• Please log in or register to access this feature.

Review

You have free access to this content

siRNA Delivery: From Lipids to Cell-penetrating Peptides and Their Mimics

  1. Matt Gooding,
  2. Lorcan P. Browne,
  3. Filipa M. Quinteiro,
  4. David L. Selwood*

Article first published online: 25 OCT 2012

DOI: 10.1111/cbdd.12052

Issue

Chemical Biology & Drug Design

Chemical Biology & Drug Design

Volume 80, Issue 6, pages 787–809, December 2012

Additional Information

How to Cite

Gooding, M., Browne, L. P., Quinteiro, F. M. and Selwood, D. L. (2012), siRNA Delivery: From Lipids to Cell-penetrating Peptides and Their Mimics. Chemical Biology & Drug Design, 80: 787–809. doi: 10.1111/cbdd.12052

Author Information

  1. The Wolfson Institute for Biomedical Research, UCL, Gower Street, London WC1E 6BT, UK

* Corrresponding author: David L. Selwood, d.selwood@ucl.ac.uk

Publication History

  1. Issue published online: 25 OCT 2012
  2. Article first published online: 25 OCT 2012
  3. Accepted manuscript online: 13 SEP 2012 11:33PM EST

SEARCH

SEARCH BY CITATION

ARTICLE TOOLS

View Full Article (HTML) Get PDF (533K)

References

  • 1
    Leaman D.W. (2008) Recent progress in oligonucleotide therapeutics: antisense to aptamers. Expert Opin Drug Discov;3:997–1009.
  • 2
    Kastelein J.J.P., Wedel M.K., Baker B.F., Su J., Bradley J.D., Yu R.Z. et al. (2006) Potent reduction of apolipoprotein B and low-density lipoprotein cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B. Circulation;114:1729–1735.
  • 3
    Fire A., Xu S.Q., Montgomery M.K., Kostas S.A., Driver S.E., Mello C.C. (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature;391:806–811.
  • 4
    Love T.M., Moffett H.F., Novina C.D. (2008) Not miR-ly small RNAs: big potential for microRNAs in therapy. J Allergy Clin Immunol;121:309–319.
  • 5
    William C.S.C. (2010) MicroRNAs: potential biomarkers for cancer diagnosis, prognosis and targets for therapy. Int J Biochem Cell Biol;42:1273–1281.
  • 6
    Bertrand J.-R., Pottier M., Vekris A., Opolon P., Maksimenko A., Malvy C. (2002) Comparison of antisense oligonucleotides and siRNAs in cell culture and in vivo. Biochem Biophys Res Commun;296:1000–1004.
  • 7
    Bennett C.F., Swayze E.E. (2010) RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu Rev Pharmacol Toxicol;50:259–293.
  • 8
    Sontheimer E.J. (2005) Assembly and function of RNA silencing complexes. Nat Rev Mol Cell Biol;6:127–138.
  • 9
    Goyal B.R., Patel M.M., Soni M.K., Bhadada S.V. (2009) Therapeutic opportunities of small interfering RNA. Fundam Clin Pharmacol;23:367–386.
    Direct Link:
  • 10
    Elbashir S.M., Harborth J., Lendeckel W., Yalcin A., Weber K., Tuschl T. (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature;411:494–498.
  • 11
    Chiu Y.-L., Ali A., Chu C.-y., Cao H., Rana T.M. (2004) Visualizing a correlation between siRNA localization, cellular uptake, and RNAi in living cells. Chem Biol;11:1165–1175.
  • 12
    Meister G., Tuschl T. (2004) Mechanisms of gene silencing by double-stranded RNA. Nature;431:343–349.
  • 13
    Wang Y., Sheng G., Juranek S., Tuschl T., Patel D.J. (2008) Structure of the guide-strand-containing argonaute silencing complex. Nature;456:209–213.
  • 14
    Tian Y., Simanshu D.K., Ma J.B., Patel D.J. (2011) Structural basis for piRNA 2′-O-methylated 3′-end recognition by Piwi PAZ (Piwi/Argonaute/Zwille) domains. Proc Natl Acad Sci USA;108:903–910.
  • 15
    Parker J.S. (2010) How to slice: snapshots of Argonaute in action. Silence;1:3.
  • 16
    Jagannath A., Wood M.J. (2009) Localization of double-stranded small interfering RNA to cytoplasmic processing bodies is Ago2 dependent and results in up-regulation of GW182 and Argonaute-2. Mol Biol Cell;20:521–529.
  • 17
    Huang L., Mollet S., Souquere S., Le Roy F., Ernoult-Lange M., Pierron G. et al. (2011) Mitochondria associate with P-bodies and modulate microRNA-mediated RNA interference. J Biol Chem;286:24219–24230.
  • 18
    Eulalio A., Behm-Ansmant I., Schweizer D., Izaurralde E. (2007) P-body formation is a consequence, not the cause, of RNA-mediated gene silencing. Mol Cell Biol;27:3970–3981.
  • 19
    Shim M.S., Kwon Y.J. (2010) Efficient and targeted delivery of siRNA in vivo. FEBS J;277:4814–4827.
    Direct Link:
  • 20
    Guo J., Fisher K.A., Darcy R., Cryan J.F., O’Driscoll C. (2010) Therapeutic targeting in the silent era: advances in non-viral siRNA delivery. Mol BioSyst;6:1143–1161.
  • 21
    Turchinovich A., Zoidl G., Dermietzel R. (2010) Non-viral siRNA delivery into the mouse retina in vivo. BMC Ophthalmol;10:25.
  • 22
    Cho W.G., Albuquerque R.J.C., Kleinman M.E., Tarallo V., Greco A., Nozaki M. et al. (2009) Small interfering RNA-induced TLR3 activation inhibits blood and lymphatic vessel growth. Proc Natl Acad Sci;106:7137–7142.
  • 23
    Whitehead K., Langer R., Anderson D. (2009) Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov;8:129–138.
  • 24
    Barquinero J., Eixarch H., Perez-Melgosa M. (2004) Retroviral vectors: new applications for an old tool. Gene Ther;11:S3–S9.
  • 25
    Zhu L., Mahato R.I. (2010) Lipid and polymeric carrier-mediated nucleic acid delivery. Expert Opin Drug Deliv;7:1209–1226.
  • 26
    Eguchi A., Meade B.R., Chang Y.C., Fredrickson C.T., Willert K., Puri N. et al. (2009) Efficient siRNA delivery into primary cells by a peptide transduction domain-dsRNA binding domain fusion protein. Nat Biotechnol;27:567–U110.
  • 27
    Omidi Y., Hollins A.J., Benboubetra M., Drayton R., Benter I.F., Akhtar S. (2003) Toxicogenomics of non-viral vectors for gene therapy: a microarray study of lipofectin- and oligofectamine-induced gene expression changes in human epithelial cells. J Drug Target;11:311–323.
  • 28
    El Andaloussi S., Lehto T., Mager I., Rosenthal-Aizman K., Oprea I.I., Simonson O.E. et al. (2011) Design of a peptide-based vector, PepFect6, for efficient delivery of siRNA in cell culture and systemically in vivo. Nucleic Acids Res;39:3972–3987.
  • 29
    Frankel A.D., Pabo C.O. (1988) Cellular uptake of the tat protein from human immunodeficiency virus. Cell;55:1189–1193.
  • 30
    Joliot A., Pernelle C., Deagostini-Bazin H., Prochiantz A. (1991) Antennapedia homeobox peptide regulates neural morphogenesis. Proc Natl Acad Sci;88:1864–1868.
  • 31
    Derossi D., Joliot A.H., Chassaing G., Prochiantz A. (1994) The third helix of the Antennapedia homeodomain translocates through biological membranes. J Biol Chem;269:10444–10450.
  • 32
    Vivès E., Brodin P., Lebleu B. (1997) A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. J Biol Chem;272:16010–16017.
  • 33
    Schwarze S.R., Ho A., Vocero-Akbani A., Dowdy S.F. (1999) In vivo protein transduction: delivery of a biologically active protein into the mouse. Science;285:1569–1572.
  • 34
    Morris M.C., Depollier J., Mery J., Heitz F., Divita G. (2001) A peptide carrier for the delivery of biologically active proteins into mammalian cells. Nat Biotechnol;19:1173–1176.
  • 35
    Fawell S., Seery J., Daikh Y., Moore C., Chen L.L., Pepinsky B. et al. (1994) Tat-mediated delivery of heterologous proteins into cells. Proc Natl Acad Sci;91:664–668.
  • 36
    Ruan G., Agrawal A., Marcus A.I., Nie S. (2007) Imaging and tracking of tat peptide-conjugated quantum dots in living cells: new insights into nanoparticle uptake, intracellular transport, and vesicle shedding. J Am Chem Soc;129:14759–14766.
  • 37
    Abes R., Arzumanov A.A., Moulton H.M., Abes S., Lvanciva G.D., Lversen P.L. et al. (2007) Cell-penetrating-peptide-based delivery of oligonucleotides: an overview. Biochem Soc Trans;35:775–779.
  • 38
    Juliano R., Alam M.R., Dixit V., Kang H. (2008) Mechanisms and strategies for effective delivery of antisense and siRNA oligonucleotides. Nucleic Acids Res;36:4158–4171.
  • 39
    Langel U. (2010) Cell-penetrating Peptides. New York: Springer.
  • 40
    Wender P.A., Galliher W.C., Goun E.A., Jones L.R., Pillow T.H. (2008) The design of guanidinium-rich transporters and their internalization mechanisms. Adv Drug Deliv Rev;60:452–472.
  • 41
    Wender P.A., Cooley C.B., Geihe E.I. (2011) Beyond cell penetrating peptides: designed molecular transporters. Drug Discov Today Technol:e49–e55.
  • 42
    Wender P.A., Mitchell D.J., Pattabiraman K., Pelkey E.T., Steinman L., Rothbard J.B. (2000) The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: peptoid molecular transporters. Proc Natl Acad Sci USA;97:13003–13008.
  • 43
    Higashi T., Khalil I.A., Maiti K.K., Lee W.S., Akita H., Harashima H. et al. (2009) Novel lipidated sorbitol-based molecular transporters for non-viral gene delivery. J Control Release;136:140–147.
  • 44
    Maiti K.K., Lee W.S., Takeuchi T., Watkins C., Fretz M., Kim D.C. et al. (2007) Guanidine-containing molecular transporters: sorbitol-based transporters show high intracellular selectivity toward mitochondria. Angew Chem;46:5880–5884.
    Direct Link:
  • 45
    Maiti K.K., Jeon O.Y., Lee W.S., Chung S.K. (2007) Design, synthesis, and delivery properties of novel guanidine-containing molecular transporters built on dimeric inositol scaffolds. Chemistry;13:762–775.
    Direct Link:
  • 46
    Biswas G., Jeon O.Y., Lee W.S., Kim D.C., Kim K.T., Lee S. et al. (2008) Novel guanidine-containing molecular transporters based on lactose scaffolds: lipophilicity effect on the intracellular organellar selectivity. Chemistry;14:9161–9168.
    Direct Link:
  • 47
    Pereira M.P., Kelley S.O. (2011) Maximizing the therapeutic window of an antimicrobial drug by imparting mitochondrial sequestration in human cells. J Am Chem Soc;133:3260–3263.
  • 48
    Ross M.F., Prime T.A., Abakumova I., James A.M., Porteous C.M., Smith R.A. et al. (2008) Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells. Biochem J;411:633–645.
  • 49
    Malouitre S., Dube H., Selwood D., Crompton M. (2010) Mitochondrial targeting of cyclosporin A enables selective inhibition of cyclophilin-D and enhanced cytoprotection after glucose and oxygen deprivation. Biochem J;425:137–148.
  • 50
    Kelley S.O., Stewart K.M., Mourtada R. (2011) Development of novel peptides for mitochondrial drug delivery: amino acids featuring delocalized lipophilic cations. Pharm Res;28:2808–2819.
  • 51
    Ross M.F., Filipovska A., Smith R.A., Gait M.J., Murphy M.P. (2004) Cell-penetrating peptides do not cross mitochondrial membranes even when conjugated to a lipophilic cation: evidence against direct passage through phospholipid bilayers. Biochem J;383:457–468.
  • 52
    Okuyama M., Laman H., Kingsbury S.R., Visintin C., Leo E., Eward K.L. et al. (2007) Small-molecule mimics of an [alpha]-helix for efficient transport of proteins into cells. Nat Methods;4:153–159.
  • 53
    Jacoby E. (2002) Biphenyls as potential mimetics of protein [alpha]-helix. Bioorg Med Chem Lett;12:891–893.
  • 54
    Ho A., Schwarze S.R., Mermelstein S.J., Waksman G., Dowdy S.F. (2001) Synthetic protein transduction domains: enhanced transduction potential in vitro and in vivo. Cancer Res;61:474–477.
  • 55
    Depamphilis M.L. (2011) Spotlight on geminin. Breast Cancer Res;13:109.
  • 56
    Okorokov A.L., Orlova E.V., Kingsbury S.R., Bagneris C., Gohlke U., Williams G.H. et al. (2004) Molecular structure of human geminin. Nat Struct Mol Biol;11:1021–1022.
  • 57
    Cooley C.B., Trantow B.M., Nederberg F., Kiesewetter M.K., Hedrick J.L., Waymouth R.M. et al. (2009) Oligocarbonate molecular transporters: oligomerization-based syntheses and cell-penetrating studies. J Am Chem Soc;131:16401–16403.
  • 58
    Bautista A.D., Craig C.J., Harker E.A., Schepartz A. (2007) Sophistication of foldamer form and function in vitro and in vivo. Curr Opin Chem Biol;11:685–692.
  • 59
    Gillies E.R., Deiss F., Staedel C., Schmitter J.M., Huc I. (2007) Development and biological assessment of fully water-soluble helical aromatic amide foldamers. Angew Chem;46:4081–4084.
    Direct Link:
  • 60
    Som A., Xu Y., Scott R.W., Tew G.N. (2012) Anion mediated activation of guanidine rich small molecules. Org Biomol Chem;10:40–42.
  • 61
    Kolonko E.M., Kiessling L.L. (2008) A polymeric domain that promotes cellular internalization. J Am Chem Soc;130:5626–5627.
  • 62
    Kolonko E.M., Pontrello J.K., Mangold S.L., Kiessling L.L. (2009) General synthetic route to cell-permeable block copolymers via ROMP. J Am Chem Soc;131:7327–7333.
  • 63
    Hennig A., Gabriel G.J., Tew G.N., Matile S. (2008) Stimuli-responsive polyguanidino-oxanorbornene membrane transporters as multicomponent sensors in complex matrices. J Am Chem Soc;130:10338–10344.
  • 64
    Wender P.A., Kreider E., Pelkey E.T., Rothbard J., Vandeusen C.L. (2005) Dendrimeric molecular transporters: synthesis and evaluation of tunable polyguanidino dendrimers that facilitate cellular uptake. Org Lett;7:4815–4818.
  • 65
    Juliano R. (2007) Challenges to macromolecular drug delivery. Biochem Soc Trans;35:41–43.
  • 66
    Merkel O.M., Mintzer M.A., Librizzi D., Samsonova O., Dicke T., Sproat B. et al. (2010) Triazine dendrimers as nonviral vectors for in vitro and in vivo RNAi: the effects of peripheral groups and core structure on biological activity. Mol Pharm;7:969–983.
  • 67
    Derossi D., Calvet S., Trembleau A., Brunissen A., Chassaing G., Prochiantz A. (1996) Cell Internalization of the third helix of the Antennapedia homeodomain is receptor-independent. J Biol Chem;271:18188–18193.
  • 68
    Richard J.P., Melikov K., Vives E., Ramos C., Verbeure B., Gait M.J. et al. (2003) Cell-penetrating peptides – a reevaluation of the mechanism of cellular uptake. J Biol Chem;278:585–590.
  • 69
    Jiao C.Y., Delaroche D., Burlina F., Alves I.D., Chassaing G., Sagan S. (2009) Translocation and endocytosis for cell-penetrating peptide internalization. J Biol Chem;284:33957–33965.
  • 70
    Guterstam P., Madani F., Hirose H., Takeuchi T., Futaki S., El Andaloussi S. et al. (2009) Elucidating cell-penetrating peptide mechanisms of action for membrane interaction, cellular uptake, and translocation utilizing the hydrophobic counter-anion pyrenebutyrate. Biochim Biophys Acta;1788:2509–2517.
  • 71
    Belting M., Wittrup A. (2009) Macromolecular drug delivery: basic principles and therapeutic applications. Mol Biotechnol;43:89–94.
  • 72
    Ezzat K., Helmfors H., Tudoran O., Juks C., Lindberg S., Padari K. et al. (2012) Scavenger receptor-mediated uptake of cell-penetrating peptide nanocomplexes with oligonucleotides. FASEB J;26:1172–1180.
  • 73
    Iversen T.-G., Skotland T., Sandvig K. (2011) Endocytosis and intracellular transport of nanoparticles: present knowledge and need for future studies. Nano Today;6:176–185.
  • 74
    Lundberg M., Wikstrom S., Johansson M. (2003) Cell surface adherence and endocytosis of protein transduction domains. Mol Ther;8:143–150.
  • 75
    Nakase I., Niwa M., Takeuchi T., Sonomura K., Kawabata N., Koike Y. et al. (2004) Cellular uptake of arginine-rich peptides: roles for macropinocytosis and actin rearrangement. Mol Ther;10:1011–1022.
  • 76
    Nakase I., Tadokoro A., Kawabata N., Takeuchi T., Katoh H., Hiramoto K. et al. (2006) Interaction of arginine-rich peptides with membrane-associated proteoglycans is crucial for induction of actin organization and macropinocytosis. Biochemistry;46:492–501.
  • 77
    Simon M.J., Gao S., Kang W.H., Banta S., Morrison B. (2009) TAT-mediated intracellular protein delivery to primary brain cells is dependent on glycosaminoglycan expression. Biotechnol Bioeng;104:10–19.
    Direct Link:
  • 78
    Patel L.N., Zaro J.L., Shen W.C. (2007) Cell penetrating peptides: intracellular pathways and pharmaceutical perspectives. Pharm Res;24:1977–1992.
  • 79
    Fuchs S.M., Raines R.T. (2004) Pathway for polyarginine entry into mammalian cells. Biochemistry;43:2438–2444.
  • 80
    Gerbal-chaloin S., Gondeau C., Aldrian-herrada G., Heitz F., Gauthier-rouvière C., Divita G. (2007) First step of the cell-penetrating peptide mechanism involves Rac1 GTPase-dependent actin-network remodelling. Biol Cell;099:223–238.
    Direct Link:
  • 81
    Couchman J.R. (2003) Syndecans: proteoglycan regulators of cell-surface microdomains? Nat Rev Mol Cell Biol;4:926–938.
  • 82
    Conner S.D., Schmid S.L. (2003) Regulated portals of entry into the cell. Nature;422:37–44.
  • 83
    Palte M.J., Raines R.T. (2012) Interaction of nucleic acids with the glycocalyx. J Am Chem Soc;134:6218–6223.
  • 84
    Ziegler A. (2008) Thermodynamic studies and binding mechanisms of cell-penetrating peptides with lipids and glycosaminoglycans. Adv Drug Deliv Rev;60:580–597.
  • 85
    Ziegler A., Seelig J. (2004) Interaction of the protein transduction domain of HIV-1 TAT with heparan sulfate: binding mechanism and thermodynamic parameters. Biophys J;86:254–263.
  • 86
    Ziegler A., Seelig J. (2008) Binding and clustering of glycosaminoglycans: a common property of mono- and multivalent cell-penetrating compounds. Biophys J;94:2142–2149.
  • 87
    Gump J.M., June R.K., Dowdy S.F. (2010) Revised role of glycosaminoglycans in TAT protein transduction domain-mediated cellular transduction. J Biol Chem;285:1500–1507.
  • 88
    Esbjorner E.K., Lincoln P., Norden B. (2007) Counterion-mediated membrane penetration: cationic cell-penetrating peptides overcome Born energy barrier by ion-pairing with phospholipids. Biochim Biophys Acta;1768:1550–1558.
  • 89
    Rothbard J.B., Jessop T.C., Wender P.A. (2005) Adaptive translocation: the role of hydrogen bonding and membrane potential in the uptake of guanidinium-rich transporters into cells. Adv Drug Deliv Rev;57:495–504.
  • 90
    El-Sayed A., Khalil I.A., Kogure K., Futaki S., Harashima H. (2008) Octaarginine- and Octalysine-modified nanoparticles have different modes of endosomal escape. J Biol Chem;283:23450–23461.
  • 91
    Sakai N., Matile S. (2003) Anion-mediated transfer of polyarginine across liquid and bilayer membranes. J Am Chem Soc;125:14348–14356.
  • 92
    Mishra A., Gordon V.D., Yang L., Coridan R., Wong G.C. (2008) HIV TAT forms pores in membranes by inducing saddle-splay curvature: potential role of bidentate hydrogen bonding. Angew Chem Int Ed;47:2986–2989.
    Direct Link:
  • 93
    Lamazière A., Wolf C., Lambert O., Chassaing G., Trugnan G., Ayala-Sanmartin J. (2008) The homeodomain derived peptide Penetratin induces curvature of fluid membrane domains. PLoS ONE;3:e1938.
  • 94
    Yezid H., Konate K., Debaisieux S., Bonhoure A., Beaumelle B. (2009) Mechanism for HIV-1 Tat insertion into the endosome membrane. J Biol Chem;284:22736–22746.
  • 95
    Koshkin A.A., Singh S.K., Nielsen P., Rajwanshi V.K., Kumar R., Meldgaard M. et al. (1998) LNA (Locked Nucleic Acids): synthesis of the adenine, cytosine, guanine, 5-methylcytosine, thymine and uracil bicyclonucleoside monomers, oligomerisation, and unprecedented nucleic acid recognition. Tetrahedron;54:3607–3630.
  • 96
    Elmén J., Thonberg H., Ljungberg K., Frieden M., Westergaard M., Xu Y. et al. (2005) Locked nucleic acid (LNA) mediated improvements in siRNA stability and functionality. Nucleic Acids Res;33:439–447.
  • 97
    Mook O.R., Baas F., de Wissel M.B., Fluiter K. (2007) Evaluation of locked nucleic acid–modified small interfering RNA in vitro and in vivo. Mol Cancer Ther;6:833–843.
  • 98
    Soutschek J., Akinc A., Bramlage B., Charisse K., Constien R., Donoghue M. et al. (2004) Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature;432:173–178.
  • 99
    Wolfrum C., Shi S., Jayaprakash K.N., Jayaraman M., Wang G., Pandey R.K. et al. (2007) Mechanisms and optimization of in vivo delivery of lipophilic siRNAs. Nat Biotechnol;25:1149–1157.
  • 100
    Crombez L., Aldrian-Herrada G., Konate K., Nguyen Q.N., McMaster G.K., Brasseur R. et al. (2009) A new potent secondary amphipathic cell-penetrating peptide for siRNA delivery into mammalian cells. Mol Ther;17:95–103.
  • 101
    Gooding M., Tudzarova S., Worthington R.J., Kingsbury S.R., Rebstock A.-S., Dube H. et al. (2011) Exploring the interaction between siRNA and the SMoC biomolecule transporters: implications for small molecule mediated delivery of siRNA. Chem Biol Drug Des;79:9–21.
  • 102
    Jarvis A., Allerston C.K., Jia H., Herzog B., Garza-Garcia A., Winfield N. et al. (2010) Small molecule inhibitors of the neuropilin-1 vascular endothelial growth factor A (VEGF-A) interaction. J Med Chem;53:2215–2226.
  • 103
    Rebstock A.S., Visintin C., Leo E., Garcia Posada C., Kingsbury S.R., Williams G.H. et al. (2008) Modular assembly using sequential palladium coupling gives easy access to the SMoC class of cellular transporters. ChemBioChem;9:1787–1796.
    Direct Link:
  • 104
    Veldhoen S., Laufer S.D., Trampe A., Restle T. (2006) Cellular delivery of small interfering RNA by a non-covalently attached cell-penetrating peptide: quantitative analysis of uptake and biological effect. Nucleic Acids Res;34:6561–6573.
  • 105
    Soenen S.J.H., Brisson A.R., De Cuyper M. (2009) Addressing the problem of cationic lipid-mediated toxicity: the magnetoliposome model. Biomaterials;30:3691–3701.
  • 106
    Jia H., Bagherzadeh A., Hartzoulakis B., Jarvis A., Lohr M., Shaikh S. et al. (2006) Characterization of a bicyclic peptide neuropilin-1 (NP-1) antagonist (EG3287) reveals importance of vascular endothelial growth factor exon 8 for NP-1 binding and role of NP-1 in KDR signaling. J Biol Chem;281:13493–13502.
  • 107
    Muratovska A., Eccles M.R. (2004) Conjugate for efficient delivery of short interfering RNA (siRNA) into mammalian cells. FEBS Lett;558:63–68.
  • 108
    Meade B.R., Dowdy S.F. (2007) Exogenous siRNA delivery using peptide transduction domains/cell penetrating peptides. Adv Drug Deliv Rev;59:134–140.
  • 109
    Davidson T.J., Harel S., Arboleda V.A., Prunell G.F., Shelanski M.L., Greene L.A. et al. (2004) Highly efficient small interfering RNA delivery to primary mammalian neurons induces microRNA-like effects before mRNA degradation. J Neurosci;24:10040–10046.
  • 110
    Moschos S.A., Jones S.W., Perry M.M., Williams A.E., Erjefalt J.S., Turner J.J. et al. (2007) Lung delivery studies using siRNA conjugated to TAT(48–60) and penetratin reveal peptide induced reduction in gene expression and induction of innate immunity. Bioconjug Chem;18:1450–1459.
  • 111
    Simeoni F., Morris M.C., Heitz F., Divita G. (2003) Insight into the mechanism of the peptide-based gene delivery system MPG: implications for delivery of siRNA into mammalian cells. Nucleic Acids Res;31:2717–2724.
  • 112
    Chan A.W., Laskowski R.A., Selwood D.L. (2010) Chemical fragments that hydrogen bond to Asp, Glu, Arg, and His side chains in protein binding sites. J Med Chem;53:3086–3094.
  • 113
    Lundberg P., El Andaloussi S., Sutlu T., Johansson H., Langel U. (2007) Delivery of short interfering RNA using endosomolytic cell-penetrating peptides. FASEB J;21:2664–2671.
  • 114
    Magzoub M., Pramanik A., Graslund A. (2005) Modeling the endosomal escape of cell-penetrating peptides: transmembrane pH gradient driven translocation across phospholipid bilayers. Biochemistry;44:14890–14897.
  • 115
    Unnamalai N., Kang B.G., Lee W.S. (2004) Cationic oligopeptide-mediated delivery of dsRNA for post-transcriptional gene silencing in plant cells. FEBS Lett;566:307–310.
  • 116
    Kim S.W., Kim N.Y., Choi Y.B., Park S.H., Yang J.M., Shin S. (2010) RNA interference in vitro and in vivo using an arginine peptide/siRNA complex system. J Controlled Release;143:335–343.
  • 117
    Konate K., Crombez L., Deshayes S., Decaffmeyer M., Thomas A., Brasseur R. et al. (2010) Insight into the cellular uptake mechanism of a secondary amphipathic cell-penetrating peptide for siRNA delivery. Biochemistry;49:3393–3402.
  • 118
    Gooding M., Tudzarova S., Worthington R.J., Kingsbury S.R., Rebstock A.S., Dube H. et al. (2012) Exploring the interaction between siRNA and the SMoC biomolecule transporters: implications for small molecule-mediated delivery of siRNA. Chem Biol Drug Des;79:9–21.
    Direct Link:
  • 119
    Arthanari Y., Pluen A., Rajendran R., Aojula H., Demonacos C. (2010) Delivery of therapeutic shRNA and siRNA by Tat fusion peptide targeting BCR-ABL fusion gene in chronic myeloid leukemia cells. J Controlled Release;145:272–280.
  • 120
    Ishihara T., Goto M., Kodera K., Kanazawa H., Murakami Y., Mizushima Y. et al. (2009) Intracellular delivery of siRNA by cell-penetrating peptides modified with cationic oligopeptides. Drug Delivery;16:153–159.
  • 121
    Endoh T., Sisido M., Ohtsuki T. (2008) Cellular siRNA delivery mediated by a cell-permeant RNA-binding protein and photoinduced RNA interference. Bioconjug Chem;19:1017–1024.
  • 122
    Lensink M.F., Christiaens B., Vandekerckhove J., Prochiantz A., Rosseneu M. (2005) Penetratin-membrane association: W48/R52/W56 shield the peptide from the aqueous phase. Biophys J;88:939–952.
  • 123
    Waite C.L., Sparks S.M., Uhrich K.E., Roth C.M. (2009) Acetylation of PAMAM dendrimers for cellular delivery of siRNA. BMC Biotechnol;9:38.
  • 124
    Waite C.L., Roth C.M. (2011) Binding and transport of PAMAM-RGD in a tumor spheroid model: the effect of RGD targeting ligand density. Biotechnol Bioeng;108:2999–3008.
    Direct Link:
  • 125
    Merkel O.M., Zheng M., Mintzer M.A., Pavan G.M., Librizzi D., Maly M. et al. (2011) Molecular modeling and in vivo imaging can identify successful flexible triazine dendrimer-based siRNA delivery systems. J Control Release;153:23–33.
  • 126
    Rao N.M. (2010) Cationic lipid-mediated nucleic acid delivery: beyond being cationic. Chem Phys Lipids;163:245–252.
  • 127
    Li W., Szoka F.C. (2007) Lipid-based nanoparticles for nucleic acid delivery. Pharm Res;24:438–449.
  • 128
    Rozema D.B., Lewis D.L., Wakefield D.H., Wong S.C., Klein J.J., Roesch P.L. et al. (2007) Dynamic polyconjugates for targeted in vivo delivery of siRNA to hepatocytes. Proc Natl Acad Sci;104:12982–12987.
  • 129
    Felgner P.L., Gadek T.R., Holm M., Roman R., Chan H.W., Wenz M. et al. (1987) Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure. Proc Natl Acad Sci;84:7413–7417.
  • 130
    Malone R.W., Felgner P.L., Verma I.M. (1989) Cationic liposome-mediated RNA transfection. Proc Natl Acad Sci;86:6077–6081.
  • 131
    Behr J.P., Demeneix B., Loeffler J.P., Perez-Mutul J. (1989) Efficient gene transfer into mammalian primary endocrine cells with lipopolyamine-coated DNA. Proc Natl Acad Sci;86:6982–6986.
  • 132
    Gao X., Huang L. (1991) A novel cationic liposome reagent for efficient transfection of mammalian cells. Biochem Biophys Res Commun;179:280–285.
  • 133
    Rose J.K., Buonocore L., Whitt M.A. (1991) A new cationic liposome reagent mediating nearly quantitative transfection of animal cells. Biotechniques;10:520–525.
  • 134
    San H., Yang Z.Y., Pompili V.J., Jaffe M.L., Plautz G.E., Xu L. et al. (1993) Safety and short-term toxicity of a novel cationic lipid formulation for human gene therapy. Hum Gene Ther;4:781–788.
  • 135
    Dalby B., Cates S., Harris A., Ohki E.C., Tilkins M.L., Price P.J. et al. (2004) Advanced transfection with Lipofectamine 2000 reagent: primary neurons, siRNA, and high-throughput applications. Methods;33:95–103.
  • 136
    Filion M.C., Phillips N.C. (1997) Toxicity and immunomodulatory activity of liposomal vectors formulated with cationic lipids toward immune effector cells. Biochim Biophys Acta;1329:345–356.
  • 137
    Hunt M.A., Currie M.J., Robinson B.A., Dachs G.U. (2010) Optimizing transfection of primary human umbilical vein endothelial cells using commercially available chemical transfection reagents. J Biomol Tech;21:66–72.
  • 138
    Yamazaki Y., Nango M., Matsuura M., Hasegawa Y., Hasegawa M., Oku N. (2000) Polycation liposomes, a novel nonviral gene transfer system, constructed from cetylated polyethylenimine. Gene Ther;7:1148–1155.
  • 139
    Zhong Y.Q., Wei J., Fu Y.R., Shao J., Liang Y.W., Lin Y.H. et al. (2008) Toxicity of cationic liposome Lipofectamine 2000 in human pancreatic cancer Capan-2 cells. Nan Fang Yi Ke Da Xue Xue Bao;28:1981–1984.
  • 140
    Kedmi R., Ben-Arie N., Peer D. (2010) The systemic toxicity of positively charged lipid nanoparticles and the role of Toll-like receptor 4 in immune activation. Biomaterials;31:6867–6875.
  • 141
    Farhood H., Serbina N., Huang L. (1995) The role of dioleoyl phosphatidylethanolamine in cationic liposome mediated gene transfer. Biochim Biophys Acta;1235:289–295.
  • 142
    Xu L., Anchordoquy T.J. (2008) Cholesterol domains in cationic lipid/DNA complexes improve transfection. Biochim Biophys Acta;1778:2177–2181.
  • 143
    Siegel D.P., Epand R.M. (1997) The mechanism of lamellar-to-inverted hexagonal phase transitions in phosphatidylethanolamine: implications for membrane fusion mechanisms. Biophys J;73:3089–3111.
  • 144
    Zhang J., Fan H., Levorse D.A., Crocker L.S. (2011) Interaction of cholesterol-conjugated ionizable amino lipids with biomembranes: lipid polymorphism, structure–activity relationship, and implications for siRNA delivery. Langmuir;27:9473–9483.
  • 145
    Simberg D., Weisman S., Talmon Y., Faerman A., Shoshani T., Barenholz Y. (2003) The role of organ vascularization and lipoplex-serum initial contact in intravenous murine lipofection. J Biol Chem;278:39858–39865.
  • 146
    Hirsch-Lerner D., Zhang M., Eliyahu H., Ferrari M.E., Wheeler C.J., Barenholz Y. (2005) Effect of “helper lipid” on lipoplex electrostatics. Biochim Biophys Acta;1714:71–84.
  • 147
    Morrissey D.V., Lockridge J.A., Shaw L., Blanchard K., Jensen K., Breen W. et al. (2005) Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat Biotechnol;23:1002–1007.
  • 148
    Zimmermann T.S., Lee A.C.H., Akinc A., Bramlage B., Bumcrot D., Fedoruk M.N. et al. (2006) RNAi-mediated gene silencing in non-human primates. Nature;441:111–114.
  • 149
    Semple S.C., Akinc A., Chen J., Sandhu A.P., Mui B.L., Cho C.K. et al. (2010) Rational design of cationic lipids for siRNA delivery. Nat Biotechnol;28:172–176.
  • 150
    Mével M., Kamaly N., Carmona S., Oliver M.H., Jorgensen M.R., Crowther C. et al. (2010) DODAG; a versatile new cationic lipid that mediates efficient delivery of pDNA and siRNA. J Controlled Release;143:222–232.
  • 151
    Klein E., Leborgne C., Ciobanu M., Klein J., Frisch B., Pons F. et al. (2010) Nucleic acid transfer with hemifluorinated polycationic lipids. Biomaterials;31:4781–4788.
  • 152
    Jayaraman M., Ansell S.M., Mui B.L., Tam Y.K., Chen J., Du X. et al. (2011) Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew Chem Int Ed;51(34):8529–8533.
    Direct Link:
  • 153
    Geisbert T.W., Lee A.C.H., Robbins M., Geisbert J.B., Honko A.N., Sood V. et al. (2010) Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study. Lancet;375:1896–1905.
  • 154
    Akinc A., Querbes W., De S., Qin J., Frank-Kamenetsky M., Jayaprakash K.N. et al. (2010) Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol Ther;18:1357–1364.
  • 155
    Kuwahara H., Nishina K., Yoshida K., Nishina T., Yamamoto M., Saito Y. et al. (2011) Efficient in vivo delivery of siRNA into brain capillary endothelial cells along with endogenous lipoprotein. Mol Ther;19(12):2213–2221.
  • 156
    Uno Y., Piao W., Miyata K., Nishina K., Mizusawa H., Yokota T. (2011) High-density lipoprotein facilitates in vivo delivery of alpha-tocopherol-conjugated short-interfering RNA to the brain. Hum Gene Ther;22:711–719.
  • 157
    Nimesh S. (2012) Polyethylenimine as a promising vector for targeted siRNA delivery. Curr Clin Pharmacol;7:121–130.
  • 158
    Urban-Klein B., Werth S., Abuharbeid S., Czubayko F., Aigner A. (2004) RNAi-mediated gene-targeting through systemic application of polyethylenimine (PEI)-complexed siRNA in vivo. Gene Ther;12:461–466.
  • 159
    Sonawane N.D., Szoka F.C., Verkman A.S. (2003) Chloride accumulation and swelling in endosomes enhances DNA transfer by polyamine-DNA polyplexes. J Biol Chem;278:44826–44831.
  • 160
    Thomas M., Lu J.J., Ge Q., Zhang C., Chen J., Klibanov A.M. (2005) Full deacylation of polyethylenimine dramatically boosts its gene delivery efficiency and specificity to mouse lung. Proc Natl Acad Sci;102:5679–5684.
  • 161
    Fischer D., Li Y., Ahlemeyer B., Krieglstein J., Kissel T. (2003) In vitro cytotoxicity testing of polycations: influence of polymer structure on cell viability and hemolysis. Biomaterials;24:1121–1131.
  • 162
    Méndez-Ardoy A., Urbiola K., Aranda C., Ortiz-Mellet C., García-Fernández J.M., Tros de Ilarduya C. (2011) Polycationic amphiphilic cyclodextrin-based nanoparticles for therapeutic gene delivery. Nanomedicine (Lond);6:1697–1707.
  • 163
    Kulkarni A., DeFrees K., Hyun S.-H., Thompson D.H. (2012) Pendant polymer: amino-β-cyclodextrin: siRNA guest: host nanoparticles as efficient vectors for gene silencing. J Am Chem Soc;134:7596–7599.
  • 164
    Zuckerman J.E., Choi C.H.J., Han H., Davis M.E. (2012) Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane. Proc Natl Acad Sci;109:3137–3142.
  • 165
    Giezen T.J., Mantel-Teeuwisse A.K., Straus S.M.J.M., Schellekens H., Leufkens H.G.M., Egberts A.C.G. (2008) Safety-related regulatory actions for biologicals approved in the United States and the European Union. JAMA;300:1887–1896.
  • 166
    de Fougerolles A., Vornlocher H.P., Maraganore J., Lieberman J. (2007) Interfering with disease: a progress report on siRNA-based therapeutics. Nat Rev Drug Discov;6:443–453.
  • 167
    Jain K., Kesharwani P., Gupta U., Jain N.K. (2010) Dendrimer toxicity: let’s meet the challenge. Int J Pharm;394:122–142.
  • 168
    Leachman S.A., Hickerson R.P., Schwartz M.E., Bullough E.E., Hutcherson S.L., Boucher K.M. et al. (2009) First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder. Mol Ther;18:442–446.
  • 169
    Clutterbuck L.A., Posada C.G., Visintin C., Riddall D.R., Lancaster B., Gane P.J. et al. (2009) Oxadiazolylindazole sodium channel modulators are neuroprotective toward hippocampal neurones. J Med Chem;52:2694–2707.
  • 170
    Kim W.J., Christensen L.V., Jo S., Yockman J.W., Jeong J.H., Kim Y.-H. et al. (2006) Cholesteryl oligoarginine delivering vascular endothelial growth factor siRNA effectively inhibits tumor growth in colon adenocarcinoma. Mol Ther;14:343–350.
  • 171
    Crombez L., Morris M.C., Dufort S., Aldrian-Herrada G., Nguyen Q., McMaster G. et al. (2009) Targeting cyclin B1 through peptide-based delivery of siRNA prevents tumour growth. Nucleic Acids Res;37:4559–4569.
View Full Article (HTML) Get PDF (533K)