创新药物体内整体分析及原位表征的新方法研究

The aim of the project is to solve the key problem regarding the dynamic change and interaction of drug and endogenous metabolites in vivo by the integrated LC-MS/MS based metabonomics and the technique of imaging mass spectrometry (IMS); and the development of a new method for overall and in situ biopharmaceutical analysis will be carried out. The objects of this study will focus on the anti-breast cancer drug candidate (LXY6006),normal Taxol injection and novol Taxol intralipid preparations. The metabonomics method will be used to discover the drug metabolic characteristics, the change pattern of endogenous metabolites and the biomarkers related to disease models or drug action. A novel AFAI-IMS method will be established to obtain in situ spatial and chemical information of parent drugs and metabolites in whole-body tissue sections; and the target organs of drugs can be directly mapped. The acquired information will lay a foundation to disclose the relevance of the biological transformation pattern and distribution characteristic with the effect and toxicity of new drugs, thus providing critical basis for the early prediction of drug effect and toxicity. This project aims at developing a novel method for overall and in situ biopharmaceutical analysis of innovative drugs, furthermore providing a creative protocol for prediction and evaluation of action mechanism, effect, metabolism and toxicity of drug candidates.

本项目针对药物及代谢产物在体内的动态变化及其与药效、毒性的相关性，药物与内源性代谢物的相互影响等关键科学问题，采用代谢组学方法与质谱分子成像新技术相结合的思路，拟开展药物体内分析新方法研究。选择抗乳腺癌候选新药（LXY6006）和阳性对照药紫杉醇普通制剂及其新型乳剂为研究对象，采用LC-MS/MS代谢组学方法同时获取药物的代谢特征和药物作用下内源性代谢物的变化规律，寻找与疾病模型、药物作用相关的生物标志物；进一步采用质谱成像新技术（AFAI-IMS），从整体动物水平进行药物及其代谢产物、生物标志物的原位表征，获取药物的器官分布和肿瘤靶向特征。在此基础上考察与总结其变化规律和分布特征与药物毒性、药效之间的相关性，为新药的药效、毒性的早期预测及肿瘤靶向特征等提供关键依据。本项目旨在建立创新药物体内整体分析及原位表征新方法，并为候选新药的作用机制、药效及毒性的预测与评价提供新的研究手段。

本项目针对药物及其代谢产物在动物体内的动态变化，药物药效、毒性与内源性代谢物的相关性等关键科学问题，采用代谢组学方法与质谱分子成像新技术相结合的思路，整合体内微量药物代谢产物分析鉴定、药物和代谢组靶向定量与非靶向相对定量同时分析、生物组织原位处理和整体动物体内药物原位表征的质谱成像方法，发展了整体分析及原位表征的药物体内分析新方法。通过建立裸鼠乳腺癌移植瘤模型，选择候选新药（LXY6006）和阳性对照药紫杉醇及不同制剂为研究对象，采用上述方法获得了药物在动物体内的代谢特征和药物作用下内源性代谢物的变化规律、药物及其作用相关的代谢物的组织分布特征和肿瘤靶向特征，发现若干个与疾病模型、药物作用相关的小分子生物标志物，为新药研发的药效、毒性早期预测及肿瘤靶向性等提供关键信息。本项目建立的创新药物体内整体分析及原位表征新方法，不仅具有发现低丰度生物标志物的优势，更能获得药物及其作用相关的生物标志物在整体动物、组织微区中的分布特征和变化规律，为候选新药的作用机制、药效及毒性的预测与评价提供新的研究手段。本项目发表论文6篇，其中Anal.Chem.2篇；培养博士研究生2名；项目负责人应邀做大会学术报告15次。