title: Sulfonate-modified phenylboronic acid-rich nanoparticles as a novel mucoadhesive drug delivery system for vaginal administration of protein therapeutics: improved stability, mucin-dependent release and effective intravaginal placement.
abstract: Effective interaction between mucoadhesive drug delivery systems and mucin is the basis of effective local placement of drugs to play its therapeutic role after mucosal administration including vaginal use, which especially requires prolonged drug presence for the treatment of gynecological infectious diseases. Our previous report on phenylboronic acid-rich nanoparticles (PBNPs) demonstrated their strong interaction with mucin and mucin-sensitive release profiles of the model protein therapeutics interferon (IFN) in vitro, but their poor stability and obvious tendency to aggregate over time severely limited future application. In this study, sulfonate-modified PBNPs (PBNP-S) were designed as a stable mucoadhesive drug delivery system where the negative charges conferred by sulfonate groups prevented aggregation of nanoparticles and the phenylboronic acid groups ensured effective interaction with mucin over a wide pH range. Results suggested that PBNP-S were of spherical morphology with narrow size distribution (123.5 nm, polydispersity index 0.050), good stability over a wide pH range and 3-month storage and considerable in vitro mucoadhesion capability at vaginal pH as shown by mucin adsorption determination. IFN could be loaded to PBNP-S by physical adsorption with high encapsulation efficiency and released in a mucin-dependent manner in vitro. In vivo near-infrared fluorescent whole animal imaging and quantitative vaginal lavage followed by enzyme-linked immunosorbent assay (ELISA) assay of IFN demonstrated that PBNP-S could stay in the vagina and maintain intravaginal IFN level for much longer time than IFN solution (24 hours vs several hours) without obvious histological irritation to vaginal mucosa after vaginal administration to mice. In summary, good stability, easy loading and controllable release of protein therapeutics, in vitro and in vivo mucoadhesive properties and local safety of PBNP-S suggested it as a promising nanoscale mucoadhesive drug delivery system for vaginal administration of protein therapeutics.
authors.affiliation: School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin.
authors.forename: ChunYan
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University.
authors.forename: ZhiGang
authors.initials: Z
authors.lastname: Huang
authors.affiliation: School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin.
authors.forename: ZheShuo
authors.initials: Z
authors.lastname: Liu
authors.affiliation: School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai, People's Republic of China.
authors.forename: LiQian
authors.initials: L
authors.lastname: Ci
authors.affiliation: School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai, People's Republic of China.
authors.forename: ZhePeng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin.
authors.forename: XueYing
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University.
authors.forename: WeiYue
authors.initials: W
authors.lastname: Lu
mesh_terms: D000268:Adhesiveness; D000282:Administration, Intravaginal; D000818:Animals; D001897:Boronic Acids / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism; D065546:Drug Liberation; D004355:Drug Stability; D005260:Female; D006801:Humans; D051379:Mice; D009077:Mucins / Q000378:metabolism*; D009092:Mucous Membrane / Q000737:chemistry / Q000378:metabolism; D050997:Nanomedicine; D053758:Nanoparticles / Q000737:chemistry*; D011506:Proteins / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use; D013451:Sulfonic Acids / Q000737:chemistry*; D014621:Vagina / Q000378:metabolism
chemical_list: D001897:Boronic Acids; D004337:Drug Carriers; D009077:Mucins; D011506:Proteins; D013451:Sulfonic Acids; C010686:benzeneboronic acid
keywords: controlled-release; mucoadhesion; nanoparticles; phenylboronic acid; protein therapeutics; stability