Brain arterioles show more active vesicular transport of blood-borne tracer molecules than capillaries and venules after focused ultrasound-evoked opening of the blood-brain barrier

Sheikov, Nickolai; McDannold, Nathan; Jólesz, Ferenc A.; Zhang, Yongzhi; Tam, Karen; Hynynen, Kullervo

doi:10.1016/j.ultrasmedbio.2006.05.015

Cited by 141 publications

(104 citation statements)

References 46 publications

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“…We have seen with immunoelectron microscopy techniques that passage through the BBB after treatment with ultrasound occurs via several routes, including (i) open endothelial cell tight junctions, (ii) enhanced active vesicular transport, (iii) endothelial cell fenestration and channel formation, and (iv) free passage through injured endothelium. 46,47 Furthermore, our previous study in rabbits using 1.63-MHz sonications provides further evidence that the ultrasound-induced BBB disruption is mechanically, rather than thermally, mediated. 17 The exact mechanism by which the ultrasound-microbubble interaction produces this bioeffect remains to be eludicated.…”

Section: Discussionmentioning

confidence: 78%

Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI‐guided focused ultrasound

Treat

McDannold

Vykhodtseva

et al. 2007

Intl Journal of Cancer

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499

399

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The clinical application of chemotherapy to brain tumors has been severely limited because antitumor agents are typically unable to penetrate an intact blood-brain barrier (BBB). Although doxorubicin (DOX) has been named as a strong candidate for chemotherapy of the central nervous system (CNS), the BBB often prevents cytotoxic levels from being achieved. In this study, we demonstrate a noninvasive method for the targeted delivery of DOX through the BBB, such that drug levels shown to be therapeutic in human tumors are achieved in the normal rat brain. Using MRI-guided focused ultrasound with preformed microbubbles (Optison) to locally disrupt the BBB and systemic administration of DOX, we achieved DOX concentrations of 886 6 327 ng/g tissue in the brain with minimal tissue effects. Tissue DOX concentrations of up to 5,366 6 659 ng/g tissue were achieved with higher Optison doses, but with more significant tissue damage. In contrast, DOX accumulation in nontargeted contralateral brain tissue remained significantly lower for all paired samples (p < 0.001). These results suggest that targeted delivery by focused ultrasound may render DOX chemotherapy a viable treatment option against CNS tumors, despite previous accessibility limitations. In addition, MRI signal enhancement in the sonicated region correlated strongly with tissue DOX concentration (r 5 0.87), suggesting that contrast-enhanced MRI could perhaps indicate drug penetration during image-guided interventions. Our technique using MRIguided focused ultrasound to achieve therapeutic levels of DOX in the brain offers a large step forward in the use of chemotherapy to treat patients with CNS malignancies. ' 2007 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 78%

Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI‐guided focused ultrasound

Treat

McDannold

Vykhodtseva

et al. 2007

Intl Journal of Cancer

Self Cite

499

399

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“…The BBB opening has also been shown to close within 1-5 days with the same bubble used in this study. 37 It has been shown that the active vesicular transport is more pronounced in arterioles than in capillaries and venules after BBB opening, 38 which provided evidence that opening is not restricted to the capillaries. As the size of the arterioles was $ 10-20 lm, 20 bubble expansion may not be the factor inducing BBB opening in arterioles.…”

Section: Discussionmentioning

confidence: 99%

The mechanism of interaction between focused ultrasound and microbubbles in blood-brain barrier opening in mice

Tung

Vlachos²,

Feshitan³

et al. 2011

The Journal of the Acoustical Society of America

174

178

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The activation of bubbles by an acoustic field has been shown to temporarily open the blood-brain barrier (BBB), but the trigger cause responsible for the physiological effects involved in the process of BBB opening remains unknown. Here, the trigger cause (i.e., physical mechanism) of the focused ultrasound-induced BBB opening with monodispersed microbubbles is identified. Sixtyseven mice were injected intravenously with bubbles of 1-2, 4-5, or 6-8 lm in diameter and the concentration of 10 7 numbers/ml. The right hippocampus of each mouse was then sonicated using focused ultrasound (1.5 MHz frequency, 100 cycles pulse length, 10 Hz pulse repetition frequency, 1 min duration). Peak-rarefactional pressures of 0.15, 0.30, 0.45, or 0.60 MPa were applied to identify the threshold of BBB opening and inertial cavitation (IC). Our results suggest that the BBB opens with nonlinear bubble oscillation when the bubble diameter is similar to the capillary diameter and with inertial cavitation when it is not. The bubble may thus have to be in contact with the capillary wall to induce BBB opening without IC. BBB opening was shown capable of being induced safely with nonlinear bubble oscillation at the pressure threshold and its volume was highly dependent on both the acoustic pressure and bubble diameter.

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“…Sheikov et al later showed that US was capable of promoting pinocytosis in the endothelial cells lining brain arterioles and capillaries (86). Thus the mechanism of this acoustic enhancement of drugs from micelles is still under debate and more research was undertaken by our research group to answer this mechanistic question.…”

Section: In Vitro Research and Mechanism Of Ultrasound-cell Interactionmentioning

confidence: 97%

The Use of Ultrasound and Micelles in Cancer Treatment

Husseini

Pitt²

2008

j nanosci nanotechnol

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The high toxicity of potent chemotherapeutic drugs like Doxorubicin (Dox) limits the therapeutic window in which they can be applied. This window can be expanded by controlling the drug delivery in both space and time such that non-targeted tissues are not adversely affected. Recent research has shown that ultrasound (US) can be used to control the release of Dox and other hydrophobic drugs from polymeric micelles in both time and space. It has also been shown using an in vivo rat tumor model that Dox activity can be enhanced by ultrasound in one region, while in an adjacent region there is little or no effect of the drug. In this article, we review the in vivo and in vitro research being conducted in the area of micellar drug delivery and ultrasound to cancerous tissues. Additionally, we summarize our previously published mathematical models that attempt to represent the release and re-encapsulation phenomena of Dox from Pluronic ® P105 micelles upon the application of ultrasound. The potential benefits of such controlled chemotherapy compels a thorough investigation of role of ultrasound (US) and the mechanisms by which US accomplishes drug release and/or enhances drug potency. Therefore we will summarize our findings related the mechanism involved in acoustically activated micellar drug delivery to tumors.

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Brain arterioles show more active vesicular transport of blood-borne tracer molecules than capillaries and venules after focused ultrasound-evoked opening of the blood-brain barrier

Cited by 141 publications

References 46 publications

Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI‐guided focused ultrasound

Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI‐guided focused ultrasound

The mechanism of interaction between focused ultrasound and microbubbles in blood-brain barrier opening in mice

The Use of Ultrasound and Micelles in Cancer Treatment

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