Institute of Protein Biochemistry, CNR, Naples, Italy.
Toxicol Lett. 2013 Mar 27;218(1):10-7. doi: 10.1016/j.toxlet.2012.12.019. Epub 2013 Jan 4.
The ultrasmall size and unique properties of polymeric nanoparticles (NPs) have led to raising concerns about their potential cyto- and genotoxicity on biological systems. Polyethylenimine (PEI) is a highly positive charged polymer and is known to have varying degree of toxic effect to cells based on its chemical structure (i.e., amount of primary and secondary amine). Herein, drug delivery carriers such as PEI-PLGA nanoparticles (PEI-NPs) and acetylated PEI-PLGA nanoparticles (AcPEI-NPs) were utilized to examine the effect of acetylation on NPs biocompatibility and genotoxicity, using human primary cells as in vitro model. Cell uptake of NPs was characterized along with their effects on cellular viability. The results indicate that both NPs showed an equivalent behavior in terms of uptake and biocompatibility. In depth analysis of NP uptake on cell biology evidenced that these nanoparticles induced dose dependant genotoxic effects. This phenomenon was significantly reduced by PEI acetylation. Endocytosed PEI-NPs trigger an oxidative stress on cells by inducing the production of reactive oxygen species (ROS), which cause DNA damage without apparently affecting cell viability. Thus, the genotoxicity of nanoparticles, that could be used as non-viral drug carriers, should be evaluated based on the intracellular level of ROS generation and DNA damage even in absence of a significant cell death.
聚合物纳米粒子（NPs）的超小尺寸和独特性质引起了人们对其在生物系统中潜在细胞毒性和遗传毒性的关注。聚乙烯亚胺（PEI）是一种带正电荷的高分子聚合物，其化学结构（即伯胺和仲胺的数量）决定了它对细胞具有不同程度的毒性作用。在此，利用聚乙烯亚胺-聚乳酸-羟基乙酸共聚物纳米粒子（PEI-NPs）和乙酰化聚乙烯亚胺-聚乳酸-羟基乙酸共聚物纳米粒子（AcPEI-NPs）等药物递送载体，以人原代细胞为体外模型，考察了乙酰化对 NPs 生物相容性和遗传毒性的影响。对 NPs 的细胞摄取及其对细胞活力的影响进行了表征。结果表明，两种 NPs 在摄取和生物相容性方面表现出相同的行为。对 NP 摄取对细胞生物学的深入分析表明，这些纳米粒子诱导了剂量依赖性的遗传毒性效应。PEI 乙酰化显著降低了这种现象。内吞的 PEI-NPs 通过诱导活性氧（ROS）的产生引发细胞氧化应激，从而导致 DNA 损伤，而不会明显影响细胞活力。因此，即使没有明显的细胞死亡，也应根据细胞内 ROS 生成和 DNA 损伤的水平来评估可作为非病毒药物载体的纳米颗粒的遗传毒性。
