title: Flavin conjugates for delivery of peptide nucleic acids.
abstract: Oligonucleotides and their analogues, such as peptide nucleic acids (PNAs), can be used in chemical strategies to artificially control gene expression. Inefficient cellular uptake and inappropriate cellular localization still remain obstacles in biological applications, however, especially for PNAs. Here we demonstrate that conjugation of PNAs to flavin resulted in efficient internalization into cells through an endocytic pathway. The flavin-PNAs exhibited antisense activity in the sub-micromolar range, in the context of a treatment facilitating endosomal escape. Increased endosomal release of flavin conjugates into the cytoplasm and/or nucleus was shown by chloroquine treatment and also--when the flavin-PNA was conjugated to rhodamine, a mild photosensitizer--upon light irradiation. In conclusion, an isoalloxazine moiety can be used as a carrier and attached to a cargo biomolecule, here a PNA, for internalization and functional cytoplasmic/nuclear delivery. Our findings could be useful for further design of PNAs and other oligonucleotide analogues as potent antisense agents.
authors.affiliation: Museum National d'Histoire Naturelle, CNRS, UMR7196 and Inserm, U565, 43 rue Cuvier, 75005 Paris, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Marlin
authors.forename: Philippe
authors.initials: P
authors.lastname: Simon
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bonneau
authors.forename: Patrizia
authors.initials: P
authors.lastname: Alberti
authors.forename: Céline
authors.initials: C
authors.lastname: Cordier
authors.forename: Charlotte
authors.initials: C
authors.lastname: Boix
authors.forename: Loïc
authors.initials: L
authors.lastname: Perrouault
authors.forename: Aurélie
authors.initials: A
authors.lastname: Fossey
authors.forename: Tula
authors.initials: T
authors.lastname: Saison-Behmoaras
authors.forename: Marc
authors.initials: M
authors.lastname: Fontecave
authors.forename: Carine
authors.initials: C
authors.lastname: Giovannangeli
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004138:Dinitrocresols / Q000378:metabolism*; D004337:Drug Carriers / Q000378:metabolism*; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D020135:Peptide Nucleic Acids / Q000235:genetics / Q000378:metabolism*
chemical_list: D004138:Dinitrocresols; D004337:Drug Carriers; D016376:Oligonucleotides, Antisense; D020135:Peptide Nucleic Acids; C024132:4,6-dinitro-o-cresol