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      International Journal of Nanomedicine (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the application of nanotechnology in diagnostics, therapeutics, and drug delivery systems throughout the biomedical field. Sign up for email alerts here.

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      Current approaches to enhance CNS delivery of drugs across the brain barriers

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          Abstract

          Although many agents have therapeutic potentials for central nervous system (CNS) diseases, few of these agents have been clinically used because of the brain barriers. As the protective barrier of the CNS, the blood–brain barrier and the blood–cerebrospinal fluid barrier maintain the brain microenvironment, neuronal activity, and proper functioning of the CNS. Different strategies for efficient CNS delivery have been studied. This article reviews the current approaches to open or facilitate penetration across these barriers for enhanced drug delivery to the CNS. These approaches are summarized into three broad categories: noninvasive, invasive, and miscellaneous techniques. The progresses made using these approaches are reviewed, and the associated mechanisms and problems are discussed.

          Most cited references121

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          Controlled ring-opening polymerization of lactide and glycolide.

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            In vivo protein transduction: delivery of a biologically active protein into the mouse.

            Delivery of therapeutic proteins into tissues and across the blood-brain barrier is severely limited by the size and biochemical properties of the proteins. Here it is shown that intraperitoneal injection of the 120-kilodalton beta-galactosidase protein, fused to the protein transduction domain from the human immunodeficiency virus TAT protein, results in delivery of the biologically active fusion protein to all tissues in mice, including the brain. These results open new possibilities for direct delivery of proteins into patients in the context of protein therapy, as well as for epigenetic experimentation with model organisms.
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              A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus.

              Tat is an 86-amino acid protein involved in the replication of human immunodeficiency virus type 1 (HIV-1). Several studies have shown that exogenous Tat protein was able to translocate through the plasma membrane and to reach the nucleus to transactivate the viral genome. A region of the Tat protein centered on a cluster of basic amino acids has been assigned to this translocation activity. Recent data have demonstrated that chemical coupling of a Tat-derived peptide (extending from residues 37 to 72) to several proteins allowed their functional internalization into several cell lines or tissues. A part of this same domain can be folded in an alpha-helix structure with amphipathic characteristics. Such helical structures have been considered as key determinants for the uptake of several enveloped viruses by fusion or endocytosis. In the present study, we have delineated the main determinants required for Tat translocation within this sequence by synthesizing several peptides covering the Tat domain from residues 37 to 60. Unexpectedly, the domain extending from amino acid 37 to 47, which corresponds to the alpha-helix structure, is not required for cellular uptake and for nuclear translocation. Peptide internalization was assessed by direct labeling with fluorescein or by indirect immunofluorescence using a monoclonal antibody directed against the Tat basic cluster. Both approaches established that all peptides containing the basic domain are taken up by cells within less than 5 min at concentrations as low as 100 nM. In contrast, a peptide with a full alpha-helix but with a truncated basic amino acid cluster is not taken up by cells. The internalization process does not involve an endocytic pathway, as no inhibition of the uptake was observed at 4 degrees C. Similar observations have been reported for a basic amino acid-rich peptide derived from the Antennapedia homeodomain (1). Short peptides allowing efficient translocation through the plasma membrane could be useful vectors for the intracellular delivery of various non-permeant drugs including antisense oligonucleotides and peptides of pharmacological interest.
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                Author and article information

                Journal
                Int J Nanomedicine
                Int J Nanomedicine
                International Journal of Nanomedicine
                Dove Medical Press
                1176-9114
                1178-2013
                2014
                10 May 2014
                : 9
                : 2241-2257
                Affiliations
                [1 ]The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province, People’s Republic of China
                [2 ]Hainan Medical College, Haikou City, Hainan Province, People’s Republic of China
                [3 ]College of Pharmaceutical Sciences, Wenzhou Medical University, Zhejiang Province, People’s Republic of China
                [4 ]School of Pharmacy, Temple University, Philadelphia, PA, USA
                [5 ]Departments of Pediatrics and Anatomical Sciences and Neurobiology, University of Louisville School of Medicine Louisville, KY, USA
                Author notes
                Correspondence: Ying-Zheng Zhao, Hainan Medical College, Haikou City, Hainan Province 325035, People’s Republic of China, Email pharmtds@ 123456163.com
                Xin-Qiao Tian, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325000, People’s Republic of China, Email tianxq2005@ 123456163.com
                Article
                ijn-9-2241
                10.2147/IJN.S61288
                4026551
                24872687
                5910f826-f61d-473b-87b5-d0095402fd01
                © 2014 Lu et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                History
                Categories
                Review

                Molecular medicine
                drug delivery system,blood–brain barrier (bbb),central nervous system,brain-targeted therapy,cerebrospinal fluid (csf)

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