抗氧化剂分子修饰的巯基聚乙二醇金纳米颗粒的合成及其抗氧化应激机制研究

Gold nanoparticles (AuNPs) have become an indispensable tool in the development of clinical diagnostics and therapy. With the widely application of AuNPs, the cytotoxicity of AuNPs became one of the most important factors that should be primarily considered and evaluated, before making their application in practice. Account of previous studies demonstrated that the cytotoxicity of AuNPs is relevant with the generation of oxidative stress, which accompanied with the production of a variety of reactive oxygen species (ROS). Althouth the cytotoxicity of AuNPs can be relieved by surface functionalized with PEG, there still exist oxidative stress that influence its application in vivo.Therefore, it is of great significant to solve the cytotoxicity of AuNPs.Herein, based on our previous study, the antioxidants with high antioxidant activity was synthesized which were used as surface functionalization ligands. Subsequently, by self-assembly method, the gold nanoparticles (4.5 nm) were synthesized using the thiolated triethylene glycol/thiolated PEG5000 and the synthesized antioxidants as ligands. Moreover, the antioxidants with high antioxidant activity were selected by bioassay and toxicity assessment; the mechanism of oxidative stress were also studied, which might provide an ideal platform for the biological application of gold nanoparticles.

随着金纳米颗粒逐步应用于临床诊断和药物输运等诸多领域，其作为载体的生物安全性就成为亟待解决的关键问题之一。目前普遍认为金纳米颗粒的毒性主要是由其造成的氧化应激损伤导致的，尽管这种氧化应激损伤可以通过表面巯基聚乙二醇化得以改善，但仍存在氧化应激损伤问题。因此，如何解决巯基聚乙二醇保护的金纳米颗粒所带来的毒性问题对于金纳米颗粒的生物学应用具有重要的现实意义。本研究在前期工作基础上，选取巯基二缩三乙二醇或巯基PEG5000作为配基，4.5nm金纳米颗粒作为纳米模型，拟通过合成不同活性的抗氧化剂分子，通过自组装方式制备抗氧化剂分子修饰的巯基聚乙二醇保护的金纳米颗粒，然后通过生物活性检测和毒性评估筛选出具有高效抑制氧化应激特性的金纳米颗粒，并对其抗氧化应激机制进行研究。基于上述研究，阐释提高巯基聚乙二醇保护的金纳米颗粒生物安全性的设计思路和方案，为巯基聚乙二醇保护的金纳米颗粒的生物学应用奠定基础。

本项目以巯基聚乙二醇为配基，制备了不同粒径的巯基聚乙二醇保护的金纳米颗粒，通过检测其对血液中红细胞携氧能力、变形能力、寿命、以及细胞毒性实验等指标，发现4.5nm金纳米颗粒具有氧化应激效应。为解决上述问题，制备了抗氧化剂分子修饰的巯基聚乙二醇保护的金纳米颗粒，并对其进行了结构表征。通过与巯基聚乙二醇修饰的金纳米颗粒细胞上的生物活性和毒性等指标的对比，如活性氧水平，线粒体膜电位，以及细胞周期等检测，获得了高效抑制氧化应激特性的金纳米颗粒。随后通过流式细胞术、western blotting等方法对其抗氧化应激的分子机制机制进行了研究。此外，本项目还探索了基于金纳米颗粒为载体的药物方面的应用。