多柔比星脂质体诱发手足综合征HFS不良反应，已成为限制其肿瘤化疗治疗效果与应用范围的重要因素。针对这一关键问题，本项目在探讨多柔比星脂质体制剂特征、药动学行为与HFS发生发展关系的基础上，将研究重点聚焦于皮肤组织，利用建立的高分辨液-质联用技术，结合局部代谢组学、AFAI-MSI原位分子成像等技术，获取与HFS发病密切相关的脂质成分、代谢产物及内源性代谢产物在皮肤部位的分布和代谢特征，为病理代谢网络的研究提供重要信息；结合代谢组学研究所获得的信息，利用基因芯片技术、分子生物学等技术手段，探寻脂质体制剂在皮肤中相互作用并高效激活的靶点，阐明通过诱发炎症及凋亡最终引发HFS不良反应的相关信号通路。本项目的实施，将为深入揭示多柔比星脂质体诱发HFS不良反应的物质基础与分子机制提供新的思路，同时也为其他化疗药物及给药体系的不良反应研究提供重要的理论支撑和技术指导。

The hand-foot syndrome (HFS) induced by doxorubicin liposome has been an important factor in the limitation in treatment efficiency and scope of tumor chemotherapy. For this key problem, this project first analyzed the relationship between the physicochemical properties and pharmacokinetic performance of doxorubicin liposome and the occurrence of HFS. Based on the information, skin tissue was focused on to obtain the distribution and metabolism characteristics of HFS-related lipid, metabolites and endogenous metabolites through the combination of LC/HRMS, local metabonomics and AFAI-MSI in situ molecular imaging technique, which would provide fundamental information for the study of metabolic networks in pathological conditions. After the systematical analysis of metabonomics data, the targets in the skin tissues interacting with doxorubicin liposome would be identified through gene microarray and molecular biology techniques, and the signaling pathway of HFS induced by inflammation and apoptosis were further reveled. The project will provide a new insight into the substance basis and molecular mechanism of doxorubicin liposome-inducing HFS, and also construct an important theoretical support and technical guidance for investigating the adverse reactions of other chemotherapeutics and delivery systems.