The kinetics of blood brain barrier permeability and targeted doxorubicin delivery into brain induced by focused ultrasound

Focused ultrasound (FUS) combined with a circulating microbubble agent is a promising strategy to non-invasively disrupt the blood-brain barrier (BBB) and could enable targeted delivery of therapeutics that normally do not leave the brain vasculature. This study investigated the kinetics of the BBB permeability using dynamic contrast-enhanced MRI (DCE-MRI) and the resulting payload of the chemotherapy agent, doxorubicin (DOX). We also investigated how the disruption and drug delivery were affected by a double sonication (DS) with two different time intervals (10 or 120 min). Two locations were sonicated transcranially in one hemisphere of the brain in 20 rats using a 690 kHz FUS transducer; the other hemisphere served as a control. For BBB disruption, 10 ms bursts were applied at 1 Hz for 60s and combined with IV injection of a microbubble ultrasound contrast agent (Definity; 10 μl/kg). DOX was injected immediately after the second location was sonicated. The transfer coefficient (K(trans)) for an MRI contrast agent (Gd-DTPA) was estimated serially at 4-5 time points ranging from 30 min to 7.5 hrs after sonication using DCE-MRI. After a single sonication (SS), the mean K(trans) was 0.0142 ± 0.006 min(-1) at 30 min and was two or more orders of magnitude higher than the non-sonicated targets. It decreased exponentially as a function of time with an estimated half-life of 2.22 hrs (95% confidence intervals (CI): 1.06-3.39 hrs). Adding a second sonication increased K(trans), and with a 120 min interval between sonications, prolonged the duration of the BBB disruption. Mean K(trans) estimates of 0.0205 (CI: 0.016-0.025) and 0.0216 (CI: 0.013-0.030) min(-1) were achieved after DS with 10 and 120 min delays, respectively. The half-life of the K(trans) decay that occurred as the barrier was restored was 1.8 hrs (CI: 1.20-2.41 hrs) for a 10 min interval between sonications and increased to 3.34 hrs (CI: 0.84-5.84 hrs) for a 120 min interval. DOX concentrations were significantly greater than in the non-sonicated brain for all experimental groups (p<0.0001), and 1.5-fold higher for DS with a 10 min interval between sonications. A linear correlation was found between the DOX concentration achieved and the K(trans) measured at 30 min after sonication (R: 0.7). These data suggest that one may be able to use Gd-DTPA as a surrogate tracer to estimate DOX delivery to the brain after FUS-induced BBB disruption. The results of this study provide information needed to take into account the dynamics BBB disruption over time after FUS.