PDF(Pubmed)
Abstract：
Nanoparticle-based formulations are considered valuable tools for diagnostic and treatment purposes. The surface decoration of nanoparticles with polyethyleneimine (PEI) is often used to enhance their targeting and functional properties. Here, we aimed at addressing the long-term fate in vivo and the potential \"off-target\" effects of PEI decorated iron oxide nanoparticles (PEI-MNPs) in individuals with low-grade and persistent systemic inflammation. For this purpose, we synthesized PEI-MNPs (core-shell method, PEI coating under high pressure homogenization). Further on, we induced a low-grade and persistent inflammation in mice through regular subcutaneous injection of pathogen-associated molecular patterns (PAMPs, from zymosan). PEI-MNPs were injected intravenously. Up to 7 weeks thereafter, the blood parameters were determined via automated fluorescence flow cytometry, animals were euthanized, and the organs analyzed for iron contents (atomic absorption spectrometry) and for expression of NF-κB associated proteins (p65, IκBα, p105/50, p100/52, COX-2, Bcl-2, SDS-PAGE and Western blotting). We observed that the PEI-MNPs had a diameter of 136 nm and a zeta-potential 56.9 mV. After injection in mice, the blood parameters were modified and the iron levels were increased in different organs. Moreover, the liver of animals showed an increased protein expression of canonical NF-κB signaling pathway members early after PEI-MNP application, whereas at the later post-observation time, members of the non-canonical signaling pathway were prominent. We conclude that the synergistic effect between PEI-MNPs and the low-grade and persistent inflammatory state is mainly due to the hepatocytes sensing infection (PAMPs), to immune responses resulting from the intracellular metabolism of the uptaken PEI-MNPs, or to hepatocyte and immune cell communications. Therefore, we suggest a careful assessment of the safety and toxicity of PEI-MNP-based carriers for gene therapy, chemotherapy, and other medical applications not only in healthy individuals but also in those suffering from chronic inflammation.
摘要：
基于纳米颗粒的制剂被认为是用于诊断和治疗目的的有价值的工具。具有聚乙烯亚胺(PEI)的纳米颗粒的表面装饰通常用于增强其靶向性和功能性质。这里,我们旨在解决体内长期命运以及PEI修饰的氧化铁纳米颗粒(PEI-MNPs)在低度和持续性全身性炎症个体中潜在的"脱靶"效应.为此,我们合成了PEI-MNPs(核壳法，高压均化下的PEI涂层)。更进一步,我们通过定期皮下注射病原体相关分子模式（PAMPs，来自酵母聚糖）。静脉内注射PEI-MNPs。此后7周，通过自动荧光流式细胞术确定血液参数，动物被安乐死，和器官分析铁含量（原子吸收光谱法）和NF-κB相关蛋白的表达（p65，IκBα，p105/50，p100/52，COX-2，Bcl-2，SDS-PAGE和Western印迹）。我们观察到PEI-MNPs具有136nm的直径和56.9mV的ζ电位。小鼠注射后，改变了血液参数，不同器官的铁水平增加。此外，动物肝脏在PEI-MNP应用后早期显示经典NF-κB信号通路成员的蛋白表达增加，而在后来的观察时间，非经典信号通路的成员是突出的。我们得出结论，PEI-MNPs与低度和持续性炎症状态之间的协同作用主要是由于肝细胞感应感染（PAMPs），从摄取的PEI-MNPs的细胞内代谢产生的免疫反应，或肝细胞和免疫细胞通讯。因此,我们建议仔细评估基于PEI-MNP的基因治疗载体的安全性和毒性，化疗,和其他医疗应用，不仅在健康的人，而且在那些患有慢性炎症。
