title: Improvements in Rational Design Strategies of Inulin Derivative Polycation for siRNA Delivery.
abstract: The advances of short interfering RNA (siRNA)-mediated therapy provide a powerful option for the treatment of many diseases, including cancer, by silencing the expression of targeted genes involved in the progression of the pathology. On this regard, a new pH-responsive polycation derived from inulin, Inulin-g-imidazole-g-diethylenetriamine (INU-IMI-DETA), was designed and employed to produce INU-IMI-DETA/siRNA "Inulin COmplex Nanoaggregates" (ICONs). The experimental results showed that INU-IMI-DETA exhibited strong cationic characteristics and high solubility in the pH range 3-5 and self-aggregation triggered by pH increase and physiological salt concentration. INU-IMI-DETA showed as well a high buffering capacity in the endosomal pH range of 7.4-5.1. In the concentration range between 25 and 1000 μg/mL INU-IMI-DETA had no cytotoxic effect on breast cancer cells (MCF-7) and no lytic effect on human red blood cells. ICONs were prepared by two-step procedure involving complexation and precipitation into DPBS buffer (pH 7.4) to produce siRNA-loaded nanoaggregates with minimized surface charge and suitable size for parenteral administration. Bafilomycin A1 inhibited transfection on MCF-7 cells, indicating that the protonation of the imidazole groups in the endolysosome pathway favors the escape of the system from endolysosomal compartment, increasing the amount of siRNA that can reach the cytoplasm.
authors.affiliation: Lab of Biocompatible Polymers, Dipartimento di Scienze e Tecnologie Biologiche, Chimiche, Farmaceutiche (STEBICEF), University of Palermo , via Archirafi 32, Palermo 90123, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Sardo
authors.affiliation: Lab of Biocompatible Polymers, Dipartimento di Scienze e Tecnologie Biologiche, Chimiche, Farmaceutiche (STEBICEF), University of Palermo , via Archirafi 32, Palermo 90123, Italy.
authors.forename: Emanuela Fabiola
authors.initials: EF
authors.lastname: Craparo
authors.affiliation: Lab of Biocompatible Polymers, Dipartimento di Scienze e Tecnologie Biologiche, Chimiche, Farmaceutiche (STEBICEF), University of Palermo , via Archirafi 32, Palermo 90123, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Porsio
authors.affiliation: Lab of Biocompatible Polymers, Dipartimento di Scienze e Tecnologie Biologiche, Chimiche, Farmaceutiche (STEBICEF), University of Palermo , via Archirafi 32, Palermo 90123, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Giammona
authors.affiliation: Lab of Biocompatible Polymers, Dipartimento di Scienze e Tecnologie Biologiche, Chimiche, Farmaceutiche (STEBICEF), University of Palermo , via Archirafi 32, Palermo 90123, Italy.
authors.forename: Gennara
authors.initials: G
authors.lastname: Cavallaro
mesh_terms: D016503:Drug Delivery Systems; D015195:Drug Design; D004705:Endocytosis; D020868:Gene Silencing; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007444:Inulin / Q000008:administration & dosage* / Q000737:chemistry; D061986:MCF-7 Cells; D011073:Polyamines / Q000008:administration & dosage* / Q000737:chemistry; D000071228:Polyelectrolytes; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D007444:Inulin; D011073:Polyamines; D000071228:Polyelectrolytes; D034741:RNA, Small Interfering; C005391:diethylenetriamine