药物经PEG化修饰后，能够明显改善其在体内的生物相容性和半衰期，具有重要的临床价值。PEG化研究亟需建立定量分析PEG及PEG化药物的方法，但传统的免疫法与放射标记法无法实现体内PEG化药物的不同形态分析，无法揭示PEG化药物体内的复杂分布平衡及代谢机制，难以阐明药物PEG化带来的药理、毒理动力学新问题，制约了PEG化药物的研究。本课题基于液相色谱-高分辨质谱SWATH新技术，为PEG化药物的形态分析提供了可能的解决方案。本课题拟以三种PEG化药物为模型，采用不同的质谱裂解和扫描模式，结合色谱与共振能量转移荧光光谱等技术，分别建立PEG、游离药物和PEG化药物的定量分析方法，研究PEG药物整体裂解规律，“颗粒药”、“高分子药”和“释放药物”三种状态在体内的动态变化规律，探索PEG化药物在细胞、组织和系统水平上复杂的DMPK关系,，为PEG化药物的科学设计及其药理毒理机制提供科学依据

With the modifying of PEG groups, the biocompatibility and half-life of drugs can be significantly improved in vivo with better prospects for clinical application. However, the large-scale research for the pegylated drugs did not bring many new pegylated drugs available, and the reason may be the traditional immunoassay and radio-labeled method can not distinguish the different forms of pegylated drugs, reveal the complex distribution equilibrium and metabolic mechanisms of the pegylated drugs, and explain the new pharmacological and toxicological problems of pegylated drugs, which restrict the rapid development of pegylated drugs. The rapid development of mass spectrometry provides the possible solution for the morphological analysis of drugs. This project intends to use three kinds of pegylated drugs as models by the combination of SWATH method and fluorescence energy transfer spectroscopy techniques. This project intends to establish a quantitative analysis method for PEG itself, free drugs and pegylated drugs, and the purpose is to study the overall fragmentation patterns of pegylated drugs, clarify the dynamic change rules of “particle drug”, “polymer drug” and “released drug” in vivo, explore the complex DMPK relationship of pegylated drugs in cell, tissue and system levels and provide a scientific basis for the design and research of pharmacology and toxicology mechanism of pegylated drugs.