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Cell Penetrating Peptides in Drug Delivery

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Abstract

Protein transduction domains (PTDs) are small cationic peptides that can facilitate the uptake of large, biologically active molecules into mammalian cells. Recent reports have suggested that PTDs may be able to mediate the delivery of cargo to tissues throughout a living organism. Such technology could eliminate the size restrictions on usable drugs, enabling previously unavailable large molecules to modulate in vivo biology and alleviate disease. In this article, we review the evidence that PTDs can be used both to deliver active molecules to pathological tissue in vivo and to treat models of disease such as ischemia, inflammation, and cancer.

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References

  1. M. A. Lindsay. Peptide-mediated cell delivery: application in protein target validation. Curr. Opin. Pharmacol. 2:587-594 (2002).

    Google Scholar 

  2. P. Fischer, E. Krausz, and D. P. Lane. Cellular delivery of impermeable effector molecules in the form of conjugates with peptides capable of mediating membrane translocation. Bioconjug. Chem. 12:825-841 (2001).

    Google Scholar 

  3. S. R. Schwarze, A. Ho, A. Vocero-Akbani, and S. F. Dowdy. In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 285:1569-1572 (1999).

    Google Scholar 

  4. A. D. Frankel and C. O. Pabo. Cellular uptake of the tat protein from human immunodeficiency virus. Cell 55:1189-1193 (1988).

    Google Scholar 

  5. M. Green and P. M. Loewenstein. Autonomous functional domains of chemically synthesized human immunodeficiency virus tat trans-activator protein. Cell 55:1179-1188 (1988).

    Google Scholar 

  6. E. Vives, P. Brodin, and B. Lebleu. A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. J. Biol. Chem. 272:16010-16017 (1997).

    Google Scholar 

  7. D. Derossi, A. H. Joliot, G. Chassaing, and A. Prochiantz. The third helix of the Antennapedia homeodomain translocates through biological membranes. J. Biol. Chem. 269:10444-10450 (1994).

    Google Scholar 

  8. J. C. Mai, H. Shen, S. C. Watkins, T. Cheng, and P. D. Robbins. Efficiency of protein transduction is cell type-dependent and is enhanced by dextran sulfate. J. Biol. Chem. 277:30208-30218 (2002).

    Google Scholar 

  9. P. A. Wender, D. J. Mitchell, K. Pattabiraman, E. T. Pelkey, L. Steinman, and J. B. Rothbard. The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: peptoid molecular transporters. Proc. Natl. Acad. Sci. U. S. A. 97:13003-13008 (2000).

    Google Scholar 

  10. H. Nagahara, A. M. Vocero-Akbani, E. L. Snyder, A. Ho, D. G. Latham, N.A. Lissy, M. Becker-Hapak, S. A. Ezhevsky, and S. F. Dowdy. Transduction of full-length TAT fusion proteins into mammalian cells: TAT-p27Kip1 induces cell migration. Nat. Med. 4:1449-1452 (1998).

    Google Scholar 

  11. M. Lewin, N. Carlesso, C. H. Tung, X. W. Tang, D. Cory, D. T. Scadden, and R. Weissleder. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nat. Biotechnol. 18:410-414 (2000).

    Google Scholar 

  12. A. Eguchi, T. Akuta, H. Okuyama, T. Senda, H. Yokoi, H. Inokuchi, S. Fujita, T. Hayakawa, K. Takeda, M. Hasegawa, and M. Nakanishi. Protein transduction domain of HIV-1 Tat protein promotes efficient delivery of DNA into mammalian cells. J. Biol. Chem. 276:26204-26210 (2001).

    Google Scholar 

  13. V. P. Torchilin, R. Rammohan, V. Weissig, and T. S. Levchenko. 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. U. S. A. 98:8786-8791 (2001).

    Google Scholar 

  14. V. P. Torchilin, T. S. Levchenko, R. Rammohan, N. Volodina, B. Papahadjopoulos-Sternberg, and G. G. D'Souza. Cell transfection in vitro and in vivo with nontoxic TAT peptide-liposome-DNA complexes. Proc. Natl. Acad. Sci. U. S. A. 100:1972-1977 (2003).

    Google Scholar 

  15. D. Derossi, S. Calvet, A. Trembleau, A. Brunissen, G. Chassaing, and A. Prochiantz. Cell internalization of the third helix of the Antennapedia homeodomain is receptor-independent. J. Biol. Chem. 271:18188-18193 (1996).

    Google Scholar 

  16. M. Tyagi, M. Rusnati, M. Presta, and M. Giacca. Internalization of HIV-1 Tat requires cell surface heparan sulfate proteoglycans. J. Biol. Chem. 276:3254-3261 (2001).

    Google Scholar 

  17. M. Silhol, M. Tyagi, M. Giacca, B. Lebleu, and E. Vives. Different mechanisms for cellular internalization of the HIV-1 Tat-derived cell penetrating peptide and recombinant proteins fused to Tat. Eur. J. Biochem. 269:494-501 (2002).

    Google Scholar 

  18. J. P. Richard, K. Melikov, E. Vives, C. Ramos, B. Verbeure, M. J. Gait, L. V. Chernomordik, and B. Lebleu. Cell-penetrating peptides: a re-evaluation of the mechanism of cellular uptake. J. Biol. Chem. 278:585-590 (2002).

    Google Scholar 

  19. A. Fittipaldi, A. Ferrari, M. Zoppe, C. Arcangeli, V. Pellegrini, F. Beltram, and M. Giacca. Cell membrane lipid rafts mediate caveolar endocytosis of HIV-1 TAT fusion proteins. J. Biol. Chem 278:34141-34149 (2003).

    Google Scholar 

  20. S. Violini, V. Sharma, J. L. Prior, M. Dyszlewski, and D. Piwnica-Worms. Evidence for a plasma membrane-mediated permeability barrier to Tat basic domain in well-differentiated epithelial cells: lack of correlation with heparan sulfate. Biochemistry 41:12652-12661 (2002).

    Google Scholar 

  21. G. Cao, W. Pei, H. Ge, Q. Liang, Y. Luo, F. R. Sharp, A. Lu, R. Ran, S. H. Graham, and J. Chen. In vivo delivery of a Bcl-xL fusion protein containing the TAT protein transduction domain protects against ischemic brain injury and neuronal apoptosis. J. Neurosci. 22:5423-5431 (2002).

    Google Scholar 

  22. E. Kilic, G. P. H. Dietz, D. M. Hermann, and M. Bahr. Intravenous TAT-Bcl-xL is protective after middle cerbral artery occlusion in mice. Ann. Neurol. 52:617-622 (2002).

    Google Scholar 

  23. G. P. H. Dietz, E. Kilic, and M. Bahr. Inhibition of neuronal apoptosis in vitro and in vivo using TAT-mediated protein transduction. Mol. Cell. Neurosci. 21:29-37 (2002).

    Google Scholar 

  24. S. Asoh, I. Ohsawa, T. Mori, K. Katsura, T. Hiraide, Y. Katayama, M. Kimura, D. Ozaki, K. Yamagata, and S. Ohta. Protection against ischemic brain injury by protein therapeutics. Proc. Natl. Acad. Sci. U. S. A. 99:17107-17112 (2002).

    Google Scholar 

  25. J. Embury, D. Klein, A. Pileggi, M. Ribeiro, S. Jayaraman, R. D. Molano, C. Fraker, N. Kenyon, C. Ricordi, L. Inverardi, and R. L. Pastori. Proteins linked to a protein transduction domain efficiently transduce pancreatic islets. Diabetes 50:1706-1713 (2001).

    Google Scholar 

  26. M. Aarts, Y. Liu, L. Liu, S. Besshoh, M. Arundine, J. W. Gurd, Y. T. Wang, M. W. Salter, and M. Tymianski. Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions. Science 298:846-850 (2002).

    Google Scholar 

  27. L. Chen, H. Hahn, G. Wu, C. H. Chen, T. Liron, D. Schechtman, G. Cavallaro, L. Banci, Y. Guo, R. Bolli, G. W. Dorn 2nd, and D. Mochly-Rosen. Opposing cardioprotective actions and parallel hypertrophic effects of deltaPKC and epsilonPKC. Proc. Natl. Acad. Sci. U. S. A. 98:11114-11119 (2001).

    Google Scholar 

  28. A. B. Gustafsson, M. R. Sayen, S. D. Williams, M. T. Crow, and R. A. Gottlieb. TAT protein transduction into isolated perfused hearts. Circulation 106:735-739 (2002).

    Google Scholar 

  29. C. R. Aarnt, M. V. Chiorean, M. P. Heldebrant, G. J. Gores, and S. Kaufman. Synthetic Smac/DIABLO peptides enhance the effects of chemotherapeutic agents by binding XIAP and cIAP1 in situ. J. Biol. Chem. 277:44236-44243 (2002).

    Google Scholar 

  30. S. Fulda, W. Wick, M. Weller, and K-M. Debatin. Smac agonists sensitize for Apo2L/TRAIL-or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat. Med. 8:808-815 (2002).

    Google Scholar 

  31. D. Vucic, K. Deshayes, H. Ackerly, M. T. Pisabarro, S. Kadkhodayan, W. J. Fairbrother, and W. M. Dixit. SMAC negatively regulates the anti-apoptotic activity of melanoma inhibitor of apoptosis (ML-IAP). J. Biol. Chem. 277:12275-12279 (2002).

    Google Scholar 

  32. J. W. Harbour, L. Worley, D. Ma, and M. Cohen. Transducible peptide therapy for uveal melanoma and retinoblastoma. Arch. Ophthalmol. 120:1341-1346 (2002).

    Google Scholar 

  33. J. C. Mai, Z. Mi, S-H. Kim, B. Ng, and P. D. Robbins. A proapoptotic peptide for the treatment of solid tumors. Cancer Res. 61:7709-7712 (2001).

    Google Scholar 

  34. H. Harada, M. Hiraoka, and S. Kizaka-Kondoh. Antitumor effect of TAT-Oxygen-dependent Degradation-Caspase-3 fusion protein specifcally stabilized and activated in hypoxic tumor cells. Cancer Res. 62:2013-2018 (2002).

    Google Scholar 

  35. K. Datta, C. Sundberg, S. A. Karumanchi, and D. Mukhopadhyay. The 104-123 amino acid sequence of the beta-domain of von Hippel-Lindau gene product is sufficient to inhibit renal tumor growth and invasion. Cancer Res. 61:1768-1775 (2001).

    Google Scholar 

  36. R. Hosotani, Y. Miyamoto, K. Fujimoto, R. Doi, A. Otaka, N. Fujii, and M. Imamura. Trojan p16 peptide suppresses pancreatic cancer growth and prolongs survival in mice. Clin. Cancer Res. 8:1271-1276 (2002).

    Google Scholar 

  37. F. E. Rey, M. E. Cifuentes, A. Kiarash, M. T. Quinn, and P. J. Pagano. Novel competitive inhibitor of NAD(P)H oxidase assembly attenuates vascular O2-and systolic blood pressure in mice. Circ. Res. 89:408-414 (2001).

    Google Scholar 

  38. M. J. May, F. D'Acquisto, L. A. Madge, J. Glockner, J. S. Pober, and S. Ghosh. Selective inhibition of NF-kB activation by a peptide that blocks the interaction of NEMO with the IkB Kinase complex. Science 289:1550-1554 (2000).

    Google Scholar 

  39. M. Bucci, J. P. Gratton, R. D. Rudic, L. Acevedo, F. Roviezzo, G. Cirino, and W. C. Sessa. In vivo delivery of the caveolin-1 scaffolding domain inhibits nitric oxide synthesis and reduces inflammation. Nat. Med. 6:1362-1367 (2000).

    Google Scholar 

  40. J. B. Rothbard, S. Garlington, Q. Lin, T. Kirschberg, E. Kreider, P. L. McGrane, P. A. Wender, and P. A. Khavari. Conjugation of arginine oligomers to cyclosporin A facilitates topical delivery and inhibition of inflammation. Nat. Med. 6:1253-1257 (2000).

    Google Scholar 

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

    Google Scholar 

  42. M. Mazel, P. Clair, C. Rousselle, P. Vidal, J. M. Scherrmann, D. Mathieu, and J. Temsamani. Doxorubicin-peptide conjugates overcome multidrug resistance. Anticancer Drugs 12:107-116 (2001).

    Google Scholar 

  43. H. J. Lee and W. M. Pardridge. Pharmacokinetics and delivery of Tat and Tat-protein conjugates to tissues in vivo. Bioconjug. Chem. 12:995-999 (2001).

    Google Scholar 

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Authors and Affiliations

  1. Howard Hughes Medical Institute and Department of Cellular & Molecular Medicine, University of California at San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA, 92093-0686

    Eric L. Snyder & Steven F. Dowdy

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  1. Eric L. Snyder
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  2. Steven F. Dowdy
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Correspondence to Steven F. Dowdy.

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Snyder, E.L., Dowdy, S.F. Cell Penetrating Peptides in Drug Delivery. Pharm Res 21, 389–393 (2004). https://doi.org/10.1023/B:PHAM.0000019289.61978.f5

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