Cellular delivery of peptide nucleic acid (PNA)

Koppelhus, Uffe; Nielsen, Peter E.

doi:10.1016/s0169-409x(02)00182-5

Cited by 230 publications

(215 citation statements)

References 58 publications

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“…As expected, Pep-2/HypNA-pPNA complexes have a potent antisense effect with an IC 50 of 1475 nM, a value that is 8.5-fold and 25-fold lower than that of Pep-2/PNA (IC 50 : 120724 nM) and classical phosphorothioate-oligonucleotide (IC 50 : 360741 nM), respectively. Cationic lipid-mediated delivery of HypNA-pPNAs was 100-fold less efficient (IC 50 : 1.370.21 mM), consistent with data already reported by other groups using lipids 10,22,36 …”

Section: Resultssupporting

confidence: 89%

“…[11][12][13][14] However, the PNAs used in these studies do not target homo-purine motifs, and would not be able to form a stable complex with DNA in order to block RNA polymerase. 10,38,39 Likewise, the antisense PNA that targets the first codons of the open reading frame of cyclin B1 gene should not be able to act as an antigene molecule. In the case of Pep-2, none of the mechanisms can be excluded, and we suggest that both steric hindrance and mRNA degradation are likely to come into play.…”

Section: Resultsmentioning

confidence: 99%

“…The inefficiency of PNAs in vivo is in part related to their poor propensity to cross the cell membrane and/or to their inappropriate cellular localization. 10 Recent work has demonstrated that cellular uptake of free PNAs can occur, although this requires very high concentrations of PNAs, except in neuronal cells, 11,12 and yields limited biological response. [13][14][15] In order to improve delivery of PNAs into cells and to reduce the doses required for detectable effects, several chemical modifications based on covalently linked cell-penetrating peptides have been successfully used.…”

Section: Introductionmentioning

confidence: 99%

“…[13][14][15] In order to improve delivery of PNAs into cells and to reduce the doses required for detectable effects, several chemical modifications based on covalently linked cell-penetrating peptides have been successfully used. 10,12,[16][17][18] Linkage of nuclear localization or polylysine sequences to PNAs have also been reported to improve both their cellular internalization and nuclear translocation. 14,19,20 Moreover, it has recently been shown that the cellular uptake of PNAs depends on the cell type and that a carrier system is required for efficient uptake.…”

Section: Introductionmentioning

confidence: 99%

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Combination of a new generation of PNAs with a peptide-based carrier enables efficient targeting of cell cycle progression

et al. 2004

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The design of potent systems for the delivery of charged and noncharged molecules that target genes of interest remains a challenge. We describe a novel technology that combines a new generation of peptide nucleic acids (PNAs), or HypNApPNAs, with a new noncovalent peptide-based delivery system, Pep-2, which promotes efficient delivery of PNAs into several cell lines. We have validated the potential of this technology by showing that Pep2-mediated delivery of an antisense HypNApPNA chimera directed specifically against cyclin B1 induces rapid and robust downregulation of its protein levels and efficiently blocks cell cycle progression of several cell lines, as well as proliferation of cells derived from a breast cancer. Pep-2-based delivery system was shown to be 100-fold more efficient in delivering HypNA-pPNAs than classical cationic lipidbased methods. Whereas Pep-2 is essential for improving the bioavailability of PNAs and HypNA-pPNAs, the latter contribute significantly to the efficiency and specificity of the biological response. We have found that Pep-2/HypNA-pPNA strategy promotes potent antisense effects, which are approximately 25-fold greater than with classical antisense oligonucleotide directed specifically against the same cyclin B1 target. Taken together, these data demonstrate that peptide-mediated delivery of HypNA-pPNAs constitutes a very promising technology for therapeutic applications.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Combination of a new generation of PNAs with a peptide-based carrier enables efficient targeting of cell cycle progression

et al. 2004

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“…A limiting factor, on the other hand, is the poor cellular (nuclear) delivery of this class of compounds [46]. These issues will be addressed in more detail in the selective examples discussed below.…”

Section: Recognition Of Biological Targets By Pseudo-peptidesmentioning

confidence: 99%