59 and 1.75 times at an FUS intensity of 1.0\u2009MPa, respectively, compared to the conventional BBBD. Other conditions also increase the drug delivery, but the increase is smaller than that at 1.0\u2009MPa (1.15 times for 0.5\u2009MPa and 1.60 times for 2.0\u2009MPa). The H&E histopathological analysis of the sonicated brain region using the proposed FUS\u2009+\u2009BBBD protocol showed no significant brain tissue damage at an FUS intensity of 0.5 and 1.0\u2009MPa. However, region cavities due to the damage were observed after an FUS intensity of 2.0\u2009MPa. These results suggest that the 1.0\u2009MPa FUS\u2009+\u2009BBBD protocol increases the BBB permeability and enhances the drug delivery efficiency without noticeable brain tissue damage, compared with the conventional BBBD. Although further studies are needed to determine the underlying mechanism of this effect, drugs that have been reported to be effective in the treatment of brain disease but had limited use due to severe systemic side effects will benefit from the FUS\u2009+\u2009BBBD protocol . Furthermore, the suggested protocol may facilitate the development of new strategies in clinical trials to treat brain disorders with improved drug delivery and safety.