This research was designed to determine whether disrupting the blood-brain barrier (BBB) in rats by applying focused ultrasound (FUS) combined with microbubbles induced changes in the density of caveolae and/or the expression of the structural protein caveolin-1. To this end, two approaches were utilized. First, using enhanced magnetic resonance imaging, characteristics of BBB disruption induced by our specific FUS parameters and dose of microbubble were recorded, and the time after treatment when the BBB was the most permeable was determined. Second, rats were treated with FUS or microbubbles alone, both or neither, and a combination of Evans blue (EB) BBB permeability assays, streptavidin-peroxidase (SP) immunohistochemistry, western blot, and transmission electron microscopy (TEM) was employed to detect any changes in caveolae density and caveolin-1 expression at the previously determined time point when the BBB was the most permeable. The first set of studies revealed that our specific FUS parameters and dose of microbubbles were able to induce a transient, targeted, and reversible BBB opening in rats, and that the BBB was the most permeable 1 h after treatment with FUS and microbubbles. In the second set of experiments, the results of the SP immunohistochemistry, western blot, and TEM, taken together, revealed that caveolae and caveolin-1 were primarily localized in the brain microvascular endothelial cells of all of the rats regardless of treatment, and that caveolin-1 expression was highest in the rats treated with both FUS and microbubbles. In summary, treatment with FUS, in combination with a dose of microbubbles, can enhance BBB permeability through a caveolae-mediated transcellular approach by upregulating the expression level of caveolin-1 and, consequently, the amount of caveolae. This caveolin-1-mediated transcellular transport pathway may cooperate with other transport pathways to induce opening of the BBB. This research sheds light on the mechanism of a transient, targeted, and reversible opening of the BBB induced by FUS combined with microbubbles.
"In a study investigating caveolae density it was found that caveolae and caveolin-1 were primarily localized in the brain microvascular endothelial cells of all the animals tested (rats) regardless of treatment, and that caveolin-1 expression was the highest in the rats treated with both FUS and microbubbles. The authors concluded that caveolin-1-mediated transcellular transport pathway may cooperate with other transport pathways (e.g., tight junctional disruption) to induce opening of the BBB . "
[Show abstract][Hide abstract] ABSTRACT: Ultrasound-mediated drug delivery under the guidance of an imaging modality can improve drug disposition and achieve site-specific drug delivery. The term focal drug delivery has been introduced to describe the focal targeting of drugs in tissues with the help of imaging and focused ultrasound. Focal drug delivery aims to improve the therapeutic profile of drugs by improving their specificity and their permeation in defined areas. Focused-ultrasound- (FUS-) mediated drug delivery has been applied with various molecules to improve their local distribution in tissues. FUS is applied with the aid of microbubbles to enhance the permeability of bioactive molecules across BBB and improve drug distribution in the brain. Recently, FUS has been utilised in combination with MRI-labelled liposomes that respond to temperature increase. This strategy aims to "activate" nanoparticles to release their cargo locally when triggered by hyperthermia induced by FUS. MRI-guided FUS drug delivery provides the opportunity to improve drug bioavailability locally and therefore improve the therapeutic profiles of drugs. This drug delivery strategy can be directly translated to clinic as MRg FUS is a promising clinically therapeutic approach. However, more basic research is required to understand the physiological mechanism of FUS-enhanced drug delivery.
"Recently, it has been demonstrated that focused ultrasound in combination with ultrasound contrast agents (UCA) can lead to a transient disruption of the BBB without relevant neuronal damage.3,4,5,6 As an underlying molecular mechanism of ultrasonographic BBB opening, both a transient disintegration of tight junctional complexes7 and an increased caveolae-mediated transcellular transport have been discussed.8 By this means, macromolecules such as antibodies9 or plasmid DNA for nonviral gene therapy10 have successfully been delivered in rodents. "
[Show abstract][Hide abstract] ABSTRACT: Delivery of drugs and macromolecules to the central nervous system (CNS) is hindered by the blood-brain barrier (BBB). Several approaches have been used to overcome this hindrance to facilitate the treatment of various CNS diseases. We now present results showing that chimeric adeno-associated virus 2/1 (AAV2/1) particles containing the coding region for the LacZ gene are efficiently delivered into the rat brain upon intravenous (IV) administration after BBB opening by focused ultrasound in the presence of vascular acoustic resonators. We show that the transgene is correctly and efficiently expressed in cells located in the neighborhood of the insonated focus, especially in the vicinity of small vessels and capillaries. Histochemical LacZ staining allows the identification of large amounts of cells expressing the enzymatically active protein. Using double immunofluorescence (IF) with antibodies against tubulinIII and bacterial LacZ, we identified these cells to be mostly neurons. A small proportion of the transduced cells was recognized as glial cells, reacting positive in the IF with antibodies against astrocytic markers. These results demonstrate that our approach allows a very specific, localized, and efficient expression of intravenously administered transgenes in the brain of rats upon ultrasound-induced BBB opening.Molecular Therapy - Nucleic Acids (2013) 2, e73; doi:10.1038/mtna.2012.64; published online 19 February 2013.
[Show abstract][Hide abstract] ABSTRACT: There is an increasing interest in the use of ultrasound to enhance drug delivery to the brain and central nervous system. Disorders of the brain and CNS historically have had poor response to drug therapy due to the presence of the blood-brain barrier (BBB). Techniques for circumventing the BBB are typically highly invasive or involve disrupting large portions of the BBB, exposing the brain to pathogens. Ultrasound can be non-invasively delivered to the brain through the intact skull. When combined with preformed microbubbles, ultrasound can safely induce transient, localised and reversible disruption of the BBB, allowing therapeutics to be delivered. Investigations to date have shown positive response to ultrasound BBB disruption combined with therapeutic agent delivery in rodent models of primary and metastatic brain cancer and Alzheimer's disease. Recent work in non-human primates has demonstrated that the technique is feasible for use in humans. This review examines the current status of drug delivery to the brain and CNS both by disruption of the BBB, and by ultrasound enhancement of drug delivery through the already compromised BBB. Cellular and physical mechanisms of disruption are discussed, as well as treatment technique, safety and monitoring.
International Journal of Hyperthermia 06/2012; 28(4):386-96. DOI:10.3109/02656736.2012.666709 · 2.65 Impact Factor
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