新型超顺磁性Janus纳米粒的可控制备及其生物医用初探

Poor stability, low controllability of size and difficulty in multi-functionalization, are the main problems for the superparamagnetic Janus nanoparticles. This project designs and constructs new superparamagnetic Janus nanoparticles via grafting of heterogenic polymer brushes onto superparamagnetic nanoparticles. These Janus nanoparticles are self-assembled in different forms of micelles, which will be used as drug carriers. Using 4-(chloromethyl)benzoic acid as the initiator, hydrophobic carboxyl-terminated polystyrene brushes are synthesized via activators regenerated by electron transfer for atom transfer radical polymerization(ARGET-ATRP). With the same polymerization mechanism, hydrophilic polyacrylic acid brushes are prepared in environment-friendly aqueous solution. The polymeric brushes are grafted onto the surface of the Fe3O4 nanoparticles sequentially by means of 'graft to' and 'graft from' via chemical coordination bonds. After solvent etching, Janus structured superparamagnetic nanoparticles are obtained, and separated under the eternal magnetic field. The superparamagnetic Janus nanoparticles posses good stability, amphiphilic property, and pH sensitivity, as well as the plenty of functional groups for the following modifications. The sizes of the Janus nanoparticles are tuned by the lengths of the polymer brushes. The superparamagnetic Janus nanoparticles and drug molecules are self-assembled as micelles with different structures and properties. Because of the potential superparamagnetism, the drug-loaded micelles are applied in biomedical field for integration of tracing,‎ magnetic-heat therapy and chemotherapy.

本项目针对超顺磁性Janus纳米粒的稳定性差、尺寸可控度低、难以多功能化等诸多问题，设计构建一种异质聚合物刷接枝的新型超顺磁性Janus纳米粒，其多种形式的自组装体可用于药物的装载。以对氯甲基苯甲酸为引发剂，以电子转移再生催化剂原子转移自由基聚合（ARGET-ATRP）反应制备了末端为羧基的疏水性聚苯乙烯刷，以相同的聚合机理在环境友好的水溶液中合成了亲水性聚丙烯酸刷。采用“graft to”和“graft from”的方法将聚合物刷以化学配位键分步接枝于超顺磁性Fe3O4纳米粒的两侧。经溶剂刻蚀，磁分离，得到具有Janus结构的超顺磁性纳米粒。设计合成的超顺磁性Janus纳米粒稳定性好，具有双亲性和pH敏感性，再修饰位点丰富，粒径可通过聚合物刷的长度调节，与药物分子形成结构、性质各异的载药胶束。由于潜在的超顺磁性，该载药胶束可实现示踪、磁热疗、药物治疗一体化的生物医用目标。

针对小尺寸超顺磁性Janus纳米粒的稳定性差、尺寸可控度低、难以多功能化等问题，本项目设计构建了一种异质（亲水-疏水）聚合物刷接枝的新型超顺磁性Janus纳米粒。该纳米粒可进行二次组装，组装体可用于药物装载和靶向运输，对病变部位实施化学和磁热的双重治疗。异质聚合物刷以反应条件温和的电子转移再生催化剂原子转移自由基聚合（ARGET-ATRP）反应合成。以甲基丙烯酸甲酯（MMA）为疏水单体，经ARGET-ATRP反应得到羧基化的聚甲基丙烯酸甲酯（PMMA）聚合物刷，利用乳化挥发法制备成表面为羧基的PMMA球。以原位沉积反应，在PMMA球表面螯合超顺磁性Fe3O4纳米粒。亲水性聚合物刷聚丙烯酸（PAA）亦采用ARGET-ATRP反应以“graft from”的方式接枝于Fe3O4纳米粒，形成磁性复合微球PMMA/Fe3O4/PAA。磁性复合微球PMMA/Fe3O4/PAA经溶剂刻蚀，磁分离，得到具有Janus结构的超顺磁性纳米粒。结构性能表征可知，Janus纳米粒稳定性好，具有良好的双亲性和高的磁饱和强度。Janus纳米粒分别与HepG 2和NIH 3T3细胞共孵育24时和48时后，细胞存活率均高于80%，表现出良好的细胞相容性。体外细胞实验中，Janus纳米粒具有高的药物装载量、快速的磁响应性和持续稳定的磁热性能。本项目采用“graft to”和“graft from”的方法构建了双亲性Janus纳米粒，该纳米粒经二次组装用于药物装载和输送，实现化疗和磁热疗的双重治疗。该研究探索了构建Janus纳米粒的技术手段，为肿瘤的联合治疗提供新材料，提升治疗效果。