The Dependence of the Ultrasound-Induced Blood-Brain Barrier Opening Characteristics on Microbubble Size In Vivo

Abstract

Recent neuropharmaceutical developments have led to potent disease‐modifying drugs. In spite of these advancements, most agents cannot traverse the blood‐brain barrier (BBB) and deposit in the brain. Focused ultrasound (FUS) with microbubbles has been shown to induce noninvasive, localized, and transient BBB opening. Although promising, safety and efficacy concerns still remain. Previously reported experiments used conventional imaging contrast agents that have a wide size distribution. In this study, we hypothesize that BBB opening characteristics are dependent on bubble diameter. A 25 μl bolus of in‐house manufactured, lipid‐shelled bubbles with either 1–2 or 4–5 μm diameter ranges was injected intravenously. Pulsed FUS (frequency: 1.5 MHz, peak‐negative pressure: 146–607 kPa, duty cycle: 20%, duration: 1‐min) was then applied to the left hippocampus of mice (n = 16) in vivo through the intact skin and skull. MRI or fluorescence microscopy was used to determine BBB opening. Contrast‐enhanced (Omniscan™; 0.75 mL; molecular weight: 574 Da) MRI (9.4‐T) was acquired on multiple days after sonication to determine BBB opening and closing. Fluorescence microscopy was also used to determine the feasibility of delivering large, 3 kDa dextran compounds through the BBB. The BBB opening acoustic pressure threshold for the 4–5μm bubbles was in the 146–304 kPa range while the threshold for the 1–2μm bubbles was higher. In conclusion, FUS‐induced BBB opening and closing was shown to be dependent on the bubble diameter indicating the possibility of specifically designing bubbles to enhance this therapeutic application.