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      Blood–Brain Barrier Modulation to Improve Glioma Drug Delivery

      review-article
      1 , 1 , 2 , *
      Pharmaceutics
      MDPI
      blood–brain barrier, drug delivery, glioma, glioblastoma, targeting

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          Abstract

          The blood–brain barrier (BBB) is formed by brain microvascular endothelial cells that are sealed by tight junctions, making it a significant obstacle for most brain therapeutics. The poor BBB penetration of newly developed therapeutics has therefore played a major role in limiting their clinical success. A particularly challenging therapeutic target is glioma, which is the most frequently occurring malignant brain tumor. Thus, to enhance therapeutic uptake in tumors, researchers have been developing strategies to modulate BBB permeability. However, most conventional BBB opening strategies are difficult to apply in the clinical setting due to their broad, non-specific modulation of the BBB, which can result in damage to normal brain tissue. In this review, we have summarized strategies that could potentially be used to selectively and efficiently modulate the tumor BBB for more effective glioma treatment.

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          Most cited references148

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          Clinical trial of blood-brain barrier disruption by pulsed ultrasound.

          The blood-brain barrier (BBB) limits the delivery of systemically administered drugs to the brain. Methods to circumvent the BBB have been developed, but none are used in standard clinical practice. The lack of adoption of existing methods is due to procedural invasiveness, serious adverse effects, and the complications associated with performing such techniques coincident with repeated drug administration, which is customary in chemotherapeutic protocols. Pulsed ultrasound, a method for disrupting the BBB, was shown to effectively increase drug concentrations and to slow tumor growth in preclinical studies. We now report the interim results of an ultrasound dose-escalating phase 1/2a clinical trial using an implantable ultrasound device system, SonoCloud, before treatment with carboplatin in patients with recurrent glioblastoma (GBM). The BBB of each patient was disrupted monthly using pulsed ultrasound in combination with systemically injected microbubbles. Contrast-enhanced magnetic resonance imaging (MRI) indicated that the BBB was disrupted at acoustic pressure levels up to 1.1 megapascals without detectable adverse effects on radiologic (MRI) or clinical examination. Our preliminary findings indicate that repeated opening of the BBB using our pulsed ultrasound system, in combination with systemic microbubble injection, is safe and well tolerated in patients with recurrent GBM and has the potential to optimize chemotherapy delivery in the brain.
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            CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011.

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              Emerging blood–brain-barrier-crossing nanotechnology for brain cancer theranostics

              The advancements, perspectives, and challenges in blood–brain-barrier (BBB)-crossing nanotechnology for effective brain tumor delivery and highly efficient brain cancer theranostics. Brain cancer, especially the most common type of glioblastoma, is highly invasive and known as one of the most devastating and deadly neoplasms. Despite surgical and medical advances, the prognosis for most brain cancer patients remains dismal and the median survival rarely exceeds 16 months. Drug delivery to the brain is significantly hindered by the existence of the blood–brain barrier (BBB), which serves as a protective semi-permeable membrane for the central nervous system. Recent breakthroughs in nanotechnology have yielded multifunctional theranostic nanoplatforms with the ability to cross or bypass the BBB, enabling accurate diagnosis and effective treatment of brain tumours. Herein, we make our efforts to present a comprehensive review on the latest remarkable advances in BBB-crossing nanotechnology, with an emphasis on the judicious design of multifunctional nanoplatforms for effective BBB penetration, efficient tumour accumulation, precise tumour imaging, and significant tumour inhibition of brain cancer. The detailed elucidation of BBB-crossing nanotechnology in this review is anticipated to attract broad interest from researchers in diverse fields to participate in the establishment of powerful BBB-crossing nanoplatforms for highly efficient brain cancer theranostics.
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                Author and article information

                Journal
                Pharmaceutics
                Pharmaceutics
                pharmaceutics
                Pharmaceutics
                MDPI
                1999-4923
                12 November 2020
                November 2020
                : 12
                : 11
                : 1085
                Affiliations
                [1 ]Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA; hluo67@ 123456wisc.edu
                [2 ]Department of Neurological Surgery, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI 53792, USA
                Author notes
                [* ]Correspondence: eshusta@ 123456wisc.edu ; Tel.: +1-608-265-5103; Fax: +1-608-262-5434
                Article
                pharmaceutics-12-01085
                10.3390/pharmaceutics12111085
                7697580
                33198244
                78a4a3c5-2235-44f0-813a-9a9626843d05
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 29 October 2020
                : 10 November 2020
                Categories
                Review

                blood–brain barrier,drug delivery,glioma,glioblastoma,targeting

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