Bioconjugate Chemistry
Article
translocation and the lower passive diffusion due to decreased
membrane permeability.
(8) Kalderon, D., Roberts, B. L., Richardson, W. D., and Smith, A. E.
1984) A short amino acid sequence able to specify nuclear location.
(
Cell 39, 499−509.
The combined biological data emphasize the complexity of
the cell uptake process that is mediated by the novel
penetrating agent. Currently, studies have been undertaken to
elucidate the cellular mechanisms involved in the translocation
of Arg -Malt-NAcC functions. These studies are aimed at
(9) Green, M., and Loewenstein, P. M. (1988) Autonomous
functional domains of chemically synthesized human immunodefi-
ciency virus tat trans-activator protein. Cell 55, 1179−1188.
(10) Futaki, S., Suzuki, T., Ohashi, W., Yagami, T., Tanaka, S., Ueda,
7
12
K., and Sugiura, Y. (2001) Arginine-rich Peptides. J. Biol. Chem. 276,
836−5840.
11) Futaki, S. (2006) Oligoarginine vectors for intracellular delivery:
comparatively examining the cell-penetrating properties of the
corona-like derivative and linear TAT-like sequences. Addi-
tional investigations will also be performed using different cell
lines and experimental conditions, namely, time, pH, and
temperature.
5
(
Design and cellular-uptake mechanisms. Pept. Sci. 84, 241−249.
(12) Patel, L., Zaro, J., and Shen, W.-C. (2007) Cell penetrating
peptides: intracellular pathways and pharmaceutical perspectives.
Pharm. Res. 24, 1977−1992.
(13) Wagstaff, K. M., and Jans, D. A. (2006) Protein transduction:
CONCLUSIONS
■
cell penetrating peptides and their therapeutic applications. Curr. Med.
Chem. 13, 1371−87.
The results reported in the present work show that a novel class
of cell-penetration enhancers with unusual chemical structures
can be easily obtained via simple and reproducible synthetic
steps. In principle, the proposed chemical synthesis protocol is
flexible and can be properly managed to obtain products that,
by virtue of their unconventional structural properties, open
new possibilities in drug delivery.
(14) Okuyama, M., Laman, H., Kingsbury, S. R., Visintin, C., Leo, E.,
Eward, K. L., Stoeber, K., Boshoff, C., Williams, G. H., and Selwood, D.
L. (2007) Small-molecule mimics of an [alpha]-helix for efficient
transport of proteins into cells. Nat. Meth. 4, 153−159.
(15) Fisher, A. A., Ye, D., Sergueev, D. S., Fisher, M. H., Shaw, B. R.,
and Juliano, R. L. (2002) Evaluating the specificity of antisense
oligonucleotide conjugates. J. Biol. Chem. 277, 22980−22984.
A wide array of cell-penetration enhancers can be obtained
by slight modifications of the main structure of these enhancers
to provide for their conjugation or physical combination with a
variety of therapeutic systems. These molecules can be
designed for conjugation to proteins or polymer therapeutics,
or for surface decoration of liposomes or nanoparticles. The
cationic features and the penetration-enhancing properties of
the star-like oligo-arginyl can also be exploited for oligonucleo-
tide, namely, siRNA, or gene delivery.
Finally, a combination of residues, such as histidines and
cysteines, that have been found to possess endosomolytic
properties or short peptides that increase the gene expression of
DNAs, can be introduced within the core structure.
(16) Veldhoen, S., Laufer, S., and Restle, T. (2008) Recent
developments in peptide-based nucleic acid delivery. Int. J. Mol. Sci.
, 1276−1320.
17) Dostmann, W. R. G., Taylor, M. S., Nickl, C. K., Brayden, J. E.,
9
(
Frank, R., and Tegge, W. J. (2000) Highly specific, membrane-
permeant peptide blockers of cgmp-dependent protein kinase iα
inhibit no-induced cerebral dilation. Proc. Natl. Acad. Sci. U.S.A. 97,
1
(
4772−14777.
18) Bonny, C., Oberson, A., Negri, S., Sauser, C., and Schorderet, D.
F. (2001) Cell-permeable peptide inhibitors of JNK. Diabetes 50, 77−
2.
19) Patsch, C., and Edenhofer, F. (2007) , Conditional Mutagenesis
8
(
by Cell-Permeable Proteins: Potential Limitations and Prospects Condi-
tional Mutagenesis: An Approach to Disease Models (Feil, R., and
Metzger, D., Eds.) pp 203−232, Springer, Berlin.
AUTHOR INFORMATION
̈ ̈
(20) Saalik, P., Elmquist, A., Hansen, M., Padari, K., Saar, K., Viht, K.,
■
̈
Langel, U., and Pooga, M. (2004) Protein cargo delivery properties of
cell-penetrating peptides. a comparative study. Bioconjugate Chem. 15,
*
1
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246−1253.
+39 049 8275366.
21) Albarran, B., To, R., and Stayton, P. S. (2005) A TAT−
streptavidin fusion protein directs uptake of biotinylated cargo into
Notes
mammalian cells. Protein Eng., Des. Sel. 18, 147−152.
The authors declare no competing financial interest.
(22) Torchilin, V. P. (2008) Tat peptide-mediated intracellular
delivery of pharmaceutical nanocarriers. Adv. Drug Delivery Rev. 60,
48−558.
23) Medintz, I. L., Pons, T., Delehanty, J. B., Susumu, K., Brunel, F.
M., Dawson, P. E., and Mattoussi, H. (2008) Intracellular delivery of
quantum dot−protein cargos mediated by cell penetrating peptides.
Bioconjugate Chem. 19, 1785−1795.
(24) Liu, B. R., Huang, Y.-w., Winiarz, J. G., Chiang, H.-J., and Lee,
H.-J. (2011) Intracellular delivery of quantum dots mediated by a
histidine- and arginine-rich HR9 cell-penetrating peptide through the
direct membrane translocation mechanism. Biomaterials 32, 3520−
3537.
REFERENCES
1) Amidon, G. L., Lennernas
1995) A theoretical basis for a biopharmaceutic drug classification:
the correlation of in vitro drug product dissolution and in vivo
bioavailability. Pharm. Res. 12, 413−420.
2) Williams, A. C., and Barry, B. W. (2004) Penetration enhancers.
Adv. Drug Delivery Rev. 56, 603−618.
3) Wadia, J. S., and Dowdy, S. F. (2002) Protein transduction
technology. Curr. Opin. Biotechnol. 13, 52−56.
4) Stewart, K. M., Horton, K. L., and Kelley, S. O. (2008) Cell-
penetrating peptides as delivery vehicles for biology and medicine. Org.
Biomol. Chem. 6, 2242−2255.
5) Fonseca, S. B., Pereira, M. P., and Kelley, S. O. (2009) Recent
advances in the use of cell-penetrating peptides for medical and
biological applications. Adv. Drug Delivery Rev. 61, 953−964.
6) Tung, C.-H., and Weissleder, R. (2003) Arginine containing
5
(
■
(
̈
, H., Shah, V. P., and Crison, J. R.
(
(
(
(
́
(25) Trehin, R., and Merkle, H. P. (2004) Chances and pitfalls of cell
penetrating peptides for cellular drug delivery. Eur. J. Pharm. Biopharm.
58, 209−223.
(
(26) Sakuma, S., Suita, M., Masaoka, Y., Kataoka, M., Nakajima, N.,
Shinkai, N., Yamauchi, H., Hiwatari, K.-i., Tachikawa, H., Kimura, R.,
and Yamashita, S. (2010) Oligoarginine-linked polymers as a new class
of penetration enhancers. J. Controlled Release 148, 187−196.
(27) Hayes, P. Y., Ross, B. P., Thomas, B. G., and Toth, I. (2006)
Polycationic lipophilic-core dendrons as penetration enhancers for the
oral administration of low molecular weight heparin. Bioorg. Med.
Chem. 14, 143−152.
(
peptides as delivery vectors. Adv. Drug Delivery Rev. 55, 281−294.
7) Jeyapaul, J., Reddy, M. R., and Khan, S. A. (1990) Activity of
synthetic tat peptides in human immunodeficiency virus type 1 long
terminal repeat-promoted transcription in a cell-free system. Proc. Natl.
Acad. Sci. U.S.A. 87, 7030−4.
(
J
dx.doi.org/10.1021/bc200666u | Bioconjugate Chem. XXXX, XXX, XXX−XXX