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      Recent Advances on Ultrasound Contrast Agents for Blood-Brain Barrier Opening with Focused Ultrasound

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          Abstract

          The blood-brain barrier is the primary obstacle to efficient intracerebral drug delivery. Focused ultrasound, in conjunction with microbubbles, is a targeted and non-invasive way to disrupt the blood-brain barrier. Many commercially available ultrasound contrast agents and agents specifically designed for therapeutic purposes have been investigated in ultrasound-mediated blood-brain barrier opening studies. The new generation of sono-sensitive agents, such as liquid-core droplets, can also potentially disrupt the blood-brain barrier after their ultrasound-induced vaporization. In this review, we describe the different compositions of agents used for ultrasound-mediated blood-brain barrier opening in recent studies, and we discuss the challenges of the past five years related to the optimal formulation of agents.

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          The blood–brain barrier and blood–tumour barrier in brain tumours and metastases

          Costas Arvanitis, Gino Ferraro, Rakesh Jain (2019)
          For a blood-borne cancer therapeutic agent to be effective, it must cross the blood vessel wall to reach cancer cells in adequate quantities, and it must overcome the resistance conferred by the local microenvironment around cancer cells. The brain microenvironment can thwart the effectiveness of drugs against primary brain tumours as well as brain metastases. In this Review, we highlight the cellular and molecular components of the blood-brain barrier (BBB), a specialized neurovascular unit evolved to maintain brain homeostasis. Tumours are known to compromise the integrity of the BBB, resulting in a vasculature known as the blood-tumour barrier (BTB), which is highly heterogeneous and characterized by numerous distinct features, including non-uniform permeability and active efflux of molecules. We discuss the challenges posed by the BBB and BTB for drug delivery, how multiple cell types dictate BBB function and the role of the BTB in disease progression and treatment. Finally, we highlight emerging molecular, cellular and physical strategies to improve drug delivery across the BBB and BTB and discuss their impact on improving conventional as well as emerging treatments, such as immune checkpoint inhibitors and engineered T cells. A deeper understanding of the BBB and BTB through the application of single-cell sequencing and imaging techniques, and the development of biomarkers of BBB integrity along with systems biology approaches, should enable new personalized treatment strategies for primary brain malignancies and brain metastases.
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            Clinical trial of blood-brain barrier disruption by pulsed ultrasound.

            Alexandre Carpentier, Michael Canney, Alexandre Vignot … (2016)
            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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              Current Strategies for Brain Drug Delivery

              Xiaowei Dong (2018)
              The blood-brain barrier (BBB) has been a great hurdle for brain drug delivery. The BBB in healthy brain is a diffusion barrier essential for protecting normal brain function by impeding most compounds from transiting from the blood to the brain; only small molecules can cross the BBB. Under certain pathological conditions of diseases such as stroke, diabetes, seizures, multiple sclerosis, Parkinson's disease and Alzheimer disease, the BBB is disrupted. The objective of this review is to provide a broad overview on current strategies for brain drug delivery and related subjects from the past five years. It is hoped that this review could inspire readers to discover possible approaches to deliver drugs into the brain. After an initial overview of the BBB structure and function in both healthy and pathological conditions, this review re-visits, according to recent publications, some questions that are controversial, such as whether nanoparticles by themselves could cross the BBB and whether drugs are specifically transferred to the brain by actively targeted nanoparticles. Current non-nanoparticle strategies are also reviewed, such as delivery of drugs through the permeable BBB under pathological conditions and using non-invasive techniques to enhance brain drug uptake. Finally, one particular area that is often neglected in brain drug delivery is the influence of aging on the BBB, which is captured in this review based on the limited studies in the literature.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Pharmaceutics
                Journal ID (iso-abbrev): Pharmaceutics
                Journal ID (publisher-id): pharmaceutics
                Title: Pharmaceutics
                Publisher: MDPI
                ISSN (Electronic): 1999-4923
                Publication date (Electronic): 21 November 2020
                Publication date Collection: November 2020
                Volume: 12
                Issue: 11
                Electronic Location Identifier: 1125
                Affiliations
                [1 ]Université Paris-Saclay, CEA, CNRS, Inserm, BioMaps, Service Hospitalier Frédéric Joliot, 91401 Orsay, France; ambre.dauba@ 123456universite-paris-saclay.fr
                [2 ]Centre de Biophysique Moléculaire and Université d’Orléans, CNRS-UPR 4301, 45071 Orléans, France; anthony.delalande@ 123456cnrs.fr
                [3 ]Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA; kamimura.hermes@ 123456columbia.edu
                [4 ]Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy; allegra.conti@ 123456uniroma2.it
                [5 ]Université Paris-Saclay, CEA, CNRS, Baobab, NeuroSpin, 91191 Gif-sur-Yvette, France; benoit.larrat@ 123456cea.fr
                [6 ]Université Paris-Saclay, CNRS, Institut Galien Paris-Saclay, 92296 Châtenay-Malabry, France; nicolas.tsapis@ 123456universite-paris-saclay.fr
                Author notes
                [* ]Correspondence: anthony.novell@ 123456universite-paris-saclay.fr ; Tel.: +33-169867727
                Author information
                https://orcid.org/0000-0001-8280-4616
                https://orcid.org/0000-0001-5846-9870
                https://orcid.org/0000-0003-4210-5065
                https://orcid.org/0000-0003-2095-2626
                https://orcid.org/0000-0003-3649-0956
                Article
                Publisher ID: pharmaceutics-12-01125
                DOI: 10.3390/pharmaceutics12111125
                PMC ID: 7700476
                PubMed ID: 33233374
                SO-VID: a93de619-699e-4098-bfeb-2e67aeff3dbc
                Copyright © © 2020 by the authors.
                License:

                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
                Date received : 19 October 2020
                Date accepted : 17 November 2020
                Categories
                Subject: Review

                Keywords: blood-brain barrier,bubble,droplet,phase-change contrast agent,ultrasound
                Data availability:
                Keywords: blood-brain barrier, bubble, droplet, phase-change contrast agent, ultrasound

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