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Peptide delivery to the brain via adsorptive-mediated endocytosis: Advances with SynB vectors

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Abstract

Biological membranes normally restrict the passage of hydrophilic molecules. This impairs the use of a wide variety of drugs for biomedical applications. To overcome this problem, researchers have developed strategies that involve conjugating the molecule of interest to one of a number of peptide entities that are efficiently transported across the cell membranes. In the past decade, a number of different peptide families with the ability to cross the cell membranes have been identified. Certain of these families enter the cells by a receptor-independent mechanism, are short (10–27 amino acid residues), and can deliver successfully various cargoes across the cell membrane into the cytoplasm or nucleus. Surprisingly, some of these vectors, the SynB vectors, have also shown the ability to deliver hydrophilic molecules across the blood-brain barrier, one of the major obstacles to the development of drugs to combat diseases affecting the CNS.

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References

  1. Brightman MW. Morphology of blood-brain interfaces. Exp Eye Res. 1977;25:1–25.

    Article  PubMed  Google Scholar 

  2. Pardridge WM. New approaches to drug delivery through the blood-brain barrier. Trends Biotechnol. 1994;12:239–245.

    Article  CAS  PubMed  Google Scholar 

  3. Pardridge WM. Brain Drug Targeting: The Future of Brain Drug Development. Cambridge, UK: Cambridge University Press; 2001.

    Book  Google Scholar 

  4. Jolliet-Riant P, Tillement JP. Drug transfer across the blood-brain barrier and improvement of brain delivery. Fundam Clin Pharmacol. 1999;13:16–26.

    Article  CAS  PubMed  Google Scholar 

  5. Temsamani J, Rousselle, C, Rees AR, Schermann JM. Vector-mediated drug delivery to the brain. Expert Opin Biol Ther. 2001;1:773–782.

    Article  CAS  PubMed  Google Scholar 

  6. Lindgren M, Hällbrink M, Prochiantz A, Langel U. Cell-penetrating peptides. Trends Pharmacol Sci. 2000;21:99–103.

    Article  CAS  PubMed  Google Scholar 

  7. Langel U. Cell, Penetrating Peptides: Processes and Applications. New York, NY: CRC Press: 2002.

    Google Scholar 

  8. Oehlke J, Scheller A, Wiesner B, et al. 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. 1998;1414:127–139.

    Article  CAS  PubMed  Google Scholar 

  9. Derossi D, Joliot AH, Chassaing G, Prochiantz A. The third helix of the Antennapedia homeodomain translocates through biological membrane. J Biol Chem. 1994;269:10444–10450.

    CAS  PubMed  Google Scholar 

  10. Pooga M, Hällbrink M, Zorko M, Langel U. Cell penetration by transportan. FASEB J. 1998;12:67–77.

    CAS  PubMed  Google Scholar 

  11. Chaloin L, Vidal P, Heitz A, et al. Conformations of primary amphipathic carrier peptides in membrane mimicking environments. Biochemistry. 1997;36:11179–11187.

    Article  CAS  PubMed  Google Scholar 

  12. Vidal P, Chaloin L, Heitz A, et al. Interactions of primary amphipathic vector peptides with membranes; conformational consequences and influence on cellular localization. J Membr Biol. 1998;162:259–264.

    Article  CAS  PubMed  Google Scholar 

  13. Vivès E, Brodin P, Lebleu B. A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. J Biol Chem. 1997;272:16010–16077.

    Article  PubMed  Google Scholar 

  14. Rousselle C, Clair P, Lefauconnier JM, Kaczorek M, Scherrmann JM, Temsamani J. New advances in the transport of doxorubicin through the blood-brain barrier by a peptide vector-mediated strategy. Mol Pharmacol. 2000;57:679–686.

    CAS  PubMed  Google Scholar 

  15. Rousselle C, Smirnova M, Clair P, et al. Enhanced delivery of doxorubicin into the brain via a peptide-vector-mediated strategy: saturation kinetics and specificity. J Pharmacol Exp Ther. 2001;296:124–131.

    CAS  PubMed  Google Scholar 

  16. Scheller A, Oehlke J, Wiesner B, et al. Structural requirements for cellular uptake of alpha-helical amphipathic peptides. J Pept Sci. 1999;5:185–194.

    Article  CAS  PubMed  Google Scholar 

  17. Dathe M, Schümann M, Wieprecht T, et al. Peptide helicity and membrane surface charge modulate the balance of electrostatic and hydrophobic interactions with lipid bilayers and biological membranes. Biochemistry. 1996;35:12612–12622.

    Article  CAS  PubMed  Google Scholar 

  18. Drin G, Déméné H, Temsamani J, Brasseur R. Translocation of the pAntp peptide and its amphipathic analogue AP-2AL. Biochemistry. 2001;40:1824–1834.

    Article  CAS  PubMed  Google Scholar 

  19. Persson D, Thorén PE, Nordén B. Penetratin-induced aggregation and subsequent dissociation of negatively charged phospholipid vesicles. FEBS Lett. 2001;505:307–312.

    Article  CAS  PubMed  Google Scholar 

  20. Hällbrink M, Florén A, Elmquist A, Pooga M, Bartfai T, Langel U. Cargo delivery kinetics of cell-penetrating peptides. Biochim Biophys Acta. 2001;1515:101–109.

    Article  PubMed  Google Scholar 

  21. Magzoub M, Kilk K, Eriksson LE, Langel U, Gräslund A. Interaction and structure induction of cell-penetrating peptides in the presence of phospholipid vesicles. Biochim Biophys Acta. 2001;1512:77–89.

    Article  CAS  PubMed  Google Scholar 

  22. Kokryakov VN, Harwig SS, Panyutich EA, et al. Protegrins: leukocyte antimicrobial peptides that combine features of corticostatic defensins and tachyplesins. FEBS Lett 1993;327:231–236.

    Article  CAS  PubMed  Google Scholar 

  23. Aumelas A, Mangoni M, Roumestand C, et al. Synthesis and solution structure of the antimicrobial peptide protegrin-1. Eur J Biochem. 1996;237:575–583.

    Article  CAS  PubMed  Google Scholar 

  24. Mangoni ME, Aumelas A, Charnet P, et al. Change in membrane permeability induced by protegrin 1: implication of disulphide bridges for pore formation. FEBS Lett. 1996;383:93–98.

    Article  CAS  PubMed  Google Scholar 

  25. Sokolov Y, Mirzabekov T, Martin DW, Lehrer RI, Kagan BL. Membrane channel formation by antimicrobial protegrins. Biochim Biophys Acta. 1999;1420:23–29.

    Article  CAS  PubMed  Google Scholar 

  26. Joliot A, Pernelle C, Deagostini-Bazin H, Prochiantz A. Antennapedia homeobox peptide regulates neural morphogenesis. Proc Natl Acad Sci U S A. 1991;88:1864–1868.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Le Roux I, Joliot A, Bloch-Gallego E, Prochiantz A, Volovitch M. Neurotrophic activity of the Antennapedia homeodomain depends on its specific DNA-binding properties. Proc Natl Acad Sci U S A. 1993;90:9120–9124.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Derossi D, Calvet S, Trembleau A, Brunissen A, Chassaing G, Prochiantz A. Cell internalization of the third-helix of the antennapedia homeodomain is receptor-independent. J Biol Chem. 1996;271:18188–18193.

    Article  CAS  PubMed  Google Scholar 

  29. Brudigou J, Legrand C, Méry J, Rabié A. The retro-inverso form of a homeobox-derived short peptide is rapidly internalised by cultured neurones: a new basis for an efficient intracellular delivery system. Biochem Biophys Res Commun. 1995;214:685–693.

    Article  Google Scholar 

  30. Fenton M, Bone N, Sinclair A. The efficient and rapid import of a peptide into primary B and T lymphocytes and a lymphoblastoid cell line. J Immunol Methods. 1998;212:41–48.

    Article  CAS  PubMed  Google Scholar 

  31. Frankel AD, Pabo CO. Cellular uptake of the tat protein from human immunodeficiency virus. Cell. 1988;55:1189–1193.

    Article  CAS  PubMed  Google Scholar 

  32. Fawell S, Seery J, Daikh Y, et al. Tat-mediated delivery of heterologous proteins into cells. Proc Natl Acad Sci U S A. 1994;91:664–668.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Suzuki T, Futaki S, Niwa M, Tanaka S, Ueda K, Sugiura Y. Possible existence of common internalization mechanisms among argininerich peptides. J Biol Chem 2001;277:2437–2443.

    Article  CAS  PubMed  Google Scholar 

  34. Mitchell DJ, Kim DT, Steinman L, Fathman CG, Rothbard JB. Polyarginine enters cells more efficiently than other polycationic homopolymers. J Peptide Res. 2000;56:318–325.

    Article  CAS  Google Scholar 

  35. Derossi D, Williams EJ, Green PJ, Dunican DJ, Doherty P. Stimulation of mitogenesis by a cell-permeable PI 3-kinase binding peptide. Biochem Biophys Res Commun. 1998;251:148–152.

    Article  CAS  PubMed  Google Scholar 

  36. Hall H, Williams EJ, Moore SE, Walsh FS, Prochiantz A, Doherty P. Inhibition of FGF-stimulated phosphatidylinositol hydrolysis and neurite outgrowth by a cell-membrane permeable phosphopeptide. Curr Biol. 1996;6:580–587.

    Article  CAS  PubMed  Google Scholar 

  37. Williams EJ, Dunican DJ, Green PJ, et al. Selective inhibition of growth factor-stimulated mitogenesis by a cell-permeable Grb2-binding peptide. J Biol Chem. 1997;272:22349–22354.

    Article  CAS  PubMed  Google Scholar 

  38. Bardelli A, Longati P, Williams TA, Benvenuti S, Comoglio PM. A peptide representing the carboxyl-terminal tail of the met receptor inhibits kinase activity and invasive growth. J Biol Chem. 1999;274:29274–29281.

    Article  CAS  PubMed  Google Scholar 

  39. Cussac D, Vidal M, Leprince C, et al. A Sos-derived peptidimer blocks the Ras signaling pathway by binding both Grb2 SH3 domains and displays antiproliferative activity. FASEB J. 1999;13:31–38.

    CAS  PubMed  Google Scholar 

  40. Mutoh M, Lung FD, Long YQ, Roller PP, Sikorski RS, O Connor PM. A p21(Waf1/Cip1)carboxyl-terminal peptide exhibited cyclin-dependent kinase-inhibitory activity and cytotoxicity when introduced into human cells. Cancer Res. 1999;59:3480–3488.

    CAS  PubMed  Google Scholar 

  41. Bonfanti M, Taverna S, Salmona M, D Incalci M, Broggini M. p21WAF1-derived peptides linked to an internalization peptide inhibit human cancer cell growth. Cancer Res. 1997;57:1442–1446.

    CAS  PubMed  Google Scholar 

  42. Fâhraeus R, Paramio JM, Ball KL, Lain S, Lane DP. Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A. Curr Biol. 1996;6:84–91.

    Article  PubMed  Google Scholar 

  43. Ezhevsky SA, Ho A, Becker-Hapak M, Davis PK, Dowdy SF. Differential regulation of retinoblastoma tumor suppressor protein by G(1) cyclin-dependent kinase complexes in vivo. Mol Cell Biol. 2001;21:4773–4784.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Caron NJ, Torrente Y, Camirand G, et al. Intracellular delivery of a Tat-eGFP fusion protein into muscle cells. Mol Ther. 2001;3:310–318.

    Article  CAS  PubMed  Google Scholar 

  45. Embury J, Klein D, Pileggi A, et al. Proteins linked to a protein transduction domain efficiently transduce pancreatic islets. Diabetes. 2001;50:1706–1713.

    Article  CAS  PubMed  Google Scholar 

  46. Troy CM, Derossi D, Prochiantz A, Greene LA, Shelanski ML. Downregulation of Cu/Zn superoxide dismutase leads to cell death via the nitric oxide-peroxynitrite pathway. J Neurosci. 1996;16:253–261.

    CAS  PubMed  Google Scholar 

  47. Pooga M, Soomets U, Hällbrink M, et al. Cell penetrating PNA constructs regulate galanin receptor levels and modify pain transmission in vivo. Nat Biotechnol. 1998;16:857–861.

    Article  CAS  PubMed  Google Scholar 

  48. Morris MC, Vidal P, Chaloin L, Heitz F, Divita G. A new peptide vector for efficient delivery of oligonucleotides into mammalian cells. Nucleic Acids Res. 1997;25:2730–2736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Mazel M, Clair P, Rousselle C, et al. Doxorubicin-peptide conjugates overcome multidrug resistance. anticancer Drugs. 2001;12:107–116.

    Article  CAS  PubMed  Google Scholar 

  50. Gottesman MM, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem. 1993;62:385–427.

    Article  CAS  PubMed  Google Scholar 

  51. Tsuji A. P-glycoprotein-mediated efflux transport of anticancer drugs at the blood-brain barrier. Ther Drug Monit. 1998;20:588–590.

    Article  CAS  PubMed  Google Scholar 

  52. Bolton SJ, Jones DN, Darker JG, Eggleston DS, Hunter AJ, Walsh FS. Cellular uptake and spread of the cell-permeable peptide penetratin in adult rat brain. Eur J Neurosci. 2000;12:2847–2855.

    Article  CAS  PubMed  Google Scholar 

  53. Rousselle C, Clair P, Temsamani J, Scherrmann JM. Improved brain delivery of benzylpenicillin with a peptide-vector-mediated strategy. J Drug Target. 2002;10:309–315.

    Article  CAS  PubMed  Google Scholar 

  54. Schwarze SR, Ho A, VoceroAkbani A, Dowdy SF. In vivo protein transduction of a biologically active protein in the mouse. Science. 1999;285:1569–1572.

    Article  CAS  PubMed  Google Scholar 

  55. Hardebo JE, Kahrstrom J. Endothelial negative surface charge areas, and blood-brain barrier function. Acta Physiol Scand. 1985;125:495–499.

    Article  CAS  PubMed  Google Scholar 

  56. Vordbrodt AW. Ultrastructural cytochemistry of blood-brain barrier endothelia. Prog Histochem Cytochem. 1988;18:1–99.

    Google Scholar 

  57. Bar RS, DeRose A, Sandra A, Peacock ML, Owen WG. Insulin binding to microvascular endothelium of intact heart: a kinetic and morphometric analysis. Am J Physiol. 1983;244:477–482.

    Google Scholar 

  58. Virgintino D, Monaghan P, Robertson D, et al. An immunohistochemical and morphometric study on astrocytes and microvasculature in the human cerebral cortex. Histochem J. 1997;29:655–660.

    Article  CAS  PubMed  Google Scholar 

  59. Bertossi M, Virgintino D, Maiorano E, Occhiogrosso M, Roncali L. Ultrastructural and morphometric investigation of human brain capillaries in normal and peritumoral tissues. Ultrastruct Pathol. 1997;21:41–49.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Jamal Temsamani.

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Published: October 1, 2002

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Drin, G., Rousselle, C., Scherrmann, JM. et al. Peptide delivery to the brain via adsorptive-mediated endocytosis: Advances with SynB vectors. AAPS J 4, 26 (2002). https://doi.org/10.1208/ps040426

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