title: Intravaginal gene silencing using biodegradable polymer nanoparticles densely loaded with small-interfering RNA.
abstract: Vaginal instillation of small-interfering RNA (siRNA) using liposomes has led to silencing of endogenous genes in the genital tract and protection against challenge from infectious disease. Although siRNA lipoplexes are easily formulated, several of the most effective transfection agents available commercially may be toxic to the mucosal epithelia and none are able to provide controlled or sustained release. Here, we demonstrate an alternative approach using nanoparticles composed entirely of FDA-approved materials. To render these materials effective for gene silencing, we developed novel approaches to load them with high amounts of siRNA. A single dose of siRNA-loaded nanoparticles to the mouse female reproductive tract caused efficient and sustained gene silencing. Knockdown of gene expression was observed proximal (in the vaginal lumen) and distal (in the uterine horns) to the site of topical delivery. In addition, nanoparticles penetrated deep into the epithelial tissue. This is the first report demonstrating that biodegradable polymer nanoparticles are effective delivery vehicles for siRNA to the vaginal mucosa.
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06511, USA.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Woodrow
authors.forename: Yen
authors.initials: Y
authors.lastname: Cu
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Booth
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Saucier-Sawyer
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Wood
authors.forename: W Mark
authors.initials: WM
authors.lastname: Saltzman
mesh_terms: D000818:Animals; D001672:Biocompatible Materials; D002460:Cell Line; D005260:Female; D005453:Fluorescence; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D019344:Lactic Acid / Q000008:administration & dosage*; D051379:Mice; D008813:Mice, Inbred ICR; D009092:Mucous Membrane; D053758:Nanoparticles; D011100:Polyglycolic Acid / Q000008:administration & dosage*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D014621:Vagina
chemical_list: D001672:Biocompatible Materials; D034741:RNA, Small Interfering; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid