Impact of Surface Polyethylene Glycol (PEG) Density on Biodegradable Nanoparticle Transport in Mucus ex Vivo and Distribution in Vivo.
Impact of Surface Polyethylene Glycol (PEG) Density on Biodegradable Nanoparticle Transport in Mucus ex Vivo and Distribution in Vivo.
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DOI：
10.1021/acsnano.5b03876
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发表时间：
2015-09-22
期刊：
影响因子：
17.1
通讯作者：
Hanes J
中科院分区：
文献类型：
--
作者：
Xu Q;Ensign LM;Boylan NJ;Schön A;Gong X;Yang JC;Lamb NW;Cai S;Yu T;Freire E;Hanes J
实现持续的药物递送到粘膜表面是一个主要的挑战，因为存在保护性粘液层，用于捕获和快速去除外来颗粒。被工程化以快速穿透粘膜屏障的纳米颗粒（粘液穿透颗粒，“MPP”）已经显示出改善药物在粘膜表面的分布、保留和功效的前景。MPP被聚乙二醇（PEG）致密地包覆，其保护纳米颗粒核心免受与粘液的粘附相互作用。然而，赋予粘液中的纳米颗粒“隐形”性质并因此在体内均匀分布所需的PEG密度仍然是未知的。我们制备了可生物降解的聚（乳酸-共-乙醇酸）（PLGA）纳米粒子的PEG表面密度的范围内，通过共混不同比例的PLGA和5 kDa的聚（乙二醇）（PLGA-PEG 5 k）与PLGA的二嵌段共聚物。然后，我们评估了使用1H NMR方法测量的PEG表面密度对体外粘蛋白结合、离体新鲜获得的人宫颈阴道粘液（CVM）中的纳米颗粒转运和体内小鼠宫颈阴道中的纳米颗粒分布的影响。我们发现，需要至少5%的PEG来有效地屏蔽纳米颗粒核心与体外和离体粘液组分的相互作用，从而导致增强的纳米颗粒在整个小鼠阴道中的体内分布。然后，我们证明了可生物降解的MPP可以由各种分子量的PLGA和PLGA-PEG聚合物的共混物配制，并且这些MPP提供可调的药物负载和药物释放速率和持续时间。总的来说，我们描述了一种合理设计生物可降解，载药MPP更均匀地输送到阴道的方法。
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 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-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.