title: Impact of Surface Polyethylene Glycol (PEG) Density on Biodegradable Nanoparticle Transport in Mucus ex Vivo and Distribution in Vivo.
abstract: Achieving sustained drug delivery to mucosal surfaces is a major challenge due to the presence of the protective mucus layer that serves to trap and rapidly remove foreign particulates. Nanoparticles engineered to rapidly penetrate mucosal barriers (mucus-penetrating particles, "MPP") have shown promise for improving drug distribution, retention and efficacy at mucosal surfaces. MPP are densely coated with polyethylene glycol (PEG), which shields the nanoparticle core from adhesive interactions with mucus. However, the PEG density required to impart the "stealth" properties to nanoparticles in mucus, and thus, uniform distribution in vivo, is still unknown. We prepared biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles with a range of PEG surface densities by blending various ratios of a diblock copolymer of PLGA and 5 kDa poly(ethylene glycol) (PLGA-PEG5k) with PLGA. We then evaluated the impact of PEG surface density, measured using an (1)H NMR method, on mucin binding in vitro, nanoparticle transport in freshly obtained human cervicovaginal mucus (CVM) ex vivo, and nanoparticle distribution in the mouse cervicovaginal tract in vivo. We found that at least 5% PEG was required to effectively shield the nanoparticle core from interacting with mucus components in vitro and ex vivo, thus leading to enhanced nanoparticle distribution throughout the mouse vagina in vivo. We then demonstrated that biodegradable MPP could be formulated from blends of PLGA and PLGA-PEG polymers of various molecular weights, and that these MPP provide tunable drug loading and drug release rates and durations. Overall, we describe a methodology for rationally designing biodegradable, drug-loaded MPP for more uniform delivery to the vagina.
authors: Department of Ophthalmology, The Wilmer Eye Institute, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States.|Center for Nanomedicine, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States.
authors: Qingguo
authors: Q
authors: Xu
authors: Department of Ophthalmology, The Wilmer Eye Institute, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States.|Center for Nanomedicine, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States.|Department of Chemical and Biomolecular Engineering, The Johns Hopkins University , Baltimore, Maryland 21218, United States.
authors: Laura M
authors: LM
authors: Ensign
authors: Center for Nanomedicine, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States.|Department of Chemical and Biomolecular Engineering, The Johns Hopkins University , Baltimore, Maryland 21218, United States.
authors: Nicholas J
authors: NJ
authors: Boylan
authors: Department of Biology, The Johns Hopkins University , Baltimore, Maryland 21218, United States.
authors: Arne
authors: A
authors: Schön
authors: Department of Ophthalmology, The Wilmer Eye Institute, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States.|Center for Nanomedicine, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States.|Institute of Nanobiotechnology, School of Materials Science and Engineering, Tianjin University , Tianjin 300072, P.R. China.|School of Life Science, Tianjin University , Tianjin 300072, P.R. China.
authors: Xiaoqun
authors: X
authors: Gong
authors: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University , Baltimore, Maryland 21218, United States.
authors: Jeh-Chang
authors: JC
authors: Yang
authors: Department of Ophthalmology, The Wilmer Eye Institute, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States.|Center for Nanomedicine, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States.
authors: Nicholas W
authors: NW
authors: Lamb
authors: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University , Baltimore, Maryland 21218, United States.
authors: Shutian
authors: S
authors: Cai
authors: Center for Nanomedicine, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States.|Department of Biomedical Engineering, The Johns Hopkins University , Baltimore, Maryland 21205, United States.
authors: Tao
authors: T
authors: Yu
authors: Department of Biology, The Johns Hopkins University , Baltimore, Maryland 21218, United States.
authors: Ernesto
authors: E
authors: Freire
authors: Department of Ophthalmology, The Wilmer Eye Institute, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States.|Center for Nanomedicine, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States.|Department of Chemical and Biomolecular Engineering, The Johns Hopkins University , Baltimore, Maryland 21218, United States.|Department of Biomedical Engineering, The Johns Hopkins University , Baltimore, Maryland 21205, United States.|Departments of Environmental Health Sciences, Oncology, Neurosurgery, and Pharmacology & Molecular Sciences, The Johns Hopkins University , Baltimore, Maryland 21231, United States.
authors: Justin
authors: J
authors: Hanes
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems; D006801:Humans; D051379:Mice; D009093:Mucus / Q000737:chemistry / Q000187:drug effects*; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry
chemical_list: D011092:Polyethylene Glycols; D017239:Paclitaxel
keywords: PLGA; drug delivery; mucosal surface; paclitaxel; vagina