'Stealth' corona-core nanoparticles surface modified by polyethylene glycol (PEG):: influences of the corona (PEG chain length and surface density) and of the core composition on phagocytic uptake and plasma protein adsorption
'Stealth' corona-core nanoparticles surface modified by polyethylene glycol (PEG):: influences of the corona (PEG chain length and surface density) and of the core composition on phagocytic uptake and plasma protein adsorption
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DOI：
10.1016/s0927-7765(99)00156-3
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发表时间：
2000-10-01
影响因子：
5.8
通讯作者：
Müller, RH
中科院分区：
文献类型：
--
作者：
Gref, R;Lück, M;Müller, RH
具有聚乙二醇（PEG）链的纳米粒是一种具有潜在应用前景的血液长效给药系统。考虑到蛋白质与注射的胶体dug载体的相互作用的重要性，就其在体内的命运，我们分析了血浆蛋白吸附到可生物降解的PEG-涂层的聚（乳酸）（PLA），聚（乳酸-共-乙醇酸）（PLGA）和聚（ε-己内酯）（PCL）纳米粒子采用二维凝胶电泳（2-D PAGE）。由二嵌段PEG-PLA、PEG-PLGA和PEG-PCL以及由PEG-PLA：PLA共混物制备尺寸为160-270 nm的一系列冠/核纳米颗粒。PEG Mw从2000-20 000 g/mol变化，并且使用不同的PEG含量制备颗粒。因此，可以研究PEG冠的厚度和密度的影响，以及核心的性质（PLA，PLGA或PCL）的影响，对竞争性血浆蛋白吸附，zeta电位和颗粒摄取的多形核细胞（PMN）细胞。2-D PAGE研究表明，血浆蛋白在PEG包被的PLA纳米球上的吸附强烈依赖于PEG分子量（Mw）（即颗粒表面处的PEG链长度）以及颗粒中的PEG含量（即颗粒表面处的PEG链密度）。无论冠层的厚度或密度如何，血浆蛋白吸附模式的定性组成非常相似，表明吸附受与或多或少受PEG链保护的PLA表面相互作用的影响。凝胶上的主要斑点是白蛋白、纤维蛋白原、IgG、IG轻链和载脂蛋白apoA-I和apoE。对于由具有不同PEG Mw的PEG-PLA 45 K制成的颗粒，发现PEG Mw为5000 g/mol时蛋白质吸附的最大降低。对于PEG含量在0.5至20重量%之间不同的纳米球，将2至5重量%之间的PEG含量确定为最佳蛋白质抗性的阈值。当将纳米颗粒中的PEG含量增加到5重量%以上时，没有实现蛋白质吸附的进一步降低。通过使用化学发光和zeta电位数据研究PMN的吞噬作用与这些发现一致：发现相同的PEG表面密度阈值同时确保有效的空间稳定性并避免PMN细胞的摄取。假设所有的PEG链都迁移到表面，这将对应于覆盖“刷”中两个末端连接的PEG链之间约1.5 nm的距离。来自PEG 5 K-PLA 45 K、PEG 5 K-PLGA 45 K和PEG 5 K-PCL 45 K共聚物的颗粒使得能够研究核心对血浆蛋白吸附的影响，所有其他参数（冠厚度和密度）保持恒定。吸附模式在良好的定性协议彼此。只有少数蛋白质物种仅存在于一种类型的纳米颗粒上。然而，蛋白质吸附的程度在很大程度上从一个颗粒到另一个颗粒不同。体内研究可以帮助阐明静脉给药后吸附在纳米颗粒命运上的蛋白质的类型和数量的作用，作为其核心性质的函数。这些结果可能是有用的，在设计长循环静脉注射可生物降解的药物载体赋予蛋白质抗性和低吞噬摄取的性能。(C)2000 Elsevier Science B. V.保留所有权利。
Nanoparticles possessing poly(ethylene glycol) (PEG) chains on their surface have been described as blood persistent drug delivery system with potential applications for intravenous drug administration. Considering the importance of protein interactions with injected colloidal dug carriers with regard to their in vivo fate, we analysed plasma protein adsorption onto biodegradable PEG-coated poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA) and poly(epsilon-caprolactone) (PCL) nanoparticles employing two-dimensional gel electrophoresis (2-D PAGE). A series of corona/core nanoparticles of sizes 160-270 nm were prepared from diblock PEG-PLA, PEG-PLGA and PEG-PCL and from PEG-PLA:PLA blends. The PEG Mw was varied from 2000-20 000 g/mole and the particles were prepared using different PEG contents. It was thus possible to study the influence of the PEG corona thickness and density, as well as the influence of the nature of the core (PLA, PLGA or PCL), on the competitive plasma protein adsorption, zeta potential and particle uptake by polymorphonuclear (PMN) cells. 2-D PAGE studies showed that plasma protein adsorption on PEG-coated PLA nanospheres strongly depends on the PEG molecular weight (Mw) (i.e. PEG chain length at the particle surface) as well as on the PEG content in the particles (i.e. PEG chain density at the surface of the particles). Whatever the thickness or the density of the corona, the qualitative composition of the plasma protein adsorption patterns was very similar, showing that adsorption was governed by interaction with a PLA surface protected more or less by PEG chains. The main spots on the gels were albumin, fibrinogen, IgG, Ig light chains, and the apolipoproteins apoA-I and apoE. For particles made of PEG-PLA45K with different PEG Mw, a maximal reduction in protein adsorption was found for a PEG Mw of 5000 g/mole. For nanospheres differing in their PEG content from 0.5 to 20 wt %, a PEG content between 2 and 5 wt % was determined as a threshold value for optimal protein resistance. When increasing the PEG content in the nanoparticles above 5 wt % no further reduction in protein adsorption was achieved. Phagocytosis by PMN studied using chemiluminescence and zeta potential data agreed well with these findings: the same PEG surface density threshold was found to ensure simultaneously efficient steric stabilization and to avoid the uptake by PMN cells. Supposing all the PEG chains migrate to the surface, this would correspond to a distance of about 1.5 nm between two terminally attached PEG chains in the covering 'brush'. Particles from PEG5K-PLA45K, PEG5K-PLGA45K; and PEG5K-PCL45K copolymers enabled to study the influence of the core on plasma protein adsorption, all other parameters (corona thickness and density) being kept constant. Adsorption patterns were in good qualitative agreement with each other. Only a few protein species were exclusively present just on one type of nanoparticle. However, the extent of proteins adsorbed differed in a large extent from one particle to another. In vivo studies could help elucidating the role of the type and amount of proteins adsorbed on the fate of the nanoparticles after intraveinous administration, as a function of the nature of their core. These results could be useful in the design of long circulating intravenously injectable biodegradable drug carriers endowed with protein resistant properties and low phagocytic uptake. (C) 2000 Elsevier Science B.V. All rights reserved.