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

Abstract

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 120min). Two locations were sonicated transcranially in one hemisphere of the brain in 20 rats using a 690kHz FUS transducer; the other hemisphere served as a control. For BBB disruption, 10ms bursts were applied at 1Hz for 60s and combined with IV injection of a microbubble ultrasound contrast agent (Definity; 10μl/kg). DOX was injected immediately after the second location was sonicated. The transfer coefficient (Ktrans) for an MRI contrast agent (Gd-DTPA) was estimated serially at 4–5 time points ranging from 30min to 7.5hrs after sonication using DCE-MRI. After a single sonication (SS), the mean Ktrans was 0.0142±0.006min−1 at 30min 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 2.22hrs (95% confidence intervals (CI): 1.06–3.39hrs). Adding a second sonication increased Ktrans, and with a 120min interval between sonications, prolonged the duration of the BBB disruption. Mean Ktrans 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 120min delays, respectively. The half-life of the Ktrans decay that occurred as the barrier was restored was 1.8hrs (CI: 1.20–2.41hrs) for a 10min interval between sonications and increased to 3.34hrs (CI: 0.84–5.84hrs) for a 120min 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 10min interval between sonications. A linear correlation was found between the DOX concentration achieved and the Ktrans measured at 30min 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.