Efficiency of drug delivery enhanced by acoustic pressure during blood-brain barrier disruption induced by focused ultrasound

Purpose: We evaluated the delivery efficiency of intravenously injected large molecular agents, before and after disruption of the blood-brain barrier (BBB-D), induced by focused ultrasound (FUS) using various acoustic parameters. Materials and methods: Male Sprague-Dawley rats were injected intravenously with Evans blue (EB) before or after BBB-D induction by pulsed FUS. We used a 1.0 MHz pulsed FUS with four acoustic power settings and an ultrasound contrast agent (UCA) at four different doses to induce BBB-D resulting from cavitation. The permeability of the BBB was assessed quantitatively based on the extravasation of EB. Contrast enhanced magnetic resonance imaging (MRI) was used to monitor the gadolinium deposition associated with FUS. Histological analysis was performed to examine tissue damage. Results: The accumulation of EB in rat brain was found to be dependent on acoustic power and UCA dosage, regardless of whether EB administration occurred before or after FUS-induced BBB-D. Administration of EB followed by sonication resulted in greater EB extravasation than that for rats subjected to sonication prior to EB injection. To reduce tissue damage, EB extravasation was enhanced by first administering EB by intravenous injection, followed by sonication at reduced acoustic power or UCA dosage. The normalized signal intensity change in rat brains that received the same dose of UCA and sonicated after gadolinium injection was significantly greater than in rats undergoing sonication followed by gadolinium administration. Moreover, contrast enhanced MRI showed a more precise distribution of gadolinium in the brain when gadolinium was administered before sonication. Conclusion: We demonstrated that a compound administered prior to sonication treatment promotes extravasation of the sonicated region. Thus, it is possible to optimize ultrasound parameters for lower sonication and reduced UCA doses, to induce BBB-D while minimizing damage to normal brain tissue.