Cahn Devorah, Duncan Gregg A
Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742 USA.
Biophysics Program, University of Maryland, College Park, MD 20742 USA.
Cell Mol Bioeng. 2022 Jul 5;15(5):355-366. doi: 10.1007/s12195-022-00727-x. eCollection 2022 Oct.
The surface modification of nanoparticles (NP) with a dense layer of polyethylene glycol (PEG) has been widely used to improve NP circulation time, bioavailability, and diffusion through biological barriers [e.g. extracellular matrix (ECM), mucus]. While linear PEG coatings are commonly used, branched PEG coatings have not been widely explored as a design parameter for NP drug delivery systems.
NPs were densely coated with either linear 2, 5, 10 kDa linear PEG or with 10 kDa star-shaped, 4-arm branched PEG. NP cellular uptake was evaluated in HEK-293T and A549 cells. NP stability was evaluated in fetal bovine serum over 24 h using dynamic light scattering. Diffusion of NPs within a Matrigel ECM model and sputum (mucus) collected from individuals with cystic fibrosis (CF) lung disease were analyzed through multiple particle tracking.
PEG-coated NPs appeared more stable in serum compared to uncoated NPs, but the reduction in total protein adsorbed was most significant for branched PEG coated NP. All PEGylated NPs had similar cellular uptake in HEK-293T and A549 cells. Interestingly, branched-PEG coated NPs had the largest diffusion coefficient and moved most rapidly through Matrigel. However in CF mucus, linear 2 and 5 kDa PEG coated NPs had the largest fraction of rapidly diffusing particles while branched PEG coated NPs had less hindered mobility compared to linear 10 kDa PEG coated NPs.
Branched PEGylation may have the potential to increase NP efficiency in reaching target cells based on an apparent increase in diffusion through an ECM model while maintaining NP stability and uptake in target cells comparable to their linear PEG counterparts.
用致密的聚乙二醇（PEG）层对纳米颗粒（NP）进行表面修饰已被广泛用于延长NP的循环时间、提高生物利用度以及促进其通过生物屏障[如细胞外基质（ECM）、黏液]扩散。虽然线性PEG涂层常用，但支化PEG涂层作为NP药物递送系统的设计参数尚未得到广泛研究。
NP分别用2 kDa、5 kDa、10 kDa的线性PEG或10 kDa的星形四臂支化PEG进行致密包被。在HEK-293T细胞和A549细胞中评估NP的细胞摄取情况。使用动态光散射在胎牛血清中评估NP在24小时内的稳定性。通过多粒子追踪分析NP在基质胶ECM模型和从囊性纤维化（CF）肺病患者收集的痰液（黏液）中的扩散情况。
与未包被的NP相比，PEG包被的NP在血清中似乎更稳定，但对于支化PEG包被的NP，吸附的总蛋白减少最为显著。所有聚乙二醇化的NP在HEK-293T细胞和A549细胞中的细胞摄取情况相似。有趣的是，支化PEG包被的NP具有最大的扩散系数，并且在基质胶中移动最快。然而，在CF黏液中，线性2 kDa和5 kDa PEG包被的NP具有快速扩散颗粒的最大比例，而与线性10 kDa PEG包被的NP相比，支化PEG包被的NP的迁移受阻碍较小。
基于通过ECM模型的扩散明显增加，同时保持NP稳定性以及在靶细胞中的摄取与线性PEG对应物相当，支化聚乙二醇化可能具有提高NP到达靶细胞效率的潜力。
