新型两性葡聚糖包覆磁性纳米粒子的设计合成及药物传输载体特性研究

Nowadays, cancer research has become one of the most important medical projects around the world. Nanotechnology-based delivery system, especially superparamagnetic iron oxide nanoparticles (SPIO-NPs), emerging as promising candidates, has brought new treatment for cancers. However, magnetic nanoparticles can easily interact with plasma proteins when exposing in a physiology environment, causing size increase and destabilization. These particles are also considered as an intruder by innate immunity system, and can be readily recognized and engulfed by the macrophage cells. Consequently, the particles will be removed from blood circulation system and lose their function quickly, leading to dramatic reductions in efficiency in therapeutics. This project aims at developing a versatile and high-performance zwitterionic dextran system that integrates antifouling properties and biodegradability. The effects of substitution degree, position of substitution groups and graft density of zwitterionic compounds as well as the average molecular weight of dextran on the antifouling properties will be investigated to find a coating material that shows ultra-low fouling adsorption property in blood. Then superparamagnetic iron oxide nanoparticles loaded with doxorubicin will be coated with the zwitterionic dextran mediated by the interaction of catechols. The fabrication is designed to render SPIO-NPs with biodegradability and longer circulation time in blood. Hence it is significant for the development of drug delivery technology.

癌症己经成为全人类共同关注的重大课题。纳米载药体系特别是以超顺磁氧化铁纳米粒子为载体的靶向药物，为肿瘤治疗带来新的机遇。然而纳米粒子表面由于非特异性蛋白吸附易被免疫系统的巨噬细胞识别和吞噬，导致药物在血液中半衰期很短，疗效大大降低。为此，本项目以葡聚糖为原料，通过化学手段在葡聚糖上接枝两性离子化合物，同时系统研究两性化合物取代位置、取代度、接枝密度以及葡聚糖分子量等对其蛋白吸附特性的影响，建立这些参数与抗非特异性蛋白吸附之间的构效关系，借助葡聚糖特殊的分子结构与两性分子的协同作用，最终获得超低蛋白吸附的两性葡聚糖。在此基础上将其包覆于负载抗癌药物磁性纳米粒子表面，考察纳米粒粒径和聚合物的密度等对抗巨噬细胞吞噬的影响，揭示抗巨噬细胞吞噬与蛋白吸附之间的相互作用规律，保证其生理条件下稳定，同时与血浆蛋白的吸附作用最低，从而实现体内长循环，制备药物可控释放和生物相容性于一体的多功能靶向药物载体。

癌症己经成为全人类共同关注的重大课题。纳米载药体系特别是以超顺磁氧化铁纳米粒子为载 体的靶向药物，为肿瘤治疗带来新的机遇。然而纳米粒子表面由于非特异性蛋白吸附易被免疫系统的巨噬细胞识别和吞噬，导致药物在血液中半衰期很短，疗效大大降低。为此，本项目以葡聚糖为原料，通过化学手段在葡聚糖上接枝两性离子化合物，合成了葡聚糖羧基甜菜碱和葡聚糖磺酸基甜菜碱；以纤维蛋白原和溶菌酶两种蛋白为模型，研究了葡聚糖羧基甜菜碱对抗非特异性蛋白吸附性能，结果发现其具有良好的蛋白质防污性能，有助于延长其在血液中的循环时间。将葡聚糖羧基甜菜碱与两种聚合度的聚己内酯作用，制备了两种不同长度疏水链的聚己内酯葡聚糖羧基甜菜碱药物载体CB-Dex-PCL，以DOX为药物模型研究药物负载与释放性能以及细胞毒性等。结果发现，CB-Dex-PCL胶束可以有效负载DOX，且对肿瘤细胞具有pH敏感选择性，Hela细胞的细胞毒性实验结果表明，该胶束作为药物纳米载体具有良好的生物相容性。上述研究表明，CB-Dex-PCL胶束有望成为治疗人类肿瘤的潜在的药物载体。此外，在两性葡聚糖包覆磁性纳米粒子的研究中，发现了多功能表面的磁性Fe3O4纳米催化剂Fe3O4@SiO2 NH2可以高效协同催化合成硝基烯烃。三功能(-COO- , -OH 和N-甲基咪唑)纤维素基Pd络合的非均相催化剂可以有效催化Suzuki碳碳偶联反应等；此外，姜黄素修饰的葡聚糖羧基甜菜碱可以有效防止Aβ蛋白聚集，从而有效防止阿尔茨海默病。