Cell-penetrating peptides as versatile vehicles for oligonucleotide delivery.

Short regulatory oligonucleotides (ONs) have a great therapeutic potential for the modulation of gene expression due to their high specificity and low toxicity. The major obstacles for in vivo clinical applications of ONs are the poor permeability of plasma membrane to nucleic acids and the sensitivity of ONs to enzymatic degradation. Hence, various delivery vehicles have been developed to ensure the transduction of ONs into cells. Among these, the cell-penetrating peptides (CPPs) have gained quickly broadening popularity as promising nonviral transmembrane delivery vectors. For coupling of nucleic acids to CPPs, two distinct strategies may be applied-covalent and noncovalent. The majority of earlier studies have used covalent coupling of CPPs to ONs. However, the number of studies demonstrating very high therapeutic potential of noncovalent complexes of ONs with novel CPP-based delivery vehicles is explosively increasing. In this review, the recent developments in the application of CPP-mediated oligonucleotide delivery by noncovalent strategy will be discussed.

[1]  M. Lafon.  Rabies virus receptors , 2005, Journal of NeuroVirology.

[2]  John Archdeacon,et al.  A non-covalent peptide-based carrier for in vivo delivery of DNA mimics , 2007, Nucleic acids research.

[3]  M. Morris,et al.  Insight into the mechanism of the peptide-based gene delivery system MPG: implications for delivery of siRNA into mammalian cells. , 2003, Nucleic acids research.

[4]  Sérgio Simões,et al.  On the mechanisms of the internalization of S4(13)-PV cell-penetrating peptide. , 2005, The Biochemical journal.

[5]  C Malvy,et al.  Polymer nanocarriers for the delivery of small fragments of nucleic acids: oligonucleotides and siRNA. , 2009, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[6]  David P. Bartel,et al.  Passenger-Strand Cleavage Facilitates Assembly of siRNA into Ago2-Containing RNAi Enzyme Complexes , 2005, Cell.

[7]  T. Lentz,et al.  Is the acetylcholine receptor a rabies virus receptor? , 1982, Science.

[8]  M. Mano,et al.  S4(13)-PV cell-penetrating peptide forms nanoparticle-like structures to gain entry into cells. , 2010, Bioconjugate chemistry.

[9]  R. Brasseur,et al.  A new potent secondary amphipathic cell-penetrating peptide for siRNA delivery into mammalian cells. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[10]  L. Liang,et al.  Nanoparticle-based delivery system for application of siRNA in vivo. , 2010, Current drug metabolism.

[11]  Annick Thomas,et al.  Insight into the cellular uptake mechanism of a secondary amphipathic cell-penetrating peptide for siRNA delivery. , 2010, Biochemistry.

[12]  M. Pooga,et al.  Penetration without cells: membrane translocation of cell-penetrating peptides in the model giant plasma membrane vesicles. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[13]  Priscille Brodin,et al.  A Truncated HIV-1 Tat Protein Basic Domain Rapidly Translocates through the Plasma Membrane and Accumulates in the Cell Nucleus* , 1997, The Journal of Biological Chemistry.

[14]  H Harashima,et al.  Mechanism of improved gene transfer by the N-terminal stearylation of octaarginine: enhanced cellular association by hydrophobic core formation , 2004, Gene Therapy.

[15]  Shiroh Futaki,et al.  Development of a non-viral multifunctional envelope-type nano device by a novel lipid film hydration method. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[16]  M. Morris,et al.  On the mechanism of non-endosomial peptide-mediated cellular delivery of nucleic acids. , 2004, Biochimica et biophysica acta.

[17]  M. Wood.  Toward an Oligonucleotide Therapy for Duchenne Muscular Dystrophy: A Complex Development Challenge , 2010, Science Translational Medicine.

[18]  L. Chaloin,et al.  Combination of a new generation of PNAs with a peptide-based carrier enables efficient targeting of cell cycle progression , 2004, Gene Therapy.

[19]  B. Davidson,et al.  Transvascular delivery of small interfering RNA to the central nervous system , 2007, Nature.

[20]  G. Divita,et al.  First step of the cell‐penetrating peptide mechanism involves Rac1 GTPase‐dependent actin‐network remodelling , 2007, Biology of the cell.

[21]  Steven F Dowdy,et al.  Transducible TAT-HA fusogenic peptide enhances escape of TAT-fusion proteins after lipid raft macropinocytosis , 2004, Nature Medicine.

[22]  C. I. Smith,et al.  PepFect 14, a novel cell-penetrating peptide for oligonucleotide delivery in solution and as solid formulation , 2011, Nucleic acids research.

[23]  H Akita,et al.  Octaarginine-modified multifunctional envelope-type nanoparticles for gene delivery , 2007, Gene Therapy.

[24]  B. L. Wylie,et al.  Arginine-rich molecular transporters for drug delivery: role of backbone spacing in cellular uptake. , 2002, Journal of medicinal chemistry.

[25]  Ű. Langel,et al.  Insights into the cellular trafficking of splice redirecting oligonucleotides complexed with chemically modified cell-penetrating peptides. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[26]  Jean-Luc Coll,et al.  Targeting cyclin B1 through peptide-based delivery of siRNA prevents tumour growth , 2009, Nucleic acids research.

[27]  Shiroh Futaki,et al.  Endosome‐disruptive peptides for improving cytosolic delivery of bioactive macromolecules , 2010, Biopolymers.

[28]  H Harashima,et al.  Stearylated arginine-rich peptides: a new class of transfection systems. , 2001, Bioconjugate chemistry.

[29]  M. Choob,et al.  PNA-related oligonucleotide mimics and their evaluation for nucleic acid hybridization studies and analysis. , 2001, Nucleosides, nucleotides & nucleic acids.

[30]  Shiroh Futaki,et al.  Octaarginine-modified multifunctional envelope-type nano device for siRNA. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[31]  M. Morris,et al.  Insight into the mechanism of internalization of the cell-penetrating carrier peptide Pep-1 through conformational analysis. , 2004, Biochemistry.

[32]  Ű. Langel,et al.  CPP-protein constructs induce a population of non-acidic vesicles during trafficking through endo-lysosomal pathway. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[33]  Ű. Langel,et al.  The use of cell-penetrating peptides as a tool for gene regulation. , 2004, Drug discovery today.

[34]  S. W. Kim,et al.  Cholesteryl oligoarginine delivering vascular endothelial growth factor siRNA effectively inhibits tumor growth in colon adenocarcinoma. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[35]  M. Pooga,et al.  NickFects, Phosphorylated Derivatives of Transportan 10 for Cellular Delivery of Oligonucleotides , 2011, International Journal of Peptide Research and Therapeutics.

[36]  T. Ohtsuki,et al.  Cellular siRNA delivery using cell-penetrating peptides modified for endosomal escape. , 2009, Advanced drug delivery reviews.

[37]  A. Metspalu,et al.  Design of a peptide-based vector, PepFect6, for efficient delivery of siRNA in cell culture and systemically in vivo , 2011, Nucleic acids research.

[38]  Z. Dominski,et al.  Restoration of correct splicing in thalassemic pre-mRNA by antisense oligonucleotides. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[39]  S. Futaki,et al.  Delivery of Macromolecules Using Arginine-Rich Cell-Penetrating Peptides: Ways to Overcome Endosomal Entrapment , 2009, The AAPS Journal.

[40]  M. Morris,et al.  The peptide carrier Pep-1 forms biologically efficient nanoparticle complexes. , 2007, Biochemical and biophysical research communications.

[41]  A. Prochiantz,et al.  The third helix of the Antennapedia homeodomain translocates through biological membranes. , 1994, The Journal of biological chemistry.

[42]  B. Lebleu,et al.  A non-covalent strategy combining cationic lipids and CPPs to enhance the delivery of splice correcting oligonucleotides. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[43]  P. Lundin,et al.  A stearylated CPP for delivery of splice correcting oligonucleotides using a non-covalent co-incubation strategy. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[44]  R. Kole,et al.  Therapeutic potential of antisense oligonucleotides as modulators of alternative splicing. , 2003, The Journal of clinical investigation.

[45]  M. Eccles,et al.  Conjugate for efficient delivery of short interfering RNA (siRNA) into mammalian cells , 2004, FEBS letters.

[46]  I. Zuhorn,et al.  Gene delivery by cationic lipid vectors: overcoming cellular barriers , 2007, European Biophysics Journal.

[47]  Hideyoshi Harashima,et al.  Construction of a multifunctional envelope-type nano device by a SUV*-fusion method. , 2005, International journal of pharmaceutics.

[48]  L. Chaloin,et al.  A new peptide vector for efficient delivery of oligonucleotides into mammalian cells. , 1997, Nucleic acids research.

[49]  Pranav Sharma,et al.  GPI-anchored proteins are delivered to recycling endosomes via a distinct cdc42-regulated, clathrin-independent pinocytic pathway. , 2002, Developmental cell.

[50]  J. Seelig,et al.  Binding and clustering of glycosaminoglycans: a common property of mono- and multivalent cell-penetrating compounds. , 2008, Biophysical journal.

[51]  Ü. Langel,et al.  Delivery of short interfering RNA using endosomolytic cell‐penetrating peptides , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[52]  R. L. Juliano,et al.  Conjugates of Antisense Oligonucleotides with the Tat and Antennapedia Cell-Penetrating Peptides: Effects on Cellular Uptake, Binding to Target Sequences, and Biologic Actions , 2004, Pharmaceutical Research.

[53]  W. Shen,et al.  Conjugation of methotrexate to poly(L-lysine) increases drug transport and overcomes drug resistance in cultured cells. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[54]  D. Maclean,et al.  Therapeutic applications of cell-penetrating peptides. , 2011, Methods in molecular biology.

[55]  Rainer Fischer,et al.  A Comprehensive Model for the Cellular Uptake of Cationic Cell‐penetrating Peptides , 2007, Traffic.

[56]  R. Parton,et al.  Lipid Rafts and Caveolae as Portals for Endocytosis: New Insights and Common Mechanisms , 2003, Traffic.

[57]  S. Dowdy,et al.  Protein transduction domain delivery of therapeutic macromolecules. , 2011, Current opinion in biotechnology.

[58]  Isabel D. Alves,et al.  Translocation and Endocytosis for Cell-penetrating Peptide Internalization , 2009, The Journal of Biological Chemistry.

[59]  R. Brasseur,et al.  New basic membrane-destabilizing peptides for plasmid-based gene delivery in vitro and in vivo. , 2002, Molecular therapy : the journal of the American Society of Gene Therapy.

[60]  Francesco M Veronese,et al.  PEGylation, successful approach to drug delivery. , 2005, Drug discovery today.

[61]  B. Lebleu,et al.  Improved cell-penetrating peptide–PNA conjugates for splicing redirection in HeLa cells and exon skipping in mdx mouse muscle , 2008, Nucleic acids research.

[62]  J. Gariépy,et al.  A peptide-based dendrimer that enhances the splice-redirecting activity of PNA conjugates in cells. , 2009, Bioconjugate chemistry.

[63]  Shiroh Futaki,et al.  A multifunctional envelope-type nano device for novel gene delivery of siRNA plasmids. , 2005, International journal of pharmaceutics.

[64]  M. Morris,et al.  A peptide carrier for the delivery of biologically active proteins into mammalian cells , 2001, Nature Biotechnology.

[65]  A. Eguchi,et al.  Efficient siRNA Delivery into Primary Cells by Peptide Transduction-dsRNA Binding Domain (PTD-DRBD) Fusion Protein , 2009, Nature Biotechnology.

[66]  Ü. Langel,et al.  Induction of splice correction by cell‐penetrating peptide nucleic acids , 2006, The journal of gene medicine.

[67]  P. Sharp,et al.  RNAi Double-Stranded RNA Directs the ATP-Dependent Cleavage of mRNA at 21 to 23 Nucleotide Intervals , 2000, Cell.

[68]  Daniel G. Anderson,et al.  Knocking down barriers: advances in siRNA delivery , 2009, Nature Reviews Drug Discovery.

[69]  T. Restle,et al.  Cellular delivery of small interfering RNA by a non-covalently attached cell-penetrating peptide: quantitative analysis of uptake and biological effect , 2006, Nucleic acids research.

[70]  Jean Gruenberg,et al.  The endocytic pathway: a mosaic of domains , 2001, Nature Reviews Molecular Cell Biology.

[71]  H. Moulton,et al.  Morpholinos and their peptide conjugates: therapeutic promise and challenge for Duchenne muscular dystrophy. , 2010, Biochimica et biophysica acta.

[72]  H. Moulton,et al.  Peptide-assisted delivery of steric-blocking antisense oligomers. , 2003, Current opinion in molecular therapeutics.

[73]  Michael D Dake,et al.  Nonclinical and clinical experiences with CPP-based self-assembling peptide systems in topical drug development. , 2011, Methods in molecular biology.

[74]  S. Futaki,et al.  Interaction of arginine-rich peptides with membrane-associated proteoglycans is crucial for induction of actin organization and macropinocytosis. , 2007, Biochemistry.

[75]  D. Corey,et al.  Silencing disease genes in the laboratory and the clinic , 2012, The Journal of pathology.

[76]  M. Stephenson,et al.  Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[77]  M. Gumbleton,et al.  Polylysine and Polyornithine Gene Transfer Complexes: A Study of Complex Stability and Cellular Uptake as a Basis for their Differential in-vitro Transfection Efficiency , 2002, Journal of drug targeting.

[78]  T. Cooper,et al.  Pre-mRNA splicing and human disease. , 2003, Genes & development.

[79]  G. Divita,et al.  Direct Translocation as Major Cellular Uptake for CADY Self-Assembling Peptide-Based Nanoparticles , 2011, PloS one.

[80]  S. Futaki,et al.  Temperature-, concentration- and cholesterol-dependent translocation of L- and D-octa-arginine across the plasma and nuclear membrane of CD34+ leukaemia cells. , 2007, The Biochemical journal.

[81]  S. Futaki,et al.  Endosomal escape and the knockdown efficiency of liposomal-siRNA by the fusogenic peptide shGALA. , 2011, Biomaterials.

[82]  L. Tönges,et al.  Stearylated octaarginine and artificial virus-like particles for transfection of siRNA into primary rat neurons. , 2006, RNA.

[83]  Eric Vives,et al.  Present and future of cell-penetrating peptide mediated delivery systems: "is the Trojan horse too wild to go only to Troy?". , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[84]  Yuma Yamada,et al.  Significant and prolonged antisense effect of a multifunctional envelope‐type nano device encapsulating antisense oligodeoxynucleotide , 2006, The Journal of pharmacy and pharmacology.

[85]  Ű. Langel,et al.  Delivery of nucleic acids with a stearylated (RxR)4 peptide using a non-covalent co-incubation strategy. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[86]  S. Hammond,et al.  An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells , 2000, Nature.

[87]  P. Lundin,et al.  Distinct uptake routes of cell-penetrating peptide conjugates. , 2008, Bioconjugate chemistry.

[88]  R. Kole,et al.  Up-regulation of luciferase gene expression with antisense oligonucleotides: implications and applications in functional assay development. , 1998, Biochemistry.

[89]  M. Pooga,et al.  The membrane repair response masks membrane disturbances caused by cell‐penetrating peptide uptake , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[90]  M. Morris,et al.  A non-covalent peptide-based strategy for siRNA delivery. , 2007, Biochemical Society transactions.

[91]  A. Behfar,et al.  Oct-3/4 dose dependently regulates specification of embryonic stem cells toward a cardiac lineage and early heart development. , 2006, Developmental cell.

[92]  T. Zatsepin,et al.  Conjugates of oligonucleotides and analogues with cell penetrating peptides as gene silencing agents. , 2005, Current pharmaceutical design.

[93]  Angel E Garcia,et al.  Molecular dynamics simulations suggest a mechanism for translocation of the HIV-1 TAT peptide across lipid membranes , 2007, Proceedings of the National Academy of Sciences.