Molecular imaging through the blood-brain barrier: Safety assessment and parameter dependence

Current treatments of neurological and neurodegenerative diseases are limited due to the lack of a truly noninvasive, transient, and regionally selective brain drug delivery method. The brain is particularly difficult to deliver drugs to because of the blood-brain barrier (BBB). Over the past few years, we have been developing methods that combine Focused Ultrasound (FUS) and microbubbles in order to noninvasively, locally and transiently open the BBB so as to treat neurodegenerative diseases. In this paper, the role of the microbubble properties in the BBB opening and its permeability is investigated. The left hippocampus of mice was sonicated (frequency: 1.525MHz, pressure: 0.33 MPa, duty cycle: 20%, duration: 1-min) in vivo through the intact skin and skull following intravenous injection of microbubbles. Two different size ranges of lipid-shelled microbubbles (1–2 and 4–5 µm in diameter) were prepared and filtered according to their size based on their buoyancy. The permeability (Ki) of the BBB was quantified using a sequence of MR T1-weighted images (9.4 T, Bruker Medical; Boston, MA) and a previously reported model in order to measure the permeability changes of the BBB as a result of the FUS-induced opening. Larger microbubbles (4–5 µm) resulted in a larger region of BBB opening in the targeted hippocampus. The increased extent of the BBB-opened region could be interpreted based on previously reported models on the relationship between microbubble resonance and vascular effects, which have shown that in compliant vessels the natural frequency of 4-µm microbubbles becomes 1.3 MHz, potentially justifying the enhanced effect in the 4–5 µm case at the frequency used in this study. Ki maps were obtained across the entire brain and were found highest at the BBB opening site equal to 7 µl/g-min. These values are in agreement with Ki values in BBB disruption reported in tumor models to range between 6.8(±3.5) and 15.1(±8.0) µl/g-min. This study showed molecular imaging of larger brain region is enabled using larger microbubbles This reinforces our hypothesis that the microbubble properties are as important of a component as the ultrasound parameters in accurately predicting the resulting BBB opening.