Fe3O4@PPy复合微球的制备及药物控释与靶向性能研究

Targeted drug therapy is the direction for the treatment of malignant tumor in the future. The magnetic targeted drug delivery system is an effective way for targeted therapy. In this program, a composite composed of conducting polypyrrole (PPy) with reversible doping-dedoping performance and Fe3O4 magnetic nanoparticles as drug carrier is proposed to improve the controlled release performance of existing drug delivery system. The preparation conditions of superparamagnetic Fe3O4 nanoparticles will be optimized systematically, and the factors affecting the size, saturation magnetization, and others of Fe3O4 nanoparticles will be investigated. With Fe3O4 particles as core, the nano Fe3O4@PPy hollow magnetic composite microspheres with bell shape will be synthesized. The coating and removal of interlayer will be studied to reveal action mechanism between the layers. The influence law of species of interlayer and surfactants, and technological conditions on targeting and controlled release of the composite microspheres will be analyzed. The main innovative point: the microspheres with a hollow structure can increase drug content and decrease the reduce degree of magnetic of Fe3O4 particles. More important, the composite microspheres can accomplish the switch function of controlled drug release with the doping-dedoping process, which will improve the controlled release properties effectively to achieve the high efficiency, accuracy and sensitivity in targeted drug delivery. It is important to realize the intelligent and controllable of targeted therapy in the future.

靶向药物治疗是未来治疗恶性肿瘤的发展方向，磁靶向药物输送系统是靶向治疗的有效途径。本项目提出将具有可逆掺杂/脱掺杂性能的导电聚吡咯（PPy）与Fe3O4磁纳米粒子复合作为药物载体，解决现有输送系统药物控释能力差的问题。系统优化超顺磁性Fe3O4纳米粒子的制备方法，探讨影响Fe3O4粒子的粒径、饱和磁化强度等的因素。以Fe3O4粒子为核，合成具有摇铃式中空结构的Fe3O4@PPy磁纳米复合微球。研究中间隔层的包覆与去除，揭示层与层之间的作用机理，分析中间隔层和表面活性剂的种类、工艺条件对复合微球的靶向性和可控释放性的影响规律。创新点在于：中空结构微球可以负载更多药物，并对Fe3O4的磁性影响较小；更重要的是，复合微球能够在掺杂/脱掺杂过程中完成对药物存储与释放的"开-关"作用，有效提高药物控释能力，能够实现靶向给药的高效、精准和灵敏性。这对未来实现靶向治疗的智能化和可控化有重要意义。

靶向药物能瞄准特定的病变部位，将药物输送到目标部位蓄积并释放有效成分，是一种疗效更好、痛苦更少的未来癌症治疗方式，是国内外研究的热点之一。本项目对负载阿霉素（DOX）和布洛芬（IBU）的Fe3O4@PPy磁靶向药物载体进行了深入研究。首先从分子层面设计了摇铃式Fe3O4@PPy中空复合微球，分别采用共沉淀法和水热法制备了不同粒径和形貌的Fe3O4纳米粒子，获得了一系列研究成果：通过调节十二烷基硫酸钠（SDS）的添加量和可见光照射时间，制备得到了球状、棒状、立方体状的Fe3O4纳米粒子，球状粒子具有超顺磁性和高饱和磁化强度；组成Fe3O4空心微球的细小粒子根据是否添加乙二胺四乙酸（EDTA）二钠盐而为近球形或八面体形粒子；制备出具有较高饱和磁化强度，粒径尺寸在100~200 nm的Fe3O4球形纳米粒子。再包覆SiO2或C分别形成核壳结构的Fe3O4/SiO2和Fe3O4/C复合微球，修饰表面活性剂后再包覆聚吡咯，制备得到Fe3O4/SiO2/PPy和Fe3O4/C/PPy复合物，最后去除SiO2和C中间层获得了Fe3O4@PPy复合材料作为药物载体。研究了Fe3O4@PPy载体对DOX和IBU的负载率、负载量、靶向性和释放性能。Fe3O4@PPy载药微球对DOX和IBU的负载率最高为78.5%和53.3%，负载率随负载量增大降低；通过测定磁性能考察了载体的靶向性；在pH为7.4和9.0的PBS缓冲溶液中，分别模拟体液和肠液，得到药物的释放曲线，发现Fe3O4@PPy载体对IBU的控释效果较差，对DOX的释放由快到慢，有较好的控释效果。对未来实现靶向给药的高效、精准和灵敏性有一定的科学研究价值。项目资助发表4篇学术研究论文，其中被SCI收录2篇；获国家发明专利授权3项；培养硕士研究生2名。