title: Cell-penetrating-peptide-based delivery of oligonucleotides: an overview.
abstract: Cationic CPPs (cell-penetrating peptides) have been used largely for intracellular delivery of low-molecular-mass drugs, biomolecules and particles. Most cationic CPPs bind to cell-associated glycosaminoglycans and are internalized by endocytosis, although the detailed mechanisms involved remain controversial. Sequestration and degradation in endocytic vesicles severely limits the efficiency of cytoplasmic and/or nuclear delivery of CPP-conjugated material. Re-routing the splicing machinery by using steric-block ON (oligonucleotide) analogues, such as PNAs (peptide nucleic acids) or PMOs (phosphorodiamidate morpholino oligomers), has consequently been inefficient when ONs are conjugated with standard CPPs such as Tat (transactivator of transcription), R(9) (nona-arginine), K(8) (octalysine) or penetratin in the absence of endosomolytic agents. New arginine-rich CPPs such as (R-Ahx-R)(4) (6-aminohexanoic acid-spaced oligo-arginine) or R(6) (hexa-arginine)-penetratin conjugated to PMO or PNA resulted in efficient splicing correction at non-cytotoxic doses in the absence of chloroquine. SAR (structure-activity relationship) analyses are underway to optimize these peptide delivery vectors and to understand their mechanisms of cellular internalization.
authors.affiliation: UMR 5235 CNRS, Université Montpellier 2, Place Eugène Bataillon, 34095 Montpellier cedex 5, France.
authors.forename: R
authors.initials: R
authors.lastname: Abes
authors.forename: A A
authors.initials: AA
authors.lastname: Arzumanov
authors.forename: H M
authors.initials: HM
authors.lastname: Moulton
authors.forename: S
authors.initials: S
authors.lastname: Abes
authors.forename: G D
authors.initials: GD
authors.lastname: Ivanova
authors.forename: P L
authors.initials: PL
authors.lastname: Iversen
authors.forename: M J
authors.initials: MJ
authors.lastname: Gait
authors.forename: B
authors.initials: B
authors.lastname: Lebleu
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems; D006801:Humans; D009841:Oligonucleotides / Q000008:administration & dosage / Q000378:metabolism*; D010455:Peptides / Q000502:physiology*; D021382:Protein Sorting Signals / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology*
chemical_list: D009841:Oligonucleotides; D010455:Peptides; D021382:Protein Sorting Signals