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      Drug Delivery Technology to the CNS in the Treatment of Brain Tumors: The Sherbrooke Experience

      research-article
      Pharmaceutics
      MDPI
      blood-brain barrier, intra-arterial chemotherapy, malignant gliomas, primary central nervous system lymphomas

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          Abstract

          Drug delivery to the central nervous system (CNS) remains a challenge in neuro-oncology. Despite decades of research in this field, no consensus has emerged as to the best approach to tackle this physiological limitation. Moreover, the relevance of doing so is still sometimes questioned in the community. In this paper, we present our experience with CNS delivery strategies that have been developed in the laboratory and have made their way to the clinic in a continuum of translational research. Using the intra-arterial (IA) route as an avenue to deliver chemotherapeutics in the treatment of brain tumors, complemented by an osmotic breach of the blood-brain barrier (BBB) in specific situations, we have developed over the years a comprehensive research effort on this specialized topic. Looking at pre-clinical work supporting the rationale for this approach, and presenting results discussing the safety of the strategy, as well as results obtained in the treatment of malignant gliomas and primary CNS lymphomas, this paper intends to comprehensively summarize our work in this field.

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          Most cited references37

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          Blood-brain barrier delivery.

          Neuropharmaceutics is the largest potential growth sector of the pharmaceutical industry. However, this growth is blocked by the problem of the blood-brain barrier (BBB). Essentially 100% of large-molecule drugs and >98% of small-molecule drugs do not cross the BBB. The BBB can be traversed because there are multiple endogenous transporters within this barrier. Therefore, brain drug development programs of the future need to be re-configured so that drugs are formulated to enable transport into the brain via endogenous BBB transporters.
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            Resonant formation of DNA strand breaks by low-energy (3 to 20 eV) electrons.

            Most of the energy deposited in cells by ionizing radiation is channeled into the production of abundant free secondary electrons with ballistic energies between 1 and 20 electron volts. Here it is shown that reactions of such electrons, even at energies well below ionization thresholds, induce substantial yields of single- and double-strand breaks in DNA, which are caused by rapid decays of transient molecular resonances localized on the DNA's basic components. This finding presents a fundamental challenge to the traditional notion that genotoxic damage by secondary electrons can only occur at energies above the onset of ionization, or upon solvation when they become a slowly reacting chemical species.
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              Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means.

              This article reviews historical aspects of the blood-brain barrier (BBB) and recent advances in mechanisms to deliver therapeutic agents across the BBB for the treatment of intracerebral tumors and other neurological diseases. The development of the osmotic BBB disruption procedure as a clinically useful technique is described. Osmotic BBB disruption is contrasted with alternative methods for opening or bypassing the BBB, including pharmacological modification of the BBB with bradykinin and direct intracerebral infusion. Laboratory studies have played a fundamental role in advancing our understanding of the BBB and delivery of agents to brain. Preclinical animal studies will continue to serve an integral function in our efforts to improve the diagnosis and treatment of a number of neurological disorders. Techniques involving the modification of the BBB and/or blood-tumor barrier to increase delivery of therapeutic agents have been advanced to clinical trials in patients with brain tumors with very favorable results. Improving delivery of agents to the brain will play a major role in the therapeutic outcome of brain neoplasms. As techniques for gene therapy are advanced, manipulation of the BBB also may be important in the treatment of central nervous system genetic disorders.
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                Author and article information

                Journal
                Pharmaceutics
                Pharmaceutics
                pharmaceutics
                Pharmaceutics
                MDPI
                1999-4923
                27 May 2019
                May 2019
                : 11
                : 5
                : 248
                Affiliations
                Division of Neurosurgery and Neuro-Oncology, Department of surgery, Faculty of Medicine and Health Science, University of Sherbrooke, Sherbrooke, QC J1H-5N4, Canada; David.fortin@ 123456usherbrooke.ca ; Tel.: +1-819-346-1110 (ext. 73324)
                Article
                pharmaceutics-11-00248
                10.3390/pharmaceutics11050248
                6571772
                31137918
                013a10e0-d7b4-4d72-b92d-919e4516939f
                © 2019 by the author.

                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
                : 08 April 2019
                : 22 May 2019
                Categories
                Article

                blood-brain barrier,intra-arterial chemotherapy,malignant gliomas,primary central nervous system lymphomas

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