Nanoparticles coated with high molecular weight PEG penetrate mucus and provide uniform vaginal and colorectal distribution in vivo.
Nanoparticles coated with high molecular weight PEG penetrate mucus and provide uniform vaginal and colorectal distribution in vivo.
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DOI：
10.2217/nnm-2016-0047
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发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Hanes J
中科院分区：
文献类型：
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作者：
Maisel K;Reddy M;Xu Q;Chattopadhyay S;Cone R;Ensign LM;Hanes J
我们先前证明了用低分子量（MW，2-5 kDa）聚乙二醇（PEG）致密涂覆的纳米颗粒（NP）通过各种粘液分泌物快速扩散，而用10 kDa PEG涂覆的NP由于推测的聚合物相互渗透和与粘蛋白缠结而具有粘膜粘附性。在这里，我们证明，如果达到足够的表面密度，MW高达40 kDa的PEG可以用作粘膜惰性NP表面涂层。我们比较了用10 kDa PEG包被模型聚苯乙烯NPs的两组反应条件，并使用优化的反应条件用MW高达40 kDa的PEG包被各种尺寸的NPs。然后，我们的特点是NP运输在人宫颈阴道粘液（CVM）离体。我们进一步将PEG包被的纳米颗粒给予小鼠宫颈阴道和结肠直肠，以评估体内粘膜分布。我们在这里证明，具有高达40 kDa的MW的PEG可以密集地接枝到NP的表面，以防止与粘液的相互作用。用10-40 kDa PEG包被的NP快速扩散通过离体人CVM，并在体内均匀地衬在小鼠结肠直肠和阴道上皮上。这不仅表明NP表面上PEG的密度以及因此的构象是防止与粘液相互作用的关键，而且还重新定义和拓宽了用于改善粘膜递送的药物和基因递送系统的设计标准。
We previously demonstrated that nanoparticles (NPs) densely coated with low molecular weight (MW, 2-5 kDa) polyethylene glycol (PEG) rapidly diffused through various mucus secretions, whereas NPs coated with 10 kDa PEG were mucoadhesive due to presumed polymer interpenetration and entanglement with mucins. Here, we demonstrate that PEG with MW as high as 40 kDa can be used as a mucoinert NP surface coating if sufficient surface density is achieved. We compared two sets of reaction conditions for coating model polystyrene NPs with 10 kDa PEG and used the optimized reaction conditions to coat various sized NPs with PEG with MW as high as 40 kDa. We then characterized NP transport in human cervicovaginal mucus (CVM) ex vivo. We further administered PEG-coated NPs to the mouse cervicovaginal tract and colorectum to assess mucosal distribution in vivo. We demonstrate here that PEG with MW as high as 40 kDa can be densely grafted to the surface of NP to prevent interactions with mucus. NP coated with 10-40 kDa PEG rapidly diffused through human CVM ex vivo, and uniformly lined the mouse colorectal and vaginal epithelium in vivo. This not only suggests that the density of PEG on the NP surface, and thus the conformation, is key for preventing interactions with mucus, but also redefines and broadens the design criteria for drug and gene delivery systems for improved mucosal delivery.