纳米金释药系统药代动力学与药效特异性的相关研究

Gold nanoparticles have recently emerged by an attractive carrier with highly targeting and inhibiting the angiogenesis. Angiogenes is one of the causative factors of rheumatoid arthritis. Some studies showed that folic acid and methotrexate are typical recognition molecules, which can be identified by folate receptor. The folic acid and methotrexate conjugated gold nanoparticle can play an active targeting in vivo. Currently, gold nanoparticle researches have been almost focused on the gold nanoparticle formulation and stayed in the particle surface modification stage. The pharmacokinetic and pharmacodynamic research of the gold nanoparticles drug delivery system have not been reported. We have already prepared the methotrexate/folic acid conjugated gold nanoparticles drug delivery system. We will study the pharmacokinetics in vivo and the cell toxicity in vitro of this system using the method of LC-MS/MS quantitative analysis and explain the drug delivery system pharmacokinetic and pharmacodynamic specificity research. We will study the pharmacokinetics role of the targeting drug and discuss the antibody-drug conjugets target to the treatment mechanism of rheumatoid arthritis in vivo. Using the study of gold nanoparticles cytotoxicity in vitro, we will discuss the system self degradation and toxicit, and then, estimate the usefulness of the gold nanoparticles drug delivery system for provide a theoretical basis in clinical applications. This study can provide the new idea for the antibody-drug conjugets’ pharmacokinetic research.

纳米金是近年来出现的一种新型药物载体，具有高度靶向，抑制血管再生等优点。研究表明，叶酸及甲氨蝶呤是两种典型的识别分子, 能被叶酸受体特定识别。在纳米金的表面偶联叶酸以及甲氨蝶呤，能使其在体内发挥主动靶向作用。目前，纳米金的研究主要集中在剂型研究方面，有关纳米金粒子的药代动力学以及药效学研究在国内外尚未见报道。本课题基于前期制备出甲氨蝶呤/叶酸偶联纳米金释药系统基础上，采用LC-MS/MS定量分析方法，通过对甲氨蝶呤/叶酸偶联纳米金释药系统的体内药物代谢与体外细胞毒性进行研究，分析其药代动力学与药效特异性，研究靶位药物的药代动力学规律，探讨纳米金抗体偶联药物在体内靶向治疗类风湿性关节炎的作用机制。通过对纳米金体外细胞毒性的研究，探索纳米金释药系统自身的降解和毒性，评价纳米金粒子载药体系的实用性，为纳米金释药系统在临床上的应用提供理论依据。本课题同时为抗体偶联药物的药代动力学研究探索思路。

本项目通过建立专属、准确、灵敏的抗体偶联药物在血浆和血清中的定量分析方法，即LC-MS/MS定量分析方法，研究了抗体偶联药物的药代动力学规律，为纳米金释药系统的药代动力学研究探索思路；对以纳米金为载体的甲氨蝶呤以及代谢产物7-羟基甲氨蝶呤进行了靶向性的研究，分析了药物浓度与药效的相关性与特异性，探讨纳米金释药系统在靶向治疗类风湿性关节炎的作用机制；通过对纳米金粒子体外细胞毒性的研究，探索纳米金释药系统自身的毒性，评价纳米金释药系统的实用性，为纳米金释药系统在临床上的应用提供理论依据。本课题同时为抗体偶联药物的合成以及药代动力学研究探索思路。