title: Cellular uptake and intracellular release are major obstacles to the therapeutic application of siRNA: novel options by phosphorothioate-stimulated delivery.
abstract: The cellular uptake of oligomeric nucleic acid-based tools and drugs including small-interfering RNA (siRNA) represents a major technical hurdle for the biologic effectiveness and therapeutic success in vivo. Subsequent to cellular delivery it is crucial to direct siRNA to the cellular location where it enters the RNA interference pathway. Here the authors summarise evidence that functionally active siRNA represents a minor fraction in the order of 1% of total siRNA inside a given target cell. Exploiting possibilities of steering intracellular release or trafficking of siRNA bears the potential of substantially increasing the biological activity of siRNA. The recently described phosphorothioate stimulated cellular delivery of siRNA makes use of the caveolar system ending in the Golgi apparatus, which contrasts all other known delivery systems. Therefore, it represents an attractive alternative to study whether promoted intracellular release is related to increased target suppression and, thus, increased phenotypic biologic effectiveness.
authors.affiliation: Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein and Zentrum für medizinische Strukturbiologie ZMSB, Institut für Molekulare Medizin, Ratzeburger Allee 160, D-23538 Lübeck, Germany.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mescalchin
authors.forename: Anke
authors.initials: A
authors.lastname: Detzer
authors.forename: Maria
authors.initials: M
authors.lastname: Wecke
authors.forename: Marita
authors.initials: M
authors.lastname: Overhoff
authors.forename: Winfried
authors.initials: W
authors.lastname: Wünsche
authors.forename: Georg
authors.initials: G
authors.lastname: Sczakiel
mesh_terms: D000818:Animals; D001692:Biological Transport; D021941:Caveolae / Q000378:metabolism*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism*; D013873:Thionucleotides / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D013873:Thionucleotides