Flavin Conjugates for Delivery of Peptide Nucleic Acids |
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Authors: | Dr. Fanny Marlin Dr. Philippe Simon Dr. Stéphanie Bonneau Dr. Patrizia Alberti Céline Cordier Charlotte Boix Loïc Perrouault Aurélie Fossey Prof. Tula Saison‐Behmoaras Prof. Marc Fontecave Dr. Carine Giovannangeli |
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Affiliation: | 1. Museum National d'Histoire Naturelle, CNRS, UMR7196 and Inserm, U565, 43 rue Cuvier, 75005 Paris (France);2. Collège de France, CNRS FRE 3488, 11 place Marcelin‐Berthelot, 75005 Paris (France);3. Université Pierre et Marie Curie Paris 6, CNRS FRE 3207, 4 place Jussieu, 75005 Paris (France) |
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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. |
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Keywords: | antisense agents drug delivery oligonucleotide conjugates peptide nucleic acids photochemical internalization riboflavin |
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