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.
Department of Radiology, Brigham and Women's hospital and Harvard Medical School, 221 Longwood Ave. Boston, MA 02115, USA. jypark@bwh.harvard.edu
Juyoung
J
Park
Yongzhi
Y
Zhang
Natalia
N
Vykhodtseva
Ferenc A
FA
Jolesz
Nathan J
NJ
McDannold
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002199:Capillary Permeability; D003287:Contrast Media / Q000008:administration & dosage / Q000032:analysis; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems / Q000379:methods*; D019786:Gadolinium DTPA / Q000008:administration & dosage / Q000032:analysis; D008279:Magnetic Resonance Imaging; D008297:Male; D045423:Microbubbles; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D013010:Sonication / Q000379:methods*
D000903:Antibiotics, Antineoplastic; D003287:Contrast Media; D004317:Doxorubicin; D019786:Gadolinium DTPA