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The kinetics of blood brain barrier permeability and targeted doxorubicin delivery into brain induced by focused ultrasound.
J Control Release. 2012 Aug 20; 162(1):134-42.JC

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 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.

Authors+Show Affiliations

Department of Radiology, Brigham and Women's hospital and Harvard Medical School, 221 Longwood Ave. Boston, MA 02115, USA. jypark@bwh.harvard.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

22709590

Citation

Park, Juyoung, et al. "The Kinetics of Blood Brain Barrier Permeability and Targeted Doxorubicin Delivery Into Brain Induced By Focused Ultrasound." Journal of Controlled Release : Official Journal of the Controlled Release Society, vol. 162, no. 1, 2012, pp. 134-42.
Park J, Zhang Y, Vykhodtseva N, et al. The kinetics of blood brain barrier permeability and targeted doxorubicin delivery into brain induced by focused ultrasound. J Control Release. 2012;162(1):134-42.
Park, J., Zhang, Y., Vykhodtseva, N., Jolesz, F. A., & McDannold, N. J. (2012). The kinetics of blood brain barrier permeability and targeted doxorubicin delivery into brain induced by focused ultrasound. Journal of Controlled Release : Official Journal of the Controlled Release Society, 162(1), 134-42. https://doi.org/10.1016/j.jconrel.2012.06.012
Park J, et al. The Kinetics of Blood Brain Barrier Permeability and Targeted Doxorubicin Delivery Into Brain Induced By Focused Ultrasound. J Control Release. 2012 Aug 20;162(1):134-42. PubMed PMID: 22709590.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The kinetics of blood brain barrier permeability and targeted doxorubicin delivery into brain induced by focused ultrasound. AU - Park,Juyoung, AU - Zhang,Yongzhi, AU - Vykhodtseva,Natalia, AU - Jolesz,Ferenc A, AU - McDannold,Nathan J, Y1 - 2012/06/15/ PY - 2012/01/20/received PY - 2012/05/29/revised PY - 2012/06/09/accepted PY - 2012/6/20/entrez PY - 2012/6/20/pubmed PY - 2013/1/3/medline SP - 134 EP - 42 JF - Journal of controlled release : official journal of the Controlled Release Society JO - J Control Release VL - 162 IS - 1 N2 - 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. SN - 1873-4995 UR - https://www.unboundmedicine.com/medline/citation/22709590/The_kinetics_of_blood_brain_barrier_permeability_and_targeted_doxorubicin_delivery_into_brain_induced_by_focused_ultrasound_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0168-3659(12)00512-3 DB - PRIME DP - Unbound Medicine ER -