化疗药体内分布缺乏选择性，导致肿瘤化疗成功率较低。主动靶向继而速释药物的给药系统是改善肿瘤治疗效果的重要手段。基于肿瘤细胞膜表面叶酸受体超高度表达及肿瘤细胞因过度代谢导致pH较低原理，提出一种肿瘤细胞胞外叶酸配体靶向、胞内因pH敏感而速释药物的双功能药物递送机制。本项目采用多学科研究手段，设计合成双功能的叶酸-聚(2-乙基-2恶唑啉)-二硬脂酰磷脂酰乙醇胺(F-PEOz-DSPE)脂质体载体材料，构建新型脂质体，重点探索F-PEOz-DSPE体内靶向性及肿瘤高效化疗等相关科学问题，阐明其与靶向相关的作用机理，实现肿瘤化疗的高效低毒性，具有重要科学与指导意义。本设计国内外未见报道，F-PEOz-DSPE及双功能脂质体均具新颖性。载体材料已成功合成，并已申请专利。

The in vivo distribution of antitumor drugs is usually lack of selectivity, and thus, leading to a low efficacy of chemotherapy on cancers and high toxicity to normal cells. Receptor-mediated targeting liposome with pH-sensitivity as a dual drug delivery system is one of the efficient approaches to overcome the disadvantages. Based on the significant characteristic of tumor cell, a novel smart polymeric material (folate-poly (2-ethyl-2-oxazoline)-distearoyl phosphatidyl ethanolamine, F-PEOz-DSPE) was synthesized, which can combine with the folate-receptor (FR) over-expressed on the surface of cancer cells and respond to pH changes in endosome-lysosome system within cancer cells to rapidly release drug simultaneously. The F-PEOz-DSPE was synthesized by the method of asymmetric synthesis of organic polymer and characterized by IR, 1H NMR, ESI-MS and GPC. The "click" (click chemistry) reaction was applied to the synthesis of liposome polymeric material. Using this liposome material, a new active targeting drug delivery system with pH-sensitivity was prepared. The aims of the study are to explore the targeting, pH-sensitivity, cytotoxicity and efficacy of chemotherapy of the bi-functional active targeting drug delivery system employing a variety of research methods from multidisciplinary, to clarify the related mechanism. It will have important scientific significance to preparation research about active targeting drug delivery system. The F-PEOz-DSPE and the bi-functional liposome are novel design, and similar reports have not been seen at home and abroad.

通过本项目的实施，获得了全新的F-PEOz-DSPE及PEOz-DSPE靶向脂质体载体材料；获得了F-PEOz修饰的及PEOz修饰的高效、靶向、低毒、稳定的2种阿霉素脂质体；建立了新型脂质体体内外靶向性及抗肿瘤药效的生物学评价方法。按计划全面完成了各项任务，其中个别研究内容属超额完成。本项目成功合成与表征了2种全新的F-PEOz-DSPE及PEOz-DSPE靶向脂质体载体材料，成功构建并表征了F-PEOz修饰的、PEOz修饰的2种阿霉素靶向脂质体（粒径约100 nm，包封率≥93%），此2种脂质体冷藏保存1年，质量稳定。F-PEOz修饰的阿霉素脂质体较游离阿霉素对叶酸受体超高表达的HeLa细胞（无叶酸培养）具有显著的抑制效果（有较好的体外抗肿瘤效果），F-PEOz修饰的阿霉素脂质体较游离阿霉素对叶酸受体不表达的A549细胞（无叶酸培养）不具有显著的抑制效果，两组细胞的抑制效果相当；PEOz修饰的阿霉素脂质体较游离阿霉素对HeLa细胞（有叶酸培养）具有显著的抑制效果（有较好的体外抗肿瘤效果）。F-PEOz修饰的阿霉素脂质体较游离阿霉素在荷瘤鼠体内肿瘤抑制效果相当的情况下，毒性较低。PEOz修饰的阿霉素脂质体在荷瘤鼠体内对皮下肿瘤组织具有一定的靶向性。本项目获授权发明专利 2 项；发表文章 2 篇，其中 SCI文章 1篇，中文核心文章 1篇；培养青年科技骨干 2 人，技术人员 1 人，研究型硕士研究生 1 人。