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Disruption of Blood–Brain Barrier by Focused Ultrasound for Targeted Drug Delivery to the Brain

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Drug Delivery to the Central Nervous System

Part of the book series: Neuromethods ((NM,volume 45))

Abstract

A major challenge to drug delivery in the brain is caused by the blood–brain barrier (BBB), a composite of endothelial structures that exclude over 98% of small-molecule drugs and almost 100% of large-molecule neurotherapeutics from being transmitted to the brain. Current strategies for overcoming the BBB are either invasive, non-targeted, or demonstrating limited carrying capacity. Alternatively, non-invasive, transient, and local, image-guided blood–brain barrier disruption (BBBD) can be accomplished using focused ultrasound (FUS) exposure with intravascular injection of pre-formed microbubbles. Low-intensity FUS administered with microbubble-based ultrasound (US) contrast agents has been shown to transiently disrupt the BBB, allowing agents into the brain over several hours. Evaluation in vivo using MRI-guided FUS showed minimal adverse effects, as compared to invasive interventions. Electron microscopy indicated FUS activated trans-cellular transport, and reversibly affected tight junctions. Transient disruption of the BBB allowed delivery of both small-molecule drugs (Doxorubicin) and large-molecule antibody-based chemotherapeutic (Herceptin). The FUS-induced BBB disruption also allowed delivery of both molecular imaging and therapeutic agents directly to amyloid plaques in Alzheimer’s disease mouse models. A detailed description of the method for MRI-guided focal BBBD in animals will be described in this chapter.

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Acknowledgments

This work was supported by NIH grants R01EB003268, R33EB000705, U41RR019703.

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Authors and Affiliations

  1. Department of Radiology, Focused Ultrasound Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Natalia Vykhodtseva

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  1. Natalia Vykhodtseva
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  1. Jain PharmaBiotech, Blaesiring 7, Basel, 4057, Switzerland

    Kewal K. Jain

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Vykhodtseva, N. (2010). Disruption of Blood–Brain Barrier by Focused Ultrasound for Targeted Drug Delivery to the Brain. In: Jain, K. (eds) Drug Delivery to the Central Nervous System. Neuromethods, vol 45. Humana Press. https://doi.org/10.1007/978-1-60761-529-3_3

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  • DOI: https://doi.org/10.1007/978-1-60761-529-3_3

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