尽管许多研究对影响肿瘤微环境响应PEG修饰的“配体外露式”主动靶向纳米粒的“长循环”、“组织分布”和“细胞摄取”的关键因素进行了系统研究，但是肿瘤微环境响应去PEG化“配体包埋式”靶向纳米粒的相关科学问题的研究还比较缺乏。因此本课题拟构建尺度一致的胞外pH响应型去PEG化透明质酸环糊精纳米粒，建立该类型纳米粒构建中PEG长度、密度和透明质酸分子量与“长循环”、 “组织分布”、“细胞摄取”等之间的关系；并与pH非响应型纳米粒进行对比，解析PEG可断裂性对该类型纳米粒药动学的调控；探讨透明质酸分子量与CD44受体的动态变化(聚集和循环再分布等)之间的关系及对纳米粒“细胞摄取”的影响。本项目通过定性定量分析体外制剂与体内药动和药效学等关键指标，筛选出体循环长、靶向性好、药效佳的去PEG化“配体包埋式”靶向纳米粒。本研究成果对基于天然配体的肿瘤微环境响应的“配体包埋式”靶向制剂的研发具有指导意义。

Although a number of studies focused on the key factors involved in the “blood circulation times”, “biodistribution” and “cellular uptake” of tumor-microenvironment sensitive peg decorated “exposed-ligands” active targeting nanoparticles, few studies concentrated on the similar key factors associated with tumor extracellular pH environment-sensitive de-pegylation “ligand-buried” active targeting nanoparticles. Thus in this study, we intended to develop the tumor extracellular pH environment-sensitive de-pegylation coated “buried” hyaluronic acid (HA)-cyclodextrin nanoparticles with uniform scale, and to estabilish the relationships between “blood long circulation”, “biodistribution” and “cellular uptake” of nanoparticles and pegylation (peg length and peg density), hyaluronic acid(molecular weight). And we focused on the effect of tumor environment sensitivity of de-pegylation on pharmacokinetics of the HA-based NPs, and highlighted the relationship between dynamic variation CD44 (clustering and re-presentation), molecular weight of hyaluronic acid and the activity of “cellular uptake”. Furthermore the key factors associated with the “blood circulation times”, “biodistribution” and “cellular uptake” of nanoparticles were estimated to optimize formulations of nanoparticles, to screen the optimal tumor extracellular pH environment-sensitive de-pegylation ligand-buried hyaluronic acid cyclodextrin nanoparticles. And the results would facilitate the design tumor extracellular pH environment-sensitive de-pegylation decorated “buried-ligand” active targeting nanoparticles based on the natural ligands.