In an attempt to design delivery vehicles to enable epitope-based vaccine uptake, we investigated the properties of a variety of synthetic, branched cationic structures. We found that branched compounds based on arginine or lysine were able to facilitate internalization of peptide cargo into cells to different degrees. Branched constructs containing only two arginine residues (R2) were not only able to bind to cells more efficiently than constructs with two lysine residues (K2) but were also internalized within vesicle like compartments in the cell. The extent of binding and uptake was enhanced when additional arginine residues were incorporated to form a tetra arginine construct (R4). An investigation into the kinetics and dose dependence of cellular uptake of these arginine-based constructs demonstrated that binding and internalization is a rapid and efficient event. We also found uptake of the peptide epitope TYQRTRALV was enhanced when it was coupled to R4. This approach may prove useful for introducing peptide epitopes into antigen presenting cells as self-adjuvanting structures and also for delivery of other peptides into different specialized cells.
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References
Amoscato A. A., Prenovitz D. A., Lotze M. T. (1998) J. Immunol. 161:4023–4032
Apostolopoulos V., Pouniotis D. S., van Maanen P. J. et al. (2006) Vaccine 24:3191–3202
Astriab-Fisher A., Sergueev D. S., Fisher M., Shaw B. R., Juliano R. L. (2000) Biochem. Pharmacol. 60:83–90
Banchereau J., Steinman R. M. (1998) Nature 392:245–252
Bodmer H. C., Pemberton R. M., Rothbard J. B., Askonas B. A. (1988) Cell 52:253–258
Bonny C., Oberson A., Negri S., Sauser C., Schorderet D. F. (2001) Diabetes 50:77–82
Buschle M., Schmidt W., Zauner W. et al. (1997) Proc. Natl. Acad. Sci. U. S. A. 94:3256–3261
Chang A. E., Redman B. G., Whitfield J. R. et al. (2002) Clin. Cancer Res. 8:1021–1032
Dallal R. M., Lotze M. T. (2000) Curr. Opin. Immunol. 12:583–588
Derossi D., Joliot A. H., Chassaing G., Prochiantz A. (1994) J. Biol. Chem. 269:10444–10450
Dostmann W. R., Taylor M. S., Nickl C. K., Brayden J. E., Frank R., Tegge W. J. (2000) Proc. Natl. Acad. Sci. U. S. A. 97:14772–14777
Fischer R., Kohler K., Fotin-Mleczek M., Brock R. (2004) J. Biol. Chem. 279:12625–12635
Futaki S., Goto S., Sugiura Y. (2003) J. Mol. Recognit. 16:260–264
Futaki S., Suzuki T., Ohashi W. et al. (2001) J. Biol. Chem. 276:5836–5840
Hall H., Williams E. J., Moore S. E., Walsh F. S., Prochiantz A., Doherty P. (1996) Curr. Biol. 6:580–587
Hancock W. S., Battersby J. E. (1976) Anal. Biochem. 71:260–264
Hart D. N. (2001) Pathology 33:479–492
Jonuleit H., Giesecke-Tuettenberg A., Tuting T. et al. (2001) Int. J. Cancer 93:243–251
Kragol G., Hoffmann R., Chattergoon M. A. et al. (2002) Eur. J. Biochem. 269:4226–4237
Lanzavecchia A., Sallusto F. (2001) Cell 106:263–266
Lewin M., Carlesso N., Tung C. H. et al. (2000) Nat. Biotechnol. 18:410–414
Mitchell D. J., Kim D. T., Steinman L., Fathman C. G., Rothbard J. B. (2000) J. Pept. Res. 56:318–325
Oehlke J., Scheller A., Wiesner B. et al.: (1998) Biochim. Biophys. Acta 1414:127–139
Otvos L., Cudic M., Chua B. Y., Deliyannis G., Jackson D. C. (2004) Mol. Pharm. 1:220–232
Peitz M., Pfannkuche K., Rajewsky K., Edenhofer F. (2002) Proc. Natl. Acad. Sci. U. S. A. 99:4489–4494
Pietersz G. A., Li W., Apostolopoulos V. (2001) Vaccine 19:1397–1405
Pooga M., Hallbrink M., Zorko M., Langel U. (1998) FASEB J. 12:67–77
Pooga M., Soomets U., Hallbrink M. et al. (1998b) Nat. Biotechnol. 16:857–861
Pouniotis D. S., Apostolopoulos V., Pietersz G. A. (2006) Immunology 117:329–339
Schutze-Redelmeier M. P., Gournier H., Garcia-Pons F. et al. (1996) J. Immunol. 157:650–655
Schwarze S. R., Ho A., Vocero-Akbani A., Dowdy S. F. (1999) Science 285:1569–1572
Shen W. C., Ryser H. J. (1978) Proc. Natl. Acad. Sci. U. S. A. 75:1872–1876
Torchilin V. P., Levchenko T. S., Rammohan R., Volodina N., Papahadjopoulos-Sternberg B., D’Souza G. G. (2003) Proc Natl. Acad. Sci. U. S. A. 100:1972–1977
Turtle C. J., Hart D. N. (2004) Curr. Drug Targets 5:17–39
Vari F., Hart D. N. (2004) Cytotherapy 6:111–121
Vives E., Brodin P., Lebleu B. (1997) J. Biol. Chem. 272:16010–16017
Wender P. A., Mitchell D. J., Pattabiraman K., Pelkey E. T., Steinman L., Rothbard J. B. (2000) Proc. Natl. Acad. Sci. U. S. A. 97:13003–13008
Williams E. J., Dunican D. J., Green P. J. et al. (1997) J. Biol. Chem. 272:22349–22354
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This work was supported by grants from the National Health and Medical Research Council of Australia and the Australian Centre for Hepatitis and HIV Virology.
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Chua, B.Y., Zeng, W. & Jackson, D.C. Simple Branched Arginine-Based Structures can Enhance the Cellular Uptake of Peptide Cargos. Int J Pept Res Ther 13, 431–437 (2007). https://doi.org/10.1007/s10989-006-9063-y
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DOI: https://doi.org/10.1007/s10989-006-9063-y