基于质谱新技术的PEG-PLA紫杉醇纳米胶束体内多形态成分的精准分析

Nanoparticles (NP) have brought breakthroughs and hopes for cancer treatment, but it also faces the scientific problems that cannot be solved via traditional pharmacokinetics. As a result, the intensive NP research has not lead to the development of many new drugs. The nanoscale effects of NP and its differential release in various environments have greatly altered the process and biodistribution of the drug in vivo. The traditional pharmacokinetic methods and theories based on the total drug concentration has not taken NP into account and can not reveal the complicated drug release process and metabolism mechanism in vivo. The "blind spot" of the NP pharmacokinetics has become the constraint to the efficacy, toxicity evaluation and clinical application of micelles. This study uses PEG-PLA paclitaxel micelles as a model drug, using LC-DMS-SWATH strategy combined with three different separation techniques to analyze the PEG-PLA nanomicelle delivery system. The one that breaks through the limits of the traditional quantitation methods will be discovered. The change of the dynamic process of drug-loaded micelles, released drug and macromolecular excipients in the body will be analyzed precisely to elucidate the complex DMPK relationship of micelles in cell, tissue and system levels, and clarify the interactions between them and biomacromolecules in vivo, which will provide a scientific basis for the drug design and the research of pharmacological and toxicological mechanisms. This study will enrich and expand the basic theory and the technolygy regarding the pharmacokinetics and drug analysis of nano-drug delivery system, it will also promote the development of micellar drug delivery system.

纳米给药系统（NP）给肿瘤治疗带来了突破和希望，但也面临着传统药代动力学无法解决的科学问题，导致大规模NP研究并未带来更多新药。NP的纳米尺度效应及其在体内不同环境下的差异化释放，极大地改变了药物的体内过程和生物分布。但是，基于总药物浓度的传统药代分析方法不能揭示NP在体内存在的具体形态及其复杂的释药过程，NP的药代动力学“盲区”已成为制约其药效、毒性评价以及临床应用的瓶颈。本课题拟以PEG-PLA紫杉醇胶束为模型药物，采用LC-DMS-SWATH-HRMS技术，综合其在时间、空间、质量上的分离优势，精准分析载药胶束、释放药、高分子聚合物在体内的动态变化过程，探索胶束在细胞、组织和系统水平上复杂的DMPK规律，并阐明其与体内生物大分子之间的相互作用关系，为胶束的科学设计和药理毒理机制研究提供科学依据，从而丰富和拓展NP药代动力学和药物分析学的基础理论与技术手段，推动胶束给药系统研发进程。

纳米给药系统（NP）给肿瘤治疗带来了突破和希望，但也面临着传统药代动力学无法解决的科学问题，导致大规模NP研究并未带来更多新药。NP的纳米尺度效应及其在体内不同环境下的差异化释放，极大地改变了药物的体内过程和生物分布。但是，基于总药物浓度的传统药代分析方法不能揭示NP在体内存在的具体形态及其复杂的释药过程，NP的药代动力学“盲区”已成为制约其药效、毒性评价以及临床应用的瓶颈。本课题以具有代表性的PEG-PLA紫杉醇胶束、直链三价PEG化伊立替康胶束、TPGS胶束等为模型，基于液相色谱-高分辨质谱SWATH新技术，建立了聚合物胶束释放药物、载药胶束、高分子聚合物及其代谢产物等多形态成分的定量分析方法，开展了聚合物胶束在细胞水平和系统水平的药代动力学研究，精准解析了载药胶束、释放药、高分子聚合物在体内的动态变化过程，揭示了胶束在细胞、组织和系统水平上复杂的DMPK规律，并阐明了其与细胞色素P450酶之间的相互作用关系。这为胶束的科学设计和药理毒理机制研究提供了科学依据，也为NP药代动力学和药物分析学提供了有力的技术手段。