title: Multifunctional dendronized peptide polymer platform for safe and effective siRNA delivery.
abstract: In this study, we designed and synthesized a biodegradable dendronized polypeptide (denpol) platform for delivery of small interfering RNA (siRNA). The novel denpol architecture combines the multivalency of dendrimers and conformational flexibility of linear polymers for optimal siRNA binding. Multifunctional amino acids were incorporated onto the dendrons and the structure was tuned both systematically and combinatorially to select optimal vectors. By screening a focused library, we identified several denpols that can effectively deliver siRNA to NIH 3T3 cells in vitro and exhibit minimal toxicity. For comparison, the best-performing denpol showed significantly improved transfection efficiency over Lipofectamine in serum-containing media. Fluorescence intracellular trafficking studies indicated that amphiphilicity is important for cell uptake and that the buffering capacity of histidine facilitates endosomal membrane rupture and therefore enhances the transfection efficiency. The combination of high delivery efficiency in serum and low cytotoxicity suggests the denpol system as a promising new carrier for siRNA delivery.
authors.affiliation: Department of Chemistry, 1102 Natural Sciences 2, University of California, Irvine , California 92697-2025, United States.
authors.forename: Hanxiang
authors.initials: H
authors.lastname: Zeng
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Little
authors.forename: Timothy N
authors.initials: TN
authors.lastname: Tiambeng
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Williams
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Guan
mesh_terms: D000818:Animals; D050091:Dendrimers / Q000737:chemistry*; D004587:Electrophoresis, Agar Gel; D005434:Flow Cytometry; D005453:Fluorescence; D018014:Gene Transfer Techniques; D051379:Mice; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000235:genetics*; D054852:Small Molecule Libraries
chemical_list: D050091:Dendrimers; D010455:Peptides; D034741:RNA, Small Interfering; D054852:Small Molecule Libraries