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      Improving the Endosomal Escape of Cell-Penetrating Peptides and Their Cargos: Strategies and Challenges

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          Abstract

          Cell penetrating peptides (CPPs) can deliver cell-impermeable therapeutic cargos into cells. In particular, CPP-cargo conjugates tend to accumulate inside cells by endocytosis. However, they often remain trapped inside endocytic organelles and fail to reach the cytosolic space of cells efficiently. In this review, the evidence for CPP-mediated endosomal escape is discussed. In addition, several strategies that have been utilized to enhance the endosomal escape of CPP-cargos are described. The recent development of branched systems that display multiple copies of a CPP is presented. The use of viral or synthetic peptides that can disrupt the endosomal membrane upon activation by the low pH of endosomes is also discussed. Finally, we survey how CPPs labeled with chromophores can be used in combination with light to stimulate endosomal lysis. The mechanisms and challenges associated with these intracellular delivery methodologies are discussed.

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          Most cited references178

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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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            The distribution and function of phosphatidylserine in cellular membranes.

            Phosphatidylserine (PS) is the most abundant negatively charged phospholipid in eukaryotic membranes. PS directs the binding of proteins that bear C2 or gamma-carboxyglutamic domains and contributes to the electrostatic association of polycationic ligands with cellular membranes. Rather than being evenly distributed, PS is found preferentially in the inner leaflet of the plasma membrane and in endocytic membranes. The loss of PS asymmetry is an early indicator of apoptosis and serves as a signal to initiate blood clotting. This review discusses the determinants and functional implications of the subcellular distribution and membrane topology of PS.
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              Transducible TAT-HA fusogenic peptide enhances escape of TAT-fusion proteins after lipid raft macropinocytosis.

              The TAT protein transduction domain (PTD) has been used to deliver a wide variety of biologically active cargo for the treatment of multiple preclinical disease models, including cancer and stroke. However, the mechanism of transduction remains unknown. Because of the TAT PTD's strong cell-surface binding, early assumptions regarding cellular uptake suggested a direct penetration mechanism across the lipid bilayer by a temperature- and energy-independent process. Here we show, using a transducible TAT-Cre recombinase reporter assay on live cells, that after an initial ionic cell-surface interaction, TAT-fusion proteins are rapidly internalized by lipid raft-dependent macropinocytosis. Transduction was independent of interleukin-2 receptor/raft-, caveolar- and clathrin-mediated endocytosis and phagocytosis. Using this information, we developed a transducible, pH-sensitive, fusogenic dTAT-HA2 peptide that markedly enhanced TAT-Cre escape from macropinosomes. Taken together, these observations provide a scientific basis for the development of new, biologically active, transducible therapeutic molecules.
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                Author and article information

                Journal
                Pharmaceuticals (Basel)
                Pharmaceuticals (Basel)
                pharmaceuticals
                Pharmaceuticals
                MDPI
                1424-8247
                01 November 2012
                November 2012
                : 5
                : 11
                : 1177-1209
                Affiliations
                Department of Biochemistry and Biophysics, Texas A&M University, Room 430, 300 Olsen Blvd., College Station, TX 77843-2128, USA; Email: alfredo_erazooliveras@ 123456tamu.edu (A.E.O.); nandhini.muthukrishnan@ 123456tamu.edu (N.M.); ryanbaker712@ 123456gmail.com (R.B.); tywangtw@ 123456tamu.edu (T.Y.W.)
                Author notes
                [†]

                These authors contributed equally to this work.

                [* ] Author to whom correspondence should be addressed; Email: pellois@ 123456tamu.edu ; Tel.: +1-979-845-0101; Fax: +1-979-862-4718.
                Article
                pharmaceuticals-05-01177
                10.3390/ph5111177
                3816665
                24223492
                41b61ccc-bc16-4611-8250-b35e7fb71076
                © 2012 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 license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 08 October 2012
                : 25 October 2012
                : 26 October 2012
                Categories
                Review

                endosomal escape,cell-penetrating peptide,photochemical internalization,multivalent peptides,ph-dependent membrane-active peptides

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