Delivery of different-size molecules by ultrasound-induced blood-brain barrier opening and its correlation with acoustic emission

Abstract

Focused ultrasound (FUS) in combination with microbubbles (MBs) has been successfully used in the delivery of therapeutic agents of various sizes through the blood-brain barrier (BBB) in preclinical studies. However, the dependence of delivery efficiency on the drug molecular size calls for further exploration. Fluorescence-labeled dextrans of molecular weights of 3, 70, 150, and 2000 kDa were used as model therapeutic compounds. Dextrans were mixed with MBs and injected intravenously to mice immediately after the onset of FUS sonication. The acoustic emission from ultrasound-activated MBs was acquired passively using a 10 MHz transducer and quantified for stable, inertial, and total cavitation doses. The drug delivery efficiency was quantified by the relative delivery amount and volume estimated based on fluorescent images of the brains. It was found that dextran of 3 kDa can be delivered trans-BBB at a pressure level below the inertial cavitation threshold; however, dextrans of 70, 150, and 2000 kDa were delivered only when the pressure was above the inertial cavitation threshold. At the same pressure level, the amount and volume of dextrans delivered decreased as the dextran size increased. A linear correlation of total cavitation dose and the fluorescence enhancement was found for each size dextran.