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- Open Access
Ultrasound-mediated delivery of brain-penetrating nanoparticles across the blood-tumor barrier
© Timbie et al; licensee BioMed Central Ltd. 2015
Published: 30 June 2015
The intact blood-brain barrier (BBB) presents a major obstacle for drug delivery to the brain. In addition, both high interstitial pressure and a nanoporous electrostatically charged tissue composition, produce a “blood-tumor barrier” (BTB), further complicating the treatment of diseases like glioblastoma. Focused ultrasound (FUS) in conjunction with microbubbles (MB) has been shown to cause reversible, localized disruption of the BBB. Incorporating MR guidance with FUS offers the ability to exquisitely target the BBB disruption to specific regions of the brain, thereby permitting drug delivery in a highly localized manner. This work examines the ability of MR guided FUS to deliver highly specialized brain-penetrating nanoparticles (NP) across both the BBB and the BTB in tumor-bearing rats. NPs were 60 nm in diameter and covered with an exceptionally dense brush layer of PEG to permit excellent diffusion through brain tissue. Initial studies utilized fluorescent polystyrene tracer particles to measure NP delivery and inform dosing of cisplatin-loaded biodegradable NPs.
One to two weeks prior to FUS treatment, 160-170 g rats were inoculated intracranially with luciferase-transfected 9L cells. On the day of treatment, the heads of the anesthetized rats were depilated and positioned in a degassed water bath coupled to the FUS system. Rats received an intravenous co-injection of NPs and MBs 30 seconds before sonication. All sonications were performed using a 1.14 MHz single element focused transducer operating at a 0.5% duty cycle for 2 minutes. Peak negative pressure was 0.6 MPa. High resolution contrast-enhanced MR images were utilized to visualize the tumor region and place sonication focal points with high accuracy. Targets were chosen to cover the entire tumor region as well as the immediate tumor periphery, thereby disrupting both the BTB and the intact BBB. Immediately following sonication, MRI contrast agent was delivered intravenously and T1-weighted contrast enhanced MRI images were captured to verify BBB disruption. Animals were recovered and monitored for 1hr-2 weeks post treatment. In animals receiving fluorescent tracer NPs, brains were perfused with 2% heparinized saline, dessicated and cryosectioned. Mounted sections were stained with BS-I lectin to reveal endothelial cells (ECs) and imaged with fluorescent microscopy. In animals receiving drug-loaded NPs, tumor growth post treatment was measured using IVIS.
Results and conclusions
Supported by the UVa Cardiovascular Research Center Training Grant, the Focused Ultrasound Foundation and NIH R01 CA164789.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.