title: SiRNA delivery systems based on neutral cross-linked dendrimers.
abstract: A neutral cross-linked dendritic system is described for use of delivering small interfering RNA (siRNA) for targeted gene silencing. By replacing the terminal amines with hydrazide groups and N-acetylgalactosamine (GalNAc) ligands, cationic polyamidoamine (PAMAM) dendrimers were transformed into neutral glycosylated carriers for siRNA delivery. Mainly owing to the pH sensitivity and the proton-absorption capability of the tertiary amines within the interior branches, these PAMAM derivatives showing neutrality under physiological conditions (pH 7.4) formed complexes with siRNA through electrostatic interactions at pH 5. Cross-linking procedures via reactions with glutaraldehyde were established, and cytocompatible cross-linked systems loaded with siRNA obtained, with the particulate properties variable with the cross-linking condition and the GalNAc level in the dendritic carrier. In vitro cellular uptake and RNAi experiments showed that the cross-linked dendritic systems with an appropriate level of GalNAc composition effectively interacted with HepG2 cells and inhibited the expression of a luciferase reporter gene. Neutral cross-linked dendritic systems provide a new paradigm for designing siRNA delivery systems with biocompatibility and targeting capability.
authors.affiliation: Department of Biomedical Engineering, College of Engineering, Peking University, Room 206, Fangzheng Building, 298 Chengfu Road, Haidian District, Beijing, China 100871.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Jihan
authors.initials: J
authors.lastname: Zhou
authors.forename: Ying
authors.initials: Y
authors.lastname: Luo
mesh_terms: D000116:Acetylgalactosamine / Q000737:chemistry*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000737:chemistry*; D050091:Dendrimers / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018014:Gene Transfer Techniques; D017930:Genes, Reporter / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D015394:Molecular Structure; D010316:Particle Size; D011073:Polyamines / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D003432:Cross-Linking Reagents; D050091:Dendrimers; D004337:Drug Carriers; D008024:Ligands; C104700:PAMAM Starburst; C531249:Poly(amidoamine); D011073:Polyamines; D034741:RNA, Small Interfering; D008156:Luciferases; D000116:Acetylgalactosamine