项目名称： 多功能桑葚状AQ4N∕噻替哌纳米载体及其乏氧选择、双药协同抗肿瘤作用

项目编号： No.81471771

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 吴道澄

作者单位： 西安交通大学

项目金额： 72万元

中文摘要： 乏氧是实体肿瘤特有现象，本项目将乏氧磷光指示、透明质酸靶向、AQ4N乏氧还原及与噻替哌协同作用等策略集成在一起。将氰基乙酸分别与PEG 2000和十六醇结合形成亲水和疏水衍生物，将它们与铱二氯联桥化合物配位并聚合为乏氧磷光高分子化合物，利用其两亲性包裹噻替哌形成微胶束，再将其表面包裹一层阳离子壳聚糖。将透明质酸与AQ4N结合成为带负电纳米小球，利用电荷的相互作用将载有AQ4N的透明质酸纳米小球组装在微胶束表面形成桑葚状AQ4N∕噻替哌纳米载体。红外光谱、核磁共振等确定其化学组成和表面结构；磷光标记、活体成像等研究其肿瘤乏氧下磷光释药指示、选择靶向特性和双药协同治疗的作用机制；体内外实验研究其抗肿瘤效果并指导载体设计。这种多功能载体系统可在透明质酸介导下将双药同时靶向到肿瘤组织与细胞，在磷光指示下AQ4N释放并乏氧还原为活性物AQ4，通过其与噻替哌的双药协同作用，达到高效、低毒抗肿瘤的目的。

中文关键词： 纳米载体；靶向治疗；肿瘤靶向；药物控释

英文摘要： Hypoxia is a specific characteristic of solid tumor. In this project, a multi-functional mulberry like AQ4N∕thiotepa nanocarrier with the characteristics of hypoxia phosphorescence indication for drug release, hyaluronic acid tumor targeting, AQ4N hypoxia-selective reduction to AQ4, which can enhance anti-tumour of thiotepa significantly is designed .The nanocarrier is prepared as follows: (1) hydrophobic and hydrophilic cyanoacetic acid derivatives are obtained using the reaction of cyanoacetic acid with MePEG 2000 and 1-hexadecanol, respectively. The hypoxia sensitive polymer is prepared by the two of the cyanoacetic acid derivatives coordinating with hypoxia phosphorescence cyclometalated iridium(III) chloro-bridged dimmers and polymerization; (2) the polymeric micelles encapsulated thiotepa are fabricated with above polymer in solution using improved surface dispersion method; then positively charged chitosan is fabricated on the surface of the micelles; (3) AQ4N small nanoparticles is fabricated with hyaluronic acid by co-precipitation method, and final mulberry like AQ4N∕thiotepa nanocarriers are obtained by assemble AQ4N small nanoparticles onto the surface of the polymeric micelles encapsulated thiotepa with electron interaction. Their surface and chemical structures can be determined by IR , NMR spectra and so on. Their characteristics, such as targeting tumor cells, hypoxia-selective reduction of AQ4N, hypoxia phosphorescence indication etc, can be measured by the phosphorescence labeling，phosphorescence lifetimes, animal fluorescence/phosphorescence imaging, respectively. Their antitumor effects will be detected by cell tests in vitro and aminal tests in vivo. These results can conduct the nanocarrier design. This kind of multi-functional mulberry like AQ4N∕thiotepa nanocarrier with the characteristics of hypoxia phosphorescence indication, hyaluronic acid tumor targeting, AQ4N hypoxia-selective reduction to AQ4，which enhance anti-tumour of thiotepa significantly, thereby obtain higher thearpy effects for tumors with lower toxcity for normal tissues.

英文关键词： Nanosized carrier;Targeting thearpy;Tumor targeting;Controlled drug release