title: Precise redox-sensitive cleavage sites for improved bioactivity of siRNA lipopolyplexes.
abstract: Lipo-oligomers have been proven as potent siRNA carriers based on stable electrostatic and hydrophobic complex formation and endosomal membrane destabilization. Although high stability of siRNA polyplexes is desirable in the extracellular space and cellular uptake, intracellular disassembly is important for the cytosolic release of siRNA and RNA-induced silencing complex formation. To improve the release, bioreducible sequence-defined lipo-oligomers were synthesized by solid-phase assisted synthesis using the disulfide building block Fmoc-succinoyl-cystamine for precise positioning of a disulfide unit between a lipophilic diacyl (bis-myristyl, bis-stearyl or bis-cholestanyl) domain and an ionizable oligocationic siRNA binding unit. Reducible siRNA polyplexes show higher gene silencing efficacy and lower cytotoxicity than their stable analogs, consistent with glutathione-triggered siRNA release and reduced lytic activity.
authors.affiliation: Pharmaceutical Biotechnology, Department of Pharmacy, Center of Nanoscience (CeNS), Ludwig-Maximilians-Universität, Butenandtstr. 5-13, 81377 München, Germany. ernst.wagner@cup.uni-muenchen.de.
authors.forename: Philipp Michael
authors.initials: PM
authors.lastname: Klein
authors.affiliation: Pharmaceutical Biotechnology, Department of Pharmacy, Center of Nanoscience (CeNS), Ludwig-Maximilians-Universität, Butenandtstr. 5-13, 81377 München, Germany. ernst.wagner@cup.uni-muenchen.de.
authors.forename: Sören
authors.initials: S
authors.lastname: Reinhard
authors.affiliation: Pharmaceutical Biotechnology, Department of Pharmacy, Center of Nanoscience (CeNS), Ludwig-Maximilians-Universität, Butenandtstr. 5-13, 81377 München, Germany. ernst.wagner@cup.uni-muenchen.de and Nanosystems Initiative Munich (NIM), Schellingstr. 4, 80799 München, Germany.
authors.forename: Dian-Jang
authors.initials: DJ
authors.lastname: Lee
authors.affiliation: Pharmaceutical Biotechnology, Department of Pharmacy, Center of Nanoscience (CeNS), Ludwig-Maximilians-Universität, Butenandtstr. 5-13, 81377 München, Germany. ernst.wagner@cup.uni-muenchen.de.
authors.forename: Katharina
authors.initials: K
authors.lastname: Müller
authors.affiliation: Max-Planck-Institute of Colloids and Interfaces, Department of Biomolecular Systems, Am Mühlenberg 1, 14476 Potsdam-Golm, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Ponader
authors.affiliation: Institut für Organische Chemie und Makromolekulare Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany. laura.hartmann@hhu.de.
authors.forename: Laura
authors.initials: L
authors.lastname: Hartmann
authors.affiliation: Pharmaceutical Biotechnology, Department of Pharmacy, Center of Nanoscience (CeNS), Ludwig-Maximilians-Universität, Butenandtstr. 5-13, 81377 München, Germany. ernst.wagner@cup.uni-muenchen.de and Nanosystems Initiative Munich (NIM), Schellingstr. 4, 80799 München, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004912:Erythrocytes; D020868:Gene Silencing; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008055:Lipids / Q000737:chemistry*; D051379:Mice; D010084:Oxidation-Reduction; D011108:Polymers / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage*
chemical_list: D008055:Lipids; D011108:Polymers; D034741:RNA, Small Interfering