Journal
JOURNAL OF CONTROLLED RELEASE
Volume 172, Issue 1, Pages 274-280Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2013.08.029
Keywords
Blood-brain barrier; Focused ultrasound; Drug delivery; Permeability; Two-photon fluorescence microscopy
Funding
- National Institutes of Health [R01 EB003268]
- Canadian Institutes of Health Research [CIHR FRN 119312]
- Natural Sciences and Engineering Research Council of Canada under NSERC CGS-D3 scholarship
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Reversible and localized blood-brain barrier disruption (BBBD) using focused ultrasound (FUS) in combination with intravascularly administered microbubbles (MBs) has been established as a non-invasive method for drug delivery to the brain. Using two-photon fluorescence microscopy (2PFM), we imaged the cerebral vasculature during BBBD and observed the extravasation of fluorescent dye in real-time in vivo. We measured the enhanced permeability upon BBBD for both 10 kDa and 70 kDa dextran conjugated Texas Red (TR) at the acoustic pressure range of 0.2-0.8 MPa and found that permeability constants of TR10kDa and TR70kDa vary from 0.0006 to 0.0359 min(-1) and from 0.0003 to 0.0231 min(-1), respectively. For both substances, a linear regression was applied on the permeability constant against the acoustic pressure and the slope from best-fit was found to be 0.039 +/- 0.005 min(-1)/MPa and 0.018 +/- 0.005 min(-1)/MPa, respectively. In addition, the pressure threshold for successfully induced BBBDwas confirmed to be 0.4-0.6 MPa. Finally, we identified two types of leakage kinetics (fast and slow) that exhibit distinct permeability constants and temporal disruption onsets, as well as demonstrated their correlations with the applied acoustic pressure and vessel diameter. Direct assessment of vascular permeability and insights on its dependency on acoustic pressure, vessel size and leakage kinetics are important for treatment strategies of BBBD-based drug delivery. (C) 2013 Elsevier B. V. All rights reserved.
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