title: Liquid crystalline phase nanodispersions enable skin delivery of siRNA.
abstract: The ability of small interfering RNAs (siRNAs) to potently but reversibly silence genes in vivo has made them particularly well suited as a new class of drugs that interfere with disease-causing or disease-promoting genes. However, the largest remaining hurdle for the widespread use of this technology in skin is the lack of an effective delivery system. The aim of the present study was to evaluate nanodispersed systems in liquid crystalline phases that deliver siRNA into the skin. The proposed systems present important properties for the delivery of macromolecules in a biological medium, as they are formed by substances that have absorption-enhancing and fusogenic effects; additionally, they facilitate entrapment by cellular membranes due to their nano-scale structure. The cationic polymer polyethylenimine (PEI) or the cationic lipid oleylamine (OAM) were added to monoolein (MO)-based systems in different concentrations, and after dispersion in aqueous medium, liquid crystalline phase nanodispersions were obtained and characterized by their physicochemical properties. Then, in vitro penetration studies using diffusion cell and pig ear skin were carried out to evaluate the effect of the nanodispersions on the skin penetration of siRNA; based on these results, the nanodispersions containing MO/OA/PEI/aqueous phase (8:2:5:85, w/w/w/w) and MO/OA/OAM/aqueous phase (8:2:2:88, w/w/w/w) were selected. These systems were investigated in vivo for skin penetration, skin irritation, and the ability to knockdown glyceraldehyde 3-phosphate dehydrogenase (GAPDH) protein levels in animal models. The results showed that the studied nanodispersions may represent a promising new non-viral vehicle and can be considered highly advantageous in the treatment of skin disorders; they were effective in optimizing the skin penetration of siRNA and reducing the levels of the model protein GAPDH without causing skin irritation.
authors.affiliation: Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Fabiana Testa Moura de Carvalho
authors.initials: FT
authors.lastname: Vicentini
authors.forename: Lívia Vieira
authors.initials: LV
authors.lastname: Depieri
authors.forename: Ana Cristina Morseli
authors.initials: AC
authors.lastname: Polizello
authors.forename: José Orestes
authors.initials: JO
authors.lastname: Del Ciampo
authors.forename: Augusto César Cropanese
authors.initials: AC
authors.lastname: Spadaro
authors.forename: Márcia C A
authors.initials: MC
authors.lastname: Fantini
authors.forename: Maria
authors.initials: M
authors.lastname: Vitória Lopes Badra Bentley
mesh_terms: D000588:Amines / Q000737:chemistry; D000818:Animals; D005260:Female; D055785:Gene Knockdown Techniques; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D005989:Glycerides / Q000737:chemistry; D050866:Liquid Crystals; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D053758:Nanoparticles; D011094:Polyethyleneimine / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000493:pharmacokinetics; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption; D013552:Swine
chemical_list: D000588:Amines; D005989:Glycerides; D034741:RNA, Small Interfering; D011094:Polyethyleneimine; C005953:monoolein; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; C008703:oleylamine