中文摘要
本项目成功构建了基于PEG-PE 胶束装载阿霉素、长春瑞滨和前列地儿的纳米胶束制剂。利用微量热、荧光能量共振转移、NMR、SAXS、Cryo-TEM等技术系统地研究了药物与PEG-PE的相互作用，揭示了它们的组装机制、结构特征及组装体表现出的特有的理化特性。采用荧光标记技术对纳米胶束进行了体内示踪和细胞内行为的研究。建立各种病理模型并考察了载药胶束制剂的治疗效果和不良反应。结果表明：1）PEG-PE胶束具有典型的核-壳结构，两亲性药物通过静电、疏水、氢键和范德华力与PEG-PE发生作用而被高效地装载于胶束的核壳界面，从而使得胶束结构更加稳定，药物的释放就有可控性；2）PEG-PE通过插入细胞膜改变膜的脂质比率和流动性显著促进药物进入细胞并在胞内长时间滞留，因此提高了药物的疗效和克服肿瘤细胞的耐药性3)PEG-PE胶束具有压力响应的变形性，可以穿过血管壁到达组织间隙并选择性被淋巴系统收集，同时PEG-PE胶束对组织具有较强的渗透性可以将药物运载至深部病变组织并维持长时间的高浓度，进而显著地提高了药物对肿瘤转移和耐药的治疗效果。本研究证明药物与一个合适的载体有机组装可以产生良好的治疗效果。
英文摘要
we have used an one-stepself-assembly procedure to load water-solubled rugs,such as doxorubicin hydrochloride, Epirubicin hydrochloride,vinorelbine tartrate and vincristine sulfate,into PEG-PE micelles in aqueous medium.We found that doxorubicin-and vinorelbine-loaded PEG-PE micelles had a very high drug-loading efciency (>99%) and superior antitumor activities to free drug both in vitro and in vivo, with a high stability in plasma and sustained releaseprofile. two water-soluble anticancer drugs,doxorubicin hydrochloride and vinorelbine tartrate,both composed of hydrophobicbulk and positive charged groups, were chosen as model drugs,and the interaction of these drugs with PEG-PE in the process of their self-assembly was investigated.The electrostatic and hydrophobic interactions between these drugs and PEG-PE were found to play critical roles in their recognition and high efcient assembly.Block copolymer micelles have proven to be a promising nano-sized system for the targeted delivery of drugs. An understanding of the in vivo behaviors of this drug deliver system at the whole body, tissue and cellular levels is critical for the translation of this drug delivery system from laboratory research to clinical uses. Using high-resolution fixed-tissue microscopy and two-photon imaging in living mice we observed mice
结题摘要
本项目成功构建了基于PEG-PE 胶束装载阿霉素、长春瑞滨和前列地儿的纳米胶束制剂。利用微量热、荧光能量共振转移、NMR、SAXS、Cryo-TEM等技术系统地研究了药物与PEG-PE的相互作用，揭示了它们的组装机制、结构特征及组装体表现出的特有的理化特性。采用荧光标记技术对纳米胶束进行了体内示踪和细胞内行为的研究。建立各种病理模型并考察了载药胶束制剂的治疗效果和不良反应。结果表明：1）PEG-PE胶束具有典型的核-壳结构，两亲性药物通过静电、疏水、氢键和范德华力与PEG-PE发生作用而被高效地装载于胶束的核壳界面，从而使得胶束结构更加稳定，药物的释放就有可控性；2）PEG-PE通过插入细胞膜改变膜的脂质比率和流动性显著促进药物进入细胞并在胞内长时间滞留，因此提高了药物的疗效和克服肿瘤细胞的耐药性3)PEG-PE胶束具有压力响应的变形性，可以穿过血管壁到达组织间隙并选择性被淋巴系统收集，同时PEG-PE胶束对组织具有较强的渗透性可以将药物运载至深部病变组织并维持长时间的高浓度，进而显著地提高了药物对肿瘤转移和耐药的治疗效果。本研究证明药物与一个合适的载体有机组装可以产生良好的治疗效果。