Classes and Prediction of Cell-Penetrating Peptides

  • Maria LindgrenEmail author
  • Ülo Langel
Part of the Methods in Molecular Biology book series (MIMB, volume 683)


The classical view on how peptides enter cells has been changed due to the development in the research field of cell-penetrating peptides (CPPs). During the last 15 years, more than 100 peptide sequences have been published to enter cells and also to bring different biological cargoes with them. Here, we present an overview of CPPs, mainly trying to analyze their common properties yielding the prediction of their cell-penetrating properties. Furthermore, examples of recent research, ideas on classification and uptake mechanisms, as well as a summary of the therapeutic potential of CPPs are presented.

Key words

Cell-penetrating peptide Cellular uptake Intracellular delivery Drug delivery siRNA Selective delivery 



The work presented in this article was supported by Swedish Research Council (VR-NT); by Center for Biomembrane Research, Stockholm; and by Knut and Alice Wallenberg’s Foundation.


  1. 1.
    Järver, P., and Langel, Ü. (2004) The use of cell-penetrating peptides as a tool for gene regulation. Drug Discov Today 9, 395–402.PubMedCrossRefGoogle Scholar
  2. 2.
    Joliot, A. (2005) Transduction peptides within naturally occurring proteins. Sci STKE 2005, pe54.PubMedCrossRefGoogle Scholar
  3. 3.
    Moschos, S. A., Jones, S. W., Perry, M. M., Williams, A. E., Erjefalt, J. S., Turner, J. J., Barnes, P. J., Sproat, B. S., Gait, M. J., and Lindsay, M. A. (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, 1450–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Dupont, E., Prochiantz, A., and Joliot, A. (2007) Identification of a signal peptide for unconventional secretion. J Biol Chem 282, 8994–9000.PubMedCrossRefGoogle Scholar
  5. 5.
    Hällbrink, M., Florén, A., Elmquist, A., Pooga, M., Bartfai, T., and Langel, Ü. (2001) Cargo delivery kinetics of cell-penetra ting peptides. Biochim Biophys Acta 1515, 101–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Lindgren, M. E., Hällbrink, M. M., Elmquist, A. M., and Langel, Ü. (2004) Passage of cell-penetrating peptides across a human epithelial cell layer in vitro. Biochem J 377, 69–76.PubMedCrossRefGoogle Scholar
  7. 7.
    Ma, H. L., Whitters, M. J., Konz, R. F., Senices, M., Young, D. A., Grusby, M. J., Collins, M., and Dunussi-Joannopoulos, K. (2003) IL-21 activates both innate and adaptive immunity to generate potent antitumor responses that require perforin but are independent of IFN-gamma. J Immunol 171, 608–15.PubMedGoogle Scholar
  8. 8.
    Joliot, A., Pernelle, C., Deagostini-Bazin, H., and Prochiantz, A. (1991) Antennapedia homeobox peptide regulates neural morphogenesis. Proc Natl Acad Sci U S A 88, 1864–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Derossi, D., Joliot, A. H., Chassaing, G., and Prochiantz, A. (1994) The third helix of the Antennapedia homeodomain translocates through biological membranes. J Biol Chem 269, 10444–50.PubMedGoogle Scholar
  10. 10.
    Derossi, D., Chassaing, G., and Prochiantz, A. (1998) Trojan peptides: the penetratin system for intracellular delivery. Trends Cell Biol 8, 84–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Derossi, D., Calvet, S., Trembleau, A., Brunissen, A., Chassaing, G., and Prochiantz, A. (1996) Cell internalization of the third helix of the Antennapedia homeodomain is receptor-independent. J Biol Chem 271, 18188–93.PubMedCrossRefGoogle Scholar
  12. 12.
    Ruben, S., Perkins, A., Purcell, R., Joung, K., Sia, R., Burghoff, R., Haseltine, W. A., and Rosen, C. A. (1989) Structural and functional characterization of human immunodeficiency virus tat protein. J Virol 63, 1–8.PubMedGoogle Scholar
  13. 13.
    Vogel, B. E., Lee, S. J., Hildebrand, A., Craig, W., Pierschbacher, M. D., Wong-Staal, F., and Ruoslahti, E. (1993) A novel integrin specificity exemplified by binding of the alpha v beta 5 integrin to the basic domain of the HIV Tat protein and vitronectin. J Cell Biol 121, 461–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Elliot, B. C., Wisnewski, A. V., Johnson, J., Fenwick-Smith, D., Wiest, P., Hamer, D., Kresina, T., and Flanigan, T. P. (1997) In vitro inhibition of Cryptosporidium parvum infection by human monoclonal antibodies. Infect Immun 65, 3933–5.PubMedGoogle Scholar
  15. 15.
    Ensoli, B., Buonaguro, L., Barillari, G., Fiorelli, V., Gendelman, R., Morgan, R. A., Wingfield, P., and Gallo, R. C. (1993) Release, uptake, and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation. J Virol 67, 277–87.PubMedGoogle Scholar
  16. 16.
    Vives, E., Brodin, P., and 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, 16010–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Schwarze, S. R., Ho, A., Vocero-Akbani, A., and Dowdy, S. F. (1999) In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 285, 1569–72.PubMedCrossRefGoogle Scholar
  18. 18.
    Futaki, S., Nakase, I., Tadokoro, A., Takeuchi, T., and Jones, A. T. (2007) Arginine-rich peptides and their internalization mechanisms. Biochem Soc Trans 35, 784–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Lin, M. L., and Bertics, P. J. (1995) Laminin responsiveness is associated with changes in fibroblast morphology, motility, and anchorage-independent growth: cell system for examining the interaction between laminin and EGF signaling pathways. J Cell Physiol 164, 593–604.PubMedCrossRefGoogle Scholar
  20. 20.
    Morris, M. C., Vidal, P., Chaloin, L., Heitz, F., and Divita, G. (1997) A new peptide vector for efficient delivery of oligonucleotides into mammalian cells. Nucleic Acids Res 25, 2730–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Chaloin, L., Vidal, P., Heitz, A., Van Mau, N., Mery, J., Divita, G., and Heitz, F. (1997) Conformations of primary amphipathic carrier peptides in membrane mimicking environments. Biochemistry 36, 11179–87.PubMedCrossRefGoogle Scholar
  22. 22.
    Zhang, M. Y., Sun, S. C., Bell, L., and Miller, B. A. (1998) NF-kappaB transcription factors are involved in normal erythropoiesis. Blood 91, 4136–44.PubMedGoogle Scholar
  23. 23.
    Chaloin, L., Vidal, P., Lory, P., Mery, J., Lautredou, N., Divita, G., and Heitz, F. (1998) Design of carrier peptide–oligonucleotide conjugates with rapid membrane translocation and nuclear localization properties. Biochem Biophys Res Commun 243, 601–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Pooga, M., Lindgren, M., Hällbrink, M., Bråkenhielm, E., and Langel, Ü. (1998) Galanin-based peptides, galparan and transportan, with receptor-dependent and independent activities. Ann N Y Acad Sci 863, 450–3.PubMedCrossRefGoogle Scholar
  25. 25.
    Pooga, M., Hällbrink, M., Zorko, M., and Langel, Ü. (1998) Cell penetration by transportan. FASEB J 12, 67–77.PubMedGoogle Scholar
  26. 26.
    Pooga, M., Soomets, U., Hällbrink, M., Valkna, A., Saar, K., Rezaei, K., Kahl, U., Hao, J. X., Xu, X. J., Wiesenfeld-Hallin, Z., Hökfelt, T., Bartfai, T., and Langel, Ü. (1998) Cell penetrating PNA constructs regulate galanin receptor levels and modify pain transmission in vivo. Nat Biotechnol 16, 857–61.PubMedCrossRefGoogle Scholar
  27. 27.
    Mäe, M., and Langel, Ü. (2006) Cell-penetrating peptides as vectors for peptide, protein and oligonucleotide delivery. Curr Opin Pharmacol 6, 509–14.PubMedCrossRefGoogle Scholar
  28. 28.
    Oehlke, J., Scheller, A., Wiesner, B., Krause, E., Beyermann, M., Klauschenz, E., Melzig, M., and Bienert, M. (1998) Cellular uptake of an alpha-helical amphipathic model peptide with the potential to deliver polar compounds into the cell interior non-endocytically. Biochim Biophys Acta 1414, 127–39.PubMedCrossRefGoogle Scholar
  29. 29.
    Oehlke, J., Krause, E., Wiesner, B., Beyermann, M., and Bienert, M. (1997) Extensive cellular uptake into endothelial cells of an amphipathic beta-sheet forming peptide. FEBS Lett 415, 196–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Scheller, A., Oehlke, J., Wiesner, B., Dathe, M., Krause, E., Beyermann, M., Melzig, M., and Bienert, M. (1999) Structural requirements for cellular uptake of alpha-helical amphipathic peptides. J Pept Sci 5, 185–94.PubMedCrossRefGoogle Scholar
  31. 31.
    Deshayes, S., Simeoni, F., Morris, M. C., Divita, G., and Heitz, F. (2007) Peptide-mediated delivery of nucleic acids into mammalian cells. Methods Mol Biol 386, 299–308.PubMedCrossRefGoogle Scholar
  32. 32.
    Crombez, L., Aldrian-Herrada, G., Konate, K., Nguyen, Q. N., McMaster, G. K., Brasseur, R., Heitz, F., and Divita, G. (2009) A new potent secondary amphipathic cell-penetrating peptide for siRNA delivery into mammalian cells. Mol Ther 17, 95–103.PubMedCrossRefGoogle Scholar
  33. 33.
    Duguid, J. G., Li, C., Shi, M., Logan, M. J., Alila, H., Rolland, A., Tomlinson, E., Sparrow, J. T., and Smith, L. C. (1998) A physicochemical approach for predicting the effectiveness of peptide-based gene delivery systems for use in plasmid-based gene therapy. Biophys J 74, 2802–14.PubMedCrossRefGoogle Scholar
  34. 34.
    Hällbrink, M., Kilk, K., Elmquist, A., Lundberg, P., Lindgren, M., Jiang, Y., Pooga, M., Soomets, U., and Langel, Ü. (2005) Prediction of cell-penetrating peptides. Int J Pept Res Ther 11, 249–59.CrossRefGoogle Scholar
  35. 35.
    Lindgren, M., Rosenthal-Aizman, K., Saar, K., Eiriksdottir, E., Jiang, Y., Sassian, M., Östlund, P., Hällbrink, M., and Langel, Ü. (2006) Overcoming methotrexate resistance in breast cancer tumour cells by the use of a new cell-penetrating peptide. Biochem Pharmacol 71, 416–25.PubMedCrossRefGoogle Scholar
  36. 36.
    Tünnemann, G., Martin, R. M., Haupt, S., Patsch, C., Edenhofer, F., and Cardoso, M. C. (2006) Cargo-dependent mode of uptake and bioavailability of TAT-containing proteins and peptides in living cells. FASEB J 20, 1775–84.PubMedCrossRefGoogle Scholar
  37. 37.
    El-Andaloussi, S., Järver, P., Johansson, H. J., and Langel, Ü. (2007) Cargo-dependent cytotoxicity and delivery efficacy of cell-penetrating peptides: a comparative study. Biochem J 407, 285–92.PubMedCrossRefGoogle Scholar
  38. 38.
    Heitz, F., Morris, M. C., and Divita, G. (2009) Twenty years of cell-penetrating peptides: from molecular mechanisms to therapeutics. Br J Pharmacol 157, 195–206.PubMedCrossRefGoogle Scholar
  39. 39.
    Wender, P. A., Mitchell, D. J., Pattabiraman, K., Pelkey, E. T., Steinman, L., and Rothbard, J. B. (2000) The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: peptoid molecular transporters. Proc Natl Acad Sci U S A 97, 13003–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Rothbard, J. B., Garlington, S., Lin, Q., Kirschberg, T., Kreider, E., McGrane, P. L., Wender, P. A., and Khavari, P. A. (2000) Conjugation of arginine oligomers to cyclosporin A facilitates topical delivery and inhibition of inflammation. Nat Med 6, 1253–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Futaki, S. (2002) Arginine-rich peptides: potential for intracellular delivery of macromolecules and the mystery of the translocation mechanisms. Int J Pharm 245, 1–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Morris, M. C., Depollier, J., Mery, J., Heitz, F., and Divita, G. (2001) A peptide carrier for the delivery of biologically active proteins into mammalian cells. Nat Biotech 19, 1173–6.CrossRefGoogle Scholar
  43. 43.
    Thorén, P. E., Persson, D., Lincoln, P., and Norden, B. (2005) Membrane destabilizing properties of cell-penetrating peptides. Biophys Chem 114, 169–79.PubMedCrossRefGoogle Scholar
  44. 44.
    Palm, C., Jayamanne, M., Kjellander, M., and Hällbrink, M. (2007) Peptide degradation is a critical determinant for cell-penetrating peptide uptake. Biochim Biophys Acta 1768, 1769–76.PubMedCrossRefGoogle Scholar
  45. 45.
    Richard, J. P., Melikov, K., Vives, E., Ramos, C., Verbeure, B., Gait, M. J., Chernomordik, L. V., and Lebleu, B. (2003) Cell-penetrating peptides. A reevaluation of the mechanism of cellular uptake. J Biol Chem 278, 585–90.PubMedCrossRefGoogle Scholar
  46. 46.
    Lundberg, M., and Johansson, M. (2002) Positively charged DNA-binding proteins cause apparent cell membrane translocation. Biochem Biophys Res Commun 291, 367–71.PubMedCrossRefGoogle Scholar
  47. 47.
    Vives, E., Richard, J. P., Rispal, C., and Lebleu, B. (2003) TAT peptide internalization: seeking the mechanism of entry. Curr Protein Pept Sci 4, 125–32.PubMedCrossRefGoogle Scholar
  48. 48.
    Almeida, P. F., and Pokorny, A. (2009) Mechanisms of antimicrobial, cytolytic, and cell-penetrating peptides: from kinetics to thermodynamics. Biochemistry 48, 8083–93.PubMedCrossRefGoogle Scholar
  49. 49.
    Palm-Apergi, C., Lorents, A., Padari, K., Pooga, M., and Hällbrink, M. (2009) The membrane repair response masks membrane disturbances caused by cell-penetrating peptide uptake. FASEB J 23, 214–23.PubMedCrossRefGoogle Scholar
  50. 50.
    Futaki, S. (2006) Oligoarginine vectors for intracellular delivery: design and cellular-uptake mechanisms. Biopolymers 84, 241–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Jones, S. W., Christison, R., Bundell, K., Voyce, C. J., Brockbank, S. M., Newham, P., and Lindsay, M. A. (2005) Characterisation of cell-penetrating peptide-mediated peptide delivery. Br J Pharmacol 145, 1093–102.PubMedCrossRefGoogle Scholar
  52. 52.
    Duchardt, F., Fotin-Mleczek, M., Schwarz, H., Fischer, R., and Brock, R. (2007) A comprehensive model for the cellular uptake of cationic cell-penetrating peptides. Traffic 8, 848–66.PubMedCrossRefGoogle Scholar
  53. 53.
    Vivés, E. (2003) Cellular uptake [correction of uptake] of the Tat peptide: an endocytosis mechanism following ionic interactions.J Mol Recognit 16, 265–71.PubMedCrossRefGoogle Scholar
  54. 54.
    Brooks, H., Lebleu, B., and Vivés, E. (2005) Tat peptide-mediated cellular delivery: back to basics. Adv Drug Deliv Rev 57, 559–77.PubMedCrossRefGoogle Scholar
  55. 55.
    Nakamura, T., Moriguchi, R., Kogure, K., Shastri, N., and Harashima, H. (2008) Efficient MHC class I presentation by controlled intracellular trafficking of antigens in octaarginine-modified liposomes. Mol Ther 16, 1507–14.PubMedCrossRefGoogle Scholar
  56. 56.
    Fittipaldi, A., Ferrari, A., Zoppe, M., Arcangeli, C., Pellegrini, V., Beltram, F., and Giacca, M. (2003) Cell membrane lipid rafts mediate caveolar endocytosis of HIV-1 Tat fusion proteins. J Biol Chem 278, 34141–9.PubMedCrossRefGoogle Scholar
  57. 57.
    Nakase, I., Niwa, M., Takeuchi, T., Sonomura, K., Kawabata, N., Koike, Y., Takehashi,M., Tanaka, S., Ueda, K., Simpson, J. C., Jones, A. T., Sugiura, Y., and Futaki, S. (2004) Cellular uptake of arginine-rich peptides: roles for macropinocytosis and actin rearrangement. Mol Ther 10, 1011–22.PubMedCrossRefGoogle Scholar
  58. 58.
    Säälik, P., Elmquist, A., Hansen, M., Padari, K., Saar, K., Viht, K., Langel, Ü., and Pooga, M. (2004) Protein cargo delivery properties of cell-penetrating peptides. A comparative study. Bioconjug Chem 15, 1246–53.PubMedCrossRefGoogle Scholar
  59. 59.
    Foerg, C., Ziegler, U., Fernandez-Carneado, J., Giralt, E., Rennert, R., Beck-Sickinger, A. G., and Merkle, H. P. (2005) Decoding the entry of two novel cell-penetrating peptides in HeLa cells: lipid raft-mediated endocytosis and endosomal escape. Biochemistry 44, 72–81.PubMedCrossRefGoogle Scholar
  60. 60.
    Futaki, S., Ohashi, W., Suzuki, T., Niwa, M., Tanaka, S., Ueda, K., Harashima, H., and Sugiura, Y. (2001) Stearylated arginine-rich peptides: a new class of transfection systems. Bioconjug Chem 12, 1005–11.PubMedCrossRefGoogle Scholar
  61. 61.
    Pujals, S., Fernandez-Carneado, J., Kogan, M. J., Martinez, J., Cavelier, F., and Giralt, E. (2006) Replacement of a proline with silaproline causes a 20-fold increase in the cellular uptake of a pro-rich peptide. J Am Chem Soc 128, 8479–83.PubMedCrossRefGoogle Scholar
  62. 62.
    Holm, T., Johansson, H., Lundberg, P., Pooga, M., Lindgren, M., and Langel, Ü. (2006) Studying the uptake of cell-penetrating peptides. Nat Protoc 1, 1001–5.PubMedCrossRefGoogle Scholar
  63. 63.
    El-Andaloussi, S., Johansson, H. J., Holm, T., and Langel, Ü. (2007) A novel cell-penetrating peptide, M918, for efficient delivery of proteins and peptide nucleic acids. Mol Ther 15, 1820–6.PubMedCrossRefGoogle Scholar
  64. 64.
    Hansen, M., Kilk, K., and Langel, Ü. (2008) Predicting cell-penetrating peptides. Adv Drug Deliv Rev 60, 572–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Liang, J. F., and Yang, V. C. (2005) Synthesis of doxorubicin-peptide conjugate with multidrug resistant tumor cell killing activity. Bioorg Med Chem Lett 15, 5071–5.PubMedCrossRefGoogle Scholar
  66. 66.
    Ruoslahti, E., Duza, T., and Zhang, L. (2005) Vascular homing peptides with cell-penetrating properties. Curr Pharm Des 11, 3655–60.PubMedCrossRefGoogle Scholar
  67. 67.
    Laakkonen, P., Akerman, M. E., Biliran, H., Yang, M., Ferrer, F., Karpanen, T., Hoffman, R. M., and Ruoslahti, E. (2004) Antitumor activity of a homing peptide that targets tumor lymphatics and tumor cells. Proc Natl Acad Sci U S A 101, 9381–6.PubMedCrossRefGoogle Scholar
  68. 68.
    Myrberg, H., Zhang, L., Mäe, M., and Langel, Ü. (2008) Design of a tumor-homing cell-penetrating peptide. Bioconjug Chem 19, 70–5.PubMedCrossRefGoogle Scholar
  69. 69.
    Dietz, G. P., and Bahr, M. (2007) Synthesis of cell-penetrating peptides and their application in neurobiology. Methods Mol Biol 399, 181–98.PubMedCrossRefGoogle Scholar
  70. 70.
    Dietz, G. P., and Bahr, M. (2005) Peptide-enhanced cellular internalization of proteins in neuroscience. Brain Res Bull 68, 103–14.PubMedCrossRefGoogle Scholar
  71. 71.
    Allinquant, B., Hantraye, P., Mailleux, P., Moya, K., Bouillot, C., and Prochiantz, A. (1995) Downregulation of amyloid precursor protein inhibits neurite outgrowth in vitro. J Cell Biol 128, 919–27.PubMedCrossRefGoogle Scholar
  72. 72.
    Pizzi, M., Sarnico, I., Boroni, F., Benarese, M., Steimberg, N., Mazzoleni, G., Dietz, G. P., Bahr, M., Liou, H. C., and Spano, P. F. (2005) NF-kappaB factor c-Rel mediates neuroprotection elicited by mGlu5 receptor agonists against amyloid beta-peptide toxicity. Cell Death Differ 12, 761–72.PubMedCrossRefGoogle Scholar
  73. 73.
    Dietz, G. P., Kilic, E., and Bahr, M. (2002) Inhibition of neuronal apoptosis in vitro and in vivo using TAT-mediated protein transduction. Mol Cell Neurosci 21, 29–37.PubMedCrossRefGoogle Scholar
  74. 74.
    Theodore, L., Derossi, D., Chassaing, G., Llirbat, B., Kubes, M., Jordan, P., Chneiweiss, H., Godement, P., and Prochiantz, A. (1995) Intraneuronal delivery of protein kinase C pseudosubstrate leads to growth cone collapse. J Neurosci 15, 7158–67.PubMedGoogle Scholar
  75. 75.
    Kilic, U., Kilic, E., Dietz, G. P., and Bahr, M. (2004) The TAT protein transduction domain enhances the neuroprotective effect of glial-cell-line-derived neurotrophic factor after optic nerve transection. Neurodegener Dis 1, 44–9.PubMedCrossRefGoogle Scholar
  76. 76.
    Morris, M. C., Chaloin, L., Heitz, F., and Divita, G. (2000) Translocating peptides and proteins and their use for gene delivery. Curr Opin Biotechnol 11, 461–6.PubMedCrossRefGoogle Scholar
  77. 77.
    Abes, R., Arzumanov, A. A., Moulton, H. M., Abes, S., Ivanova, G. D., Iversen, P. L., Gait, M. J., and Lebleu, B. (2007) Cell-penetrating-peptide-based delivery of oligonucleotides: an overview. Biochem Soc Trans 35, 775–9.PubMedCrossRefGoogle Scholar
  78. 78.
    Deshayes, S., Morris, M., Heitz, F., and Divita, G. (2008) Delivery of proteins and nucleic acids using a non-covalent peptide-based strategy. Adv Drug Deliv Rev 60, 537–47.PubMedCrossRefGoogle Scholar
  79. 79.
    Turner, J. J., Ivanova, G. D., Verbeure, B., Williams, D., Arzumanov, A. A., Abes, S., Lebleu, B., and Gait, M. J. (2005) Cell-penetrating peptide conjugates of peptide nucleic acids (PNA) as inhibitors of HIV-1 Tat-dependent trans-activation in cells. Nucleic Acids Res 33, 6837–49.PubMedCrossRefGoogle Scholar
  80. 80.
    Morris, M. C., Gros, E., Aldrian-Herrada, G., Choob, M., Archdeacon, J., Heitz, F., and Divita, G. (2007) A non-covalent peptide-based carrier for in vivo delivery of DNA mimics. Nucleic Acids Res 35, e49.PubMedCrossRefGoogle Scholar
  81. 81.
    Simeoni, F., Morris, M. C., Heitz, F., and Divita, G. (2005) Peptide-based strategy for siRNA delivery into mammalian cells. Methods Mol Biol 309, 251–60.PubMedGoogle Scholar
  82. 82.
    Meade, B. R., and Dowdy, S. F. (2007) Exogenous siRNA delivery using peptide transduction domains/cell penetrating peptides. Adv Drug Deliv Rev 59, 134–40.PubMedCrossRefGoogle Scholar
  83. 83.
    Lundberg, P., El-Andaloussi, S., Sutlu, T., Johansson, H., and Langel, Ü. (2007) Delivery of short interfering RNA using endosomolytic cell-penetrating peptides. FASEB J 21, 2664–71.PubMedCrossRefGoogle Scholar
  84. 84.
    Mäe, M., El Andaloussi, S., Lundin, P., Oskolkov, N., Johansson, H. J., Guterstam, P., and Langel, Ü. (2009) A stearylated CPP for delivery of splice correcting oligonucleotides using a non-covalent co-incubation strategy. J Control Release 134, 221–7.PubMedCrossRefGoogle Scholar
  85. 85.
    Khafagy El, S., Morishita, M., Isowa, K., Imai, J., and Takayama, K. (2009) Effect of cell-penetrating peptides on the nasal absorption of insulin. J Control Release 133, 103–8.CrossRefGoogle Scholar
  86. 86.
    Johnson, L. N., Cashman, S. M., and Kumar-Singh, R. (2008) Cell-penetrating peptide for enhanced delivery of nucleic acids and drugs to ocular tissues including retina and cornea. Mol Ther 16, 107–14.PubMedCrossRefGoogle Scholar
  87. 87.
    Eguchi, A., Meade, B. R., Chang, Y. C., Fredrickson, C. T., Willert, K., Puri, N., and Dowdy, S. F. (2009) Efficient siRNA delivery into primary cells by a peptide transduction domain-dsRNA binding domain fusion protein. Nat Biotechnol 27, 567–71.PubMedCrossRefGoogle Scholar
  88. 88.
    Vivés, E., Schmidt, J., and Pelegrin, A. (2008) Cell-penetrating and cell-targeting peptides in drug delivery. Biochim Biophys Acta 1786, 126–38.PubMedGoogle Scholar
  89. 89.
    Jiang, T., Olson, E. S., Nguyen, Q. T., Roy, M., Jennings, P. A., and Tsien, R. Y. (2004) Tumor imaging by means of proteolytic activation of cell-penetrating peptides. Proc Natl Acad Sci U S A 101, 17867–72.PubMedCrossRefGoogle Scholar
  90. 90.
    Pipkorn, R., Waldeck, W., Spring, H., Jenne, J. W., and Braun, K. (2006) Delivery of substances and their target-specific topical activation. Biochim Biophys Acta 1758, 606–10.PubMedCrossRefGoogle Scholar
  91. 91.
    Sethuraman, V. A., and Bae, Y. H. (2007) TAT peptide-based micelle system for potential active targeting of anti-cancer agents to acidic solid tumors. J Control Release 118, 216–24.PubMedCrossRefGoogle Scholar
  92. 92.
    Aroui, S., Brahim, S., Hamelin, J., De Waard, M., Breard, J., and Kenani, A. (2009) Conjugation of doxorubicin to cell-penetrating peptides sensitizes human breast MDA-MB 231 cancer cells to endogenous TRAIL-induced apoptosis. Apoptosis 14, 1352–65.PubMedCrossRefGoogle Scholar
  93. 93.
    Maxwell, D., Chang, Q., Zhang, X., Barnett, E. M., and Piwnica-Worms, D. (2009) An improved cell-penetrating, caspase-activatable, near-infrared fluorescent peptide for apoptosis imaging. Bioconjug Chem 20, 702–9.PubMedCrossRefGoogle Scholar
  94. 94.
    Orive, G., Hernandez, R. M., Rodriguez Gascon, A., Dominguez-Gil, A., and Pedraz, J. L. (2003) Drug delivery in biotechnology: present and future. Curr Opin Biotechnol 14, 659–64.PubMedCrossRefGoogle Scholar
  95. 95.
    Amantana, A., Moulton, H. M., Cate, M. L., Reddy, M. T., Whitehead, T., Hassinger, J. N., Youngblood, D. S., and Iversen, P. L. (2007) Pharmacokinetics, biodistribution, stability and toxicity of a cell-penetrating peptide-morpholino oligomer conjugate. Bioconjug Chem 18, 1325–31.PubMedCrossRefGoogle Scholar
  96. 96.
    Pujals, S., Fernandez-Carneado, J., Ludevid, M. D., and Giralt, E. (2008) D-SAP: a new, noncytotoxic, and fully protease resistant cell-penetrating peptide. ChemMedChem 3, 296–301.PubMedCrossRefGoogle Scholar
  97. 97.
    Neundorf, I., Rennert, R., Franke, J., Kozle, I., and Bergmann, R. (2008) Detailed analysis concerning the biodistribution and metabolism of human calcitonin-derived cell-penetrating peptides. Bioconjug Chem 19, 1596–603.PubMedCrossRefGoogle Scholar
  98. 98.
    Weiss, H. M., Wirz, B., Schweitzer, A., Amstutz, R., Rodriguez Perez, M. I., Andres, H., Metz, Y., Gardiner, J., and Seebach, D. (2007) ADME investigations of unnatural peptides: distribution of a 14C-labeled beta 3-octaarginine in rats. Chem Biodivers 4, 1413–37.PubMedCrossRefGoogle Scholar
  99. 99.
    Torchilin, V. P. (2007) Targeted pharmaceutical nanocarriers for cancer therapy and imaging. AAPS J 9, E128–47.PubMedCrossRefGoogle Scholar
  100. 100.
    Brooks, N. A., Pouniotis, D. S., Tang, C. K., Apostolopoulos, V., and Pietersz, G. A. (2010) Cell penetrating peptides: application in vaccine delivery. Biochim Biophys Acta 1805, 25–34.PubMedGoogle Scholar
  101. 101.
    Lebleu, B., Moulton, H. M., Abes, R., Ivanova, G. D., Abes, S., Stein, D. A., Iversen, P. L., Arzumanov, A. A., and Gait, M. J. (2008) Cell penetrating peptide conjugates of steric block oligonucleotides. Adv Drug Deliv Rev 60, 517–29.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Cepep II ABStockholmSweden
  2. 2.Department of NeurochemistryStockholm UniversityStockholmSweden
  3. 3.Laboratory of Molecular Biotechnology, Institute of TechnologyTartu UniversityTartuEstonia

Personalised recommendations