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      How to Make Anticancer Drugs Cross the Blood–Brain Barrier to Treat Brain Metastases

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          Abstract

          The incidence of brain metastases has increased in the last 10 years. However, the survival of patients with brain metastases remains poor and challenging in daily practice in medical oncology. One of the mechanisms suggested for the persistence of a high incidence of brain metastases is the failure to cross the blood–brain barrier of most chemotherapeutic agents, including the more recent targeted therapies. Therefore, new pharmacological approaches are needed to optimize the efficacy of anticancer drug protocols. In this article, we present recent findings in molecular data on brain metastases. We then discuss published data from pharmacological studies on the crossing of the blood–brain barrier by anticancer agents. We go on to discuss future developments to facilitate drug penetration across the blood–brain barrier for the treatment of brain metastases among cancer patients, using physical methods or physiological transporters.

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          Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity.

          Peter Ballard, James W T Yates, Zhenfan Yang … (2016)
          Approximately one-third of patients with non-small cell lung cancer (NSCLC) harboring tumors with EGFR-tyrosine kinase inhibitor (TKI)-sensitizing mutations (EGFRm) experience disease progression during treatment due to brain metastases. Despite anecdotal reports of EGFR-TKIs providing benefit in some patients with EGFRm NSCLC brain metastases, there is a clinical need for novel EGFR-TKIs with improved efficacy against brain lesions.
          Article 0 comments Cited 263 times – based on 0 reviews     Review now
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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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              Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration.

              R Thorne, G Pronk, V. Padmanabhan … (2004)
              We investigated the CNS delivery of insulin-like growth factor-I (IGF-I), a 7.65 kDa protein neurotrophic factor, following intranasal administration and the possible pathways and mechanisms underlying transport from the nasal passages to the CNS. Anesthetized adult male Sprague-Dawley rats were given [125I]-IGF-I intranasally or intravenously and then killed by perfusion-fixation within 30 min. Other animals were killed following cisternal puncture and withdrawal of cerebrospinal fluid (CSF) or intranasal administration of unlabeled IGF-I or vehicle. Both gamma counting of microdissected tissue and high resolution phosphor imaging of tissue sections showed that the tissue concentrations and distribution following intranasal administration were consistent with two routes of rapid entry into the CNS: one associated with the peripheral olfactory system connecting the nasal passages with the olfactory bulbs and rostral brain regions (e.g. anterior olfactory nucleus and frontal cortex) and the other associated with the peripheral trigeminal system connecting the nasal passages with brainstem and spinal cord regions. Intranasal administration of [125I]-IGF-I also targeted the deep cervical lymph nodes, consistent with their possible role in lymphatic drainage of both the nasal passages and the CNS. Cisternal CSF did not contain [125I]-IGF-I following intranasal administration. Intravenous [125I]-IGF-I resulted in blood and peripheral tissue exposure similar to that seen following intranasal administration but CNS concentrations were significantly lower. Finally, delivery of IGF-I into the CNS activated IGF-I signaling pathways, confirming some portion of the IGF-I that reached CNS target sites was functionally intact. The results suggest intranasally delivered IGF-I can bypass the blood-brain barrier via olfactory- and trigeminal-associated extracellular pathways to rapidly elicit biological effects at multiple sites within the brain and spinal cord.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 18 December 2019
                Publication date Collection: January 2020
                Volume: 21
                Issue: 1
                Electronic Location Identifier: 22
                Affiliations
                [1 ]Institut National de la Santé Et de la Recherche Médicale (INSERM), U942, 9 Rue de Chablis, 93000 Bobigny, France; dr.thuynguyen2401@ 123456gmail.com (T.T.N.); anne_janin@ 123456yahoo.com (A.J.)
                [2 ]Assistance Publique Hôpitaux de Paris, Avicenne Hospital, Department of medical oncology, 93000 Bobigny, France
                [3 ]Medical Oncology Department A, National Cancer Hospital, Ha Noi 110000, Viet Nam
                [4 ]AP-HP Saint-Louis Hospital, Laboratory of Pathology, 75010 Paris, France
                [5 ]Paris Diderot University/ Université Sorbonne Paris Cité, 5 rue Thomas Mann, 75013 Paris, France
                [6 ]INSERM, U1165, 1 Avenue Claude Vellefaux, 75010 Paris, France
                [7 ]Paris 13 University, 99 Avenue Jean Baptiste Clément, 93430 Villetaneuse, France
                Author notes
                Author information
                https://orcid.org/0000-0001-5594-6694
                Article
                Publisher ID: ijms-21-00022
                DOI: 10.3390/ijms21010022
                PMC ID: 6981899
                PubMed ID: 31861465
                SO-VID: e8aeba17-e1df-43dd-9361-aa96fbf6c8ae
                Copyright © © 2019 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 : 23 November 2019
                Date accepted : 16 December 2019
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: brain metastases,blood–brain barrier,blood–tumor barrier,copy number profiling,mutation,anticancer drugs,pharmacokinetics
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: brain metastases, blood–brain barrier, blood–tumor barrier, copy number profiling, mutation, anticancer drugs, pharmacokinetics

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