Skip to main content

Targeting the Choroid Plexus-CSF-Brain Nexus Using Peptides Identified by Phage Display

  • Protocol
  • First Online:
The Blood-Brain and Other Neural Barriers

Part of the book series: Methods in Molecular Biology ((MIMB,volume 686))

Abstract

Drug delivery to the central nervous system requires the use of specific portals to enable drug entry into the brain and, as such, there is a growing need to identify processes that can enable drug transfer across both blood-brain and blood–cerebrospinal fluid barriers. Phage display is a powerful combinatorial technique that identifies specific peptides that can confer new activities to inactive particles. Identification of these peptides is directly dependent on the specific screening strategies used for their selection and retrieval. This chapter describes three selection strategies, which can be used to identify peptides that target the choroid plexus (CP) directly or for drug translocation across the CP and into cerebrospinal fluid.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Smith GP (1985) Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science 228:1315–1317

    Article  CAS  PubMed  Google Scholar 

  2. Barbas CF (2001) Phage display: a laboratory manual. Cold Spring Harbor: Cold Spring Harbor Laboratory

    Google Scholar 

  3. Pasqualini R, Arap W, McDonald DM (2002) Probing the structural and molecular diversity of tumor vasculature. Trends Mol Med 8:563–571

    Article  CAS  PubMed  Google Scholar 

  4. Larocca D, Baird A (2001) Receptor-mediated gene transfer by phage-display vectors: applications in functional genomics and gene therapy. Drug Discov Today 6:793–801

    Article  CAS  PubMed  Google Scholar 

  5. Larocca D, Burg MA, Jensen-Pergakes K, Ravey EP, Gonzalez AM, Baird A (2002) Evolving phage vectors for cell targeted gene delivery. Curr Pharm Biotechnol 3:45–57

    Article  CAS  PubMed  Google Scholar 

  6. Larocca D, Jensen-Pergakes K, Burg MA, Baird A (2001) Receptor-targeted gene delivery using multivalent phagemid particles. Mol Ther 3:476–484

    Article  CAS  PubMed  Google Scholar 

  7. Larocca D, Jensen-Pergakes K, Burg MA, Baird A (2002) Gene transfer using targeted filamentous bacteriophage. Methods Mol Biol 185:393–401

    CAS  PubMed  Google Scholar 

  8. Larocca D, Kassner PD, Witte A, Ladner RC, Pierce GF, Baird A (1999) Gene transfer to mammalian cells using genetically targeted filamentous bacteriophage. Faseb J 13:727–734

    CAS  PubMed  Google Scholar 

  9. Larocca D, Witte A, Johnson W, Pierce GF, Baird A (1998) Targeting bacteriophage to mammalian cell surface receptors for gene delivery. Hum Gene Ther 9:2393–2399

    Article  CAS  PubMed  Google Scholar 

  10. Hart SL, Knight AM, Harbottle RP, Mistry A, Hunger HD, Cutler DF, Williamson R, Coutelle C (1994) Cell binding and internalization by filamentous phage displaying a cyclic Arg-Gly-Asp-containing peptide. J Biol Chem 269:12468–12474

    CAS  PubMed  Google Scholar 

  11. Ivanenkov VV, Menon AG (2000) Peptide-mediated transcytosis of phage display vectors in MDCK cells. Biochem Biophys Res Commun 276:251–257

    Article  CAS  PubMed  Google Scholar 

  12. Merril CR, Biswas B, Carlton R, Jensen NC, Creed GJ, Zullo S, Adhya S (1996) Long-circulating bacteriophage as antibacterial agents. Proc Natl Acad Sci U S A 93:3188–3192

    Article  CAS  PubMed  Google Scholar 

  13. Muruganandam A, Tanha J, Narang S, Stanimirovic D (2002) Selection of phage-displayed llama single-domain antibodies that transmigrate across human blood-brain barrier endothelium. Faseb J 16:240–242

    CAS  PubMed  Google Scholar 

  14. Pasqualini R (1999) Vascular targeting with phage peptide libraries. Q J Nucl Med 43:159–162

    CAS  PubMed  Google Scholar 

  15. Pasqualini R, Ruoslahti E (1996) Organ targeting in vivo using phage display peptide libraries. Nature 380:364–366

    Article  CAS  PubMed  Google Scholar 

  16. Pasqualini R, Ruoslahti E (1996) Searching for a molecular address in the brain. Mol Psychiatry 1:421–422

    CAS  PubMed  Google Scholar 

  17. Pasqualini R, Ruoslahti E (1996) Tissue targeting with phage peptide libraries. Mol Psychiatry 1:423

    CAS  PubMed  Google Scholar 

  18. Petrenko VA, Smith GP (2000) Phage from landscape libraries as substitute antibodies. Protein Eng 13:589–592

    Article  CAS  PubMed  Google Scholar 

  19. Petrenko VA, Smith GP, Gong X, Quinn T (1996) A library of organic landscapes on filamentous phage. Protein Eng 9:797–801

    Article  CAS  PubMed  Google Scholar 

  20. Poul MA, Marks JD (1999) Targeted gene delivery to mammalian cells by filamentous bacteriophage. J Mol Biol 288:203–211

    Article  CAS  PubMed  Google Scholar 

  21. Rajotte D, Arap W, Hagedorn M, Koivunen E, Pasqualini R, Ruoslahti E (1998) Molecular heterogeneity of the vascular endothelium revealed by in vivo phage display. J Clin Invest 102:430–437

    Article  CAS  PubMed  Google Scholar 

  22. Sokoloff AV, Bock I, Zhang G, Sebestyen MG, Wolff JA (2000) The interactions of peptides with the innate immune system studied with use of T7 phage peptide display. Mol Ther 2:131–139

    Article  CAS  PubMed  Google Scholar 

  23. Yip YL, Hawkins NJ, Smith G, Ward RL (1999) Biodistribution of filamentous phage-Fab in nude mice. J Immunol Methods 225:171–178

    Article  CAS  PubMed  Google Scholar 

  24. Koivunen E, Arap W, Valtanen H, Rainisalo A, Medina OP, Heikkila P, Kantor C, Gahmberg CG, Salo T, Konttinen YT, Sorsa T, Ruoslahti E, Pasqualini R (1999) Tumor targeting with a selective gelatinase inhibitor. Nat Biotechnol 17:768–774

    Article  CAS  PubMed  Google Scholar 

  25. Koivunen E, Restel BH, Rajotte D, Lahdenranta J, Hagedorn M, Arap W, Pasqualini R (1999) Integrin-binding peptides derived from phage display libraries. Methods Mol Biol 129:3–17

    CAS  PubMed  Google Scholar 

  26. Trepel M, Arap W, Pasqualini R (2000) Exploring vascular heterogeneity for gene therapy targeting. Gene Ther 7:2059–2060

    Article  CAS  PubMed  Google Scholar 

  27. Trepel M, Grifman M, Weitzman MD, Pasqualini R (2000) Molecular adaptors for vascular-targeted adenoviral gene delivery. Hum Gene Ther 11:1971–1981

    Article  CAS  PubMed  Google Scholar 

  28. Burg MA, Jensen-Pergakes K, Gonzalez AM, Ravey P, Baird A, Larocca D (2002) Enhanced phagemid particle gene transfer in camptothecin-treated carcinoma cells. Cancer Res 62:977–981

    CAS  PubMed  Google Scholar 

  29. Burg M, Ravey EP, Gonzales M, Amburn E, Faix PH, Baird A, Larocca D (2004) Selection of internalizing ligand-display phage using rolling circle amplification for phage recovery. DNA Cell Biol 23:457–462

    Article  CAS  PubMed  Google Scholar 

  30. Kassner PD, Burg MA, Baird A, Larocca D (1999) Genetic selection of phage engineered for receptor-mediated gene transfer to mammalian cells. Biochem Biophys Res Commun 264:921–928

    Article  CAS  PubMed  Google Scholar 

  31. Chodobski A, Szmydynger-Chodobska J (2001) Choroid plexus: target for polypeptides and site of their synthesis. Microsc Res Tech 52:65–82

    Article  CAS  PubMed  Google Scholar 

  32. Emerich DF, Vasconcellos AV, Elliott RB, Skinner SJ, Borlongan CV (2004) The choroid plexus: function, pathology and therapeutic potential of its transplantation. Expert Opin Biol Ther 4:1191–1201

    Article  CAS  PubMed  Google Scholar 

  33. Ghersi-Egea JF, Strazielle N (2002) Choroid plexus transporters for drugs and other xenobiotics. J Drug Target 10:353–357

    Article  CAS  PubMed  Google Scholar 

  34. Johanson CE, Duncan JA, Stopa EG, Baird A (2005) Enhanced prospects for drug delivery and brain targeting by the choroid plexus-CSF route. Pharm Res 22:1011–1037

    Article  CAS  PubMed  Google Scholar 

  35. Silverberg GD, Huhn S, Jaffe RA, Chang SD, Saul T, Heit G, Von Essen A, Rubenstein E (2002) Downregulation of cerebrospinal fluid production in patients with chronic hydrocephalus. J Neurosurg 97:1271–1275

    Article  PubMed  Google Scholar 

  36. Spector R, Johanson C (2006) Micronutrient and urate transport in choroid plexus and kidney: implications for drug therapy. Pharm Res 23:2515–2524

    Article  CAS  PubMed  Google Scholar 

  37. Carro E, Spuch C, Trejo JL, Antequera D, Torres-Aleman I (2005) Choroid plexus megalin is involved in neuroprotection by serum insulin-like growth factor I. J Neurosci 25:10884–10893

    Article  CAS  PubMed  Google Scholar 

  38. Hakvoort A, Haselbach M, Galla HJ (1998) Active transport properties of porcine choroid plexus cells in culture. Brain Res 795:247–256

    Article  CAS  PubMed  Google Scholar 

  39. Johanson CE, Gonzalez AM, Stopa EG (2001) Water-imbalance-induced expression of FGF-2 in fluid-regulatory centers: choroid plexus and neurohypophysis. Eur J Pediatr Surg 11 Suppl 1:S37–38

    PubMed  Google Scholar 

  40. Liao CW, Fan CK, Kao TC, Ji DD, Su KE, Lin YH, Cho WL (2008) Brain injury-associated biomarkers of TGF-beta1, S100B, GFAP, NF-L, tTG, AbetaPP, and tau were concomitantly enhanced and the UPS was impaired during acute brain injury caused by Toxocara canis in mice. BMC Infect Dis 8:84

    Article  PubMed  Google Scholar 

  41. Parandoosh Z, Johanson CE (1982) Ontogeny of blood-brain barrier permeability to, and cerebrospinal fluid sink action on, [14C] urea. Am J Physiol 243:R400–407

    CAS  PubMed  Google Scholar 

  42. Schreiber G (2002) The evolution of transthyretin synthesis in the choroid plexus. Clin Chem Lab Med 40:1200–1210

    Article  CAS  PubMed  Google Scholar 

  43. Borlongan CV, Thanos CG, Skinner SJ, Geaney M, Emerich DF (2008) Transplants of encapsulated rat choroid plexus cells exert neuroprotection in a rodent model of Huntington’s disease. Cell Transplant 16:987–992

    Article  PubMed  Google Scholar 

  44. Emerich DF, Skinner SJ, Borlongan CV, Thanos CG (2005) A role of the choroid plexus in transplantation therapy. Cell Transplant 14:715–725

    Article  PubMed  Google Scholar 

  45. Johanson CE, Szmydynger-Chodobska J, Chodobski A, Baird A, McMillan P, Stopa EG (1999) Altered formation and bulk absorption of cerebrospinal fluid in FGF-2-induced hydrocephalus. Am J Physiol 277:R263–271

    CAS  PubMed  Google Scholar 

  46. Logan A, Frautschy SA, Gonzalez AM, Sporn MB, Baird A (1992) Enhanced expression of transforming growth factor beta 1 in the rat brain after a localized cerebral injury. Brain Res 587:216–225

    Article  CAS  PubMed  Google Scholar 

  47. Stopa EG, Berzin TM, Kim S, Song P, Kuo-LeBlanc V, Rodriguez-Wolf M, Baird A, Johanson CE (2001) Human choroid plexus growth factors: What are the implications for CSF dynamics in Alzheimer’s disease? Exp Neurol 167:40–47

    Article  CAS  PubMed  Google Scholar 

  48. Strazielle N, Ghersi-Egea JF (1999) Demonstration of a coupled metabolism-efflux process at the choroid plexus as a mechanism of brain protection toward xenobiotics. J Neurosci 19:6275–6289

    CAS  PubMed  Google Scholar 

  49. Vercellino M, Votta B, Condello C, Piacentino C, Romagnolo A, Merola A, Capello E, Mancardi GL, Mutani R, Giordana MT, Cavalla P (2008) Involvement of the choroid plexus in multiple sclerosis autoimmune inflammation: a neuropathological study. J Neuroimmunol 199:133–141

    Article  CAS  PubMed  Google Scholar 

  50. Saggio I, Gloaguen I, Laufer R (1995) Functional phage display of ciliary neurotrophic factor. Gene 152:35–39

    Article  CAS  PubMed  Google Scholar 

  51. Buchli PJ, Wu Z, Ciardelli TL (1997) The functional display of interleukin-2 on filamentous phage. Arch Biochem Biophys 339:79–84

    Article  CAS  PubMed  Google Scholar 

  52. Hosoya K, Hori S, Ohtsuki S, Terasaki T (2004) A new in vitro model for blood-cerebrospinal fluid barrier transport studies: an immortalized choroid plexus epithelial cell line derived from the tsA58 SV40 large T-antigen gene transgenic rat. Adv Drug Deliv Rev 56:1875–1885

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by the National Institutes of Health (USA) and the Biochemistry and Biotechnology Research Council (UK). The authors would like to thank Drs. Paul Kassner and David Larocca who first engineered the initial EGF-displayed phage that helped establish the feasibility of CP targeting, Dr. Michael Burg who helped identify CP-targeting peptides in peptide libraries, and Ms. Emelie Amburn and Dr. Karen Sims who assisted in their characterization.

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Baird, A., Eliceiri, B.P., Gonzalez, A.M., Johanson, C.E., Leadbeater, W., Stopa, E.G. (2011). Targeting the Choroid Plexus-CSF-Brain Nexus Using Peptides Identified by Phage Display. In: Nag, S. (eds) The Blood-Brain and Other Neural Barriers. Methods in Molecular Biology, vol 686. Humana Press. https://doi.org/10.1007/978-1-60761-938-3_25

Download citation

  • DOI: https://doi.org/10.1007/978-1-60761-938-3_25

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60761-937-6

  • Online ISBN: 978-1-60761-938-3

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics