Impact of Surface Polyethylene Glycol (PEG) Density on Biodegradable Nanoparticle Transport in Mucus ex Vivo and Distribution in Vivo

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• 作者：Qingguo Xu ; Laura M. Ensign ; Nicholas J. Boylan ; Arne Sch枚n ; Xiaoqun Gong ; Jeh-Chang Yang ; Nicholas W. Lamb ; Shutian Cai ; Tao Yu ; Ernesto Freire ; Justin Hanes
• 刊名：ACS Nano
• 出版年：2015
• 出版时间：September 22, 2015
• 年：2015
• 卷：9
• 期：9
• 页码：9217-9227
• 全文大小：669K
• ISSN：1936-086X

文摘

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, 鈥淢PP鈥? 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 鈥渟tealth鈥?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鈥揚EG_5k) with PLGA. We then evaluated the impact of PEG surface density, measured using an ¹H 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鈥揚EG 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.