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Polyarginine segments in block copolypeptides drive both vesicular assembly and intracellular delivery


Polymeric vesicles are a relatively new class of nanoscale self-assembled materials that show great promise as robust encapsulants. Compared with liposomes, use of polymeric building blocks for membrane formation allows increased stability, stimuli responsiveness and chemical diversity, which may prove advantageous for drug-delivery applications 1. A major drawback of most polymeric vesicles is the lack of biofunctionality, which restricts their ability to interact with cells and tissues. We have prepared vesicles composed of polyarginine and polyleucine segments that are stable in media, can entrap water soluble species, and can be processed to different sizes and prepared in large quantities. The remarkable feature of these materials is that the polyarginine segments both direct structure for vesicle formation and provide functionality for efficient intracellular delivery of the vesicles. This unique synergy between nanoscale self-assembly and inherent peptide functionality provides a new approach for design of multifunctional materials for drug delivery.

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Figure 1: Formation and properties of R60L20 vesicles.
Figure 2: Transport of polypeptide vesicles across bulk membranes.
Figure 3: Transport of polypeptide vesicles into cells in vitro.


  1. 1

    Discher, D. E. & Eisenberg, A. Polymer vesicles. Science 297, 967–973 (2002).

    CAS  Article  Google Scholar 

  2. 2

    Holowka, E. P., Pochan, D. J. & Deming, T. J. Charged polypeptide vesicles with controllable diameter. J. Am. Chem. Soc. 127, 12423–12428 (2005).

    CAS  Article  Google Scholar 

  3. 3

    Rothbard, J. B., Jessop, T. C. & Wender, P. A. 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 (2005).

    CAS  Article  Google Scholar 

  4. 4

    Futaki, S. Membrane-permeable arginine-rich peptides and the translocation mechanisms. Adv. Drug Deliv. Rev. 57, 547–558 (2005).

    CAS  Article  Google Scholar 

  5. 5

    Brooks, H., Lebleu, B. & Vivès, E. Tat peptide-mediated cellular delivery: back to basics. Adv. Drug Deliv. Rev. 57, 559–577 (2005).

    CAS  Article  Google Scholar 

  6. 6

    Wadia, J. S. & Dowdy, S. F. Transmembrane delivery of protein and peptide drugs by TAT-mediated transduction in the treatment of cancer. Adv. Drug Deliv. Rev. 57, 579–596 (2005).

    CAS  Article  Google Scholar 

  7. 7

    Calnan, B. J., Tidor, B., Biancalana, S., Hudson, D. & Frankel, A. D. Arginine-mediated RNA recognition: the arginine fork. Science 252, 1167–1171 (1991).

    CAS  Article  Google Scholar 

  8. 8

    Mitchell, D. J., Kim, D. T., Steinman, L., Fathman, C. G. & Rothbard, J. B. Polyarginine enters cells more efficiently than other polycationic homopolymers. J. Peptide Res. 56, 318–325 (2000).

    CAS  Article  Google Scholar 

  9. 9

    Rothbard, J. B. et al. Conjugation of arginine oligomers to cyclosporin A facilitates topical delivery and inhibition of inflammation. Nature Med. 6, 1253–1257 (2000).

    CAS  Article  Google Scholar 

  10. 10

    Torchilin, V. P., Rammohan, R., Weissig, V. & Levchenko, T. S. TAT peptide on the surface of liposomes affords their efficient intracellular delivery even at low temperature and in the presence of metabolic inhibitors. Proc. Natl Acad. Sci. USA 98, 8786–8791 (2001).

    CAS  Article  Google Scholar 

  11. 11

    Tseng, Y.-L., Liu, J.-J. & Hong, R.-L. Translocation of liposomes into cancer cells by cell-penetrating peptides penetratin and tat: A kinetic and efficacy study. Mol. Pharmacol. 62, 864–872 (2002).

    CAS  Article  Google Scholar 

  12. 12

    Bermudez, H., Brannan, A. K., Hammer, D. A., Bates, F. S. & Discher, D. E. Molecular weight dependence of polymersome membrane structure, elasticity, and stability. Macromolecules 35, 8203–8208 (2002).

    CAS  Article  Google Scholar 

  13. 13

    Rodriguez-Hernandez, J. & Lecommandoux, S. Reversible inside-out micellization of pH-responsive and water-soluble vesicles based on polypeptide diblock copolymers. J. Am. Chem. Soc. 127, 2026–2027 (2005).

    CAS  Article  Google Scholar 

  14. 14

    Ranquin, A., Versees, W., Meier, W., Steyaert, J. & Van Gelder, P. Therapeutic nanoreactors: Combining chemistry and biology in a novel triblock copolymer drug delivery system. Nano Lett. 5, 2220–2224 (2005).

    CAS  Article  Google Scholar 

  15. 15

    Deming, T. J. Facile synthesis of block copolypeptides of defined architecture. Nature 390, 386–389 (1997).

    CAS  Article  Google Scholar 

  16. 16

    Discher, B. M., Hammer, D. A., Bates, F. S. & Discher, D. E. Polymer vesicles in various media. Curr. Opin. Colloid Interface Sci. 5, 125–145 (2000).

    CAS  Article  Google Scholar 

  17. 17

    Sakai, N. & Matile, S. Anion-mediated transfer of polyarginine across liquid and bilayer membranes. J. Am. Chem. Soc. 125, 14348–14356 (2003).

    CAS  Article  Google Scholar 

  18. 18

    Rothbard, J. B., Jessop, T. C., Lewis, R. S., Murray, B. A. & Wender, P. A. Role of membrane potential and hydrogen bonding in the mechanism of translocation of guanidinium-rich peptides into cells. J. Am. Chem. Soc. 126, 9506–9507 (2004).

    CAS  Article  Google Scholar 

  19. 19

    Wadia, J. S., Stan, R. V. & Dowdy, S. F. Transducible TAT-HA fusogenic peptide enhances escape of TAT-fusion proteins after lipid raft macropinocytosis. Nature Med. 10, 310–315 (2004).

    CAS  Article  Google Scholar 

  20. 20

    Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods 65, 55–63 (1983).

    CAS  Article  Google Scholar 

  21. 21

    Pakstis, L., Ozbas, B., Nowak, A. P., Deming, T. J. & Pochan, D. J. The effect of chemistry and morphology on the biofunctionality of self-assembling diblock copolypeptide hydrogels. Biomacromolecules 5, 312–318 (2004).

    CAS  Article  Google Scholar 

  22. 22

    Sela, M. & Katchalski, E. Biological properties of poly α-amino acids. Adv. Protein Chem. 14, 391–478 (1959).

    CAS  Article  Google Scholar 

  23. 23

    Deming, T. J. Cobalt and iron initiators for the controlled polymerization of alpha-amino acid-N-carboxyanhydrides. Macromolecules 32, 4500–4502 (1999).

    CAS  Article  Google Scholar 

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This work was supported by a grant from the National Science Foundation (CHE-0415275) to T.J.D. and by a Sidney Kimmel Scholar Award to D.T.K.

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E.P.H. and V.Z.S.: experimental work and data analysis; T.J.D. and D.T.K.: project planning, data analysis and manuscript writing.

Corresponding author

Correspondence to Timothy J. Deming.

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The authors declare no competing financial interests.

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Supplementary information and figures S1-S3 (PDF 185 kb)

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Holowka, E., Sun, V., Kamei, D. et al. Polyarginine segments in block copolypeptides drive both vesicular assembly and intracellular delivery. Nature Mater 6, 52–57 (2007).

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