A non-covalent peptide-based carrier for in vivo delivery of DNA mimics.
The dramatic acceleration in identification of new nucleic-acid-based therapeutic molecules has provided new perspectives in pharmaceutical research. However, their development is limited by their poor cellular uptake and inefficient trafficking. Here we describe a short amphipathic peptide, Pep-3, that combines a tryptophan/phenylalanine domain with a lysine/arginine-rich hydrophilic motif. Pep-3 forms stable nano-size complexes with peptide-nucleic acid analogues and promotes their efficient delivery into a wide variety of cell lines, including primary and suspension lines, without any associated cytotoxicity. We demonstrate that Pep-3-mediated delivery of antisense-cyclin B1-charged-PNA blocks tumour growth in vivo upon intratumoral and intravenous injection. Moreover, we show that PEGylation of Pep-3 significantly improves complex stability in vivo and consequently the efficiency of antisense cyclin B1 administered intravenously. Given the biological characteristics of these vectors, we believe that peptide-based delivery technologies hold a true promise for therapeutic applications of DNA mimics.
Morris
May C
MC
Centre de Recherches en Biochimie Macromoléculaire, Department of Molecular Biophysics and Therapeutics, FRE-2593 CNRS, Montpellier, France.
Gros
Edwige
E
Aldrian-Herrada
Gudrun
G
Choob
Michael
M
Archdeacon
John
J
Heitz
Frederic
F
Divita
Gilles
G
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D019926:Cyclin B / Q000037:antagonists & inhibitors / Q000235:genetics; D056744:Cyclin B1; D005260:Female; D006801:Humans; D007267:Injections; D051379:Mice; D008819:Mice, Nude; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000737:chemistry; D020135:Peptide Nucleic Acids / Q000008:administration & dosage* / Q000737:chemistry; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D016415:Sequence Alignment; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; D019926:Cyclin B; D056744:Cyclin B1; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; C520006:Pep-3 peptide; D020135:Peptide Nucleic Acids; D010455:Peptides; C505966:hydroxyprolyl-phospho peptide nucleic acid antisense oligonucleotide; D011092:Polyethylene Glycols