多功能仿生聚合物的设计合成及其对纳米颗粒长循环和靶向性能的研究

Cancer chemotherapy shows serious side effects since chemotherapy cannot distinguish healthy cells from cancer cells. After surface modification with targeting and long-circulating functionalities, the drug loaded nanoparticles can be selectively concentrated in cancer, resulting in safe and highly effective diagnosis and therapy. However, the present nanoparticle modification methods of covalently binding targeting and long-circulating groups or polymers on the surface, not only need many steps of reactions under aggresive conditions, the high temperature, strong acid, base and oxidant in the reaction may destroy the loaded drug or diagnostic agent. This project plans to synthesize a multifunctional polymer containing all the funtionalities required for nanoparticle surface modification. Specifically, catechols of mussel adhesive protein are grafted on the polymer side chains to anchor the polymer to nanoparticle surfaces; Cell membrane antifouling phosphorylcholine groups, PEG chains and tumor-targeting folic acid are grafted onto the other side chains of the multifunctional polymer backbone. A novel and versatile one-step surface modification method for nanoparticles from the multifunctional polymer aqueous solution will be developed. This project will provide new materials and a novel method for the research of functional polymers and tumor-targeting nanoparticles.

癌症化疗药物的靶向性差，在杀死肿瘤过程中对全身的正常细胞及组织也有较大破坏作用。通过对载药纳米颗粒表面进行靶向性及长循环性能修饰，使其高选择性结合或富集在肿瘤细胞中或其表面，可实现安全、高效的诊断及治疗。然而，目前用多步化学反应将靶向基团及长循环基团或聚合物共价固定在纳米载体表面的改性方法，不仅步骤繁琐、条件苛刻，而且还会因加热、酸、碱、氧化剂等对所包载的治疗药物或诊断试剂产生不良影响。本项目拟将纳米颗粒表面改性所需的长循环、靶向及表面固定多种功能基团集成在共聚物侧链上，设计合成多功能仿生聚合物。具体用侧链末端邻苯二酚基团仿照贻贝粘附蛋白的万能粘附作用将多功能仿生聚合物固定在纳米颗粒表面，其余侧链末端以叶酸为肿瘤靶向基团，以细胞膜抗生物污染的磷酰胆碱基团及PEG链共同构成长循环界面，研究在水溶液中一步完成多功能改性的新方法。本项目将为功能高分子及肿瘤靶向纳米载体研究提供新材料及新途径。

按计划设计合成了4种类型共12种不同组成的含细胞膜磷酰胆碱基团的功能聚合物，完成了分析、鉴定、溶液性质、表面粘附等基本性能研究。制备了含仿细胞膜磷酰胆碱基团表面的两亲性聚合物胶束、壳聚糖及聚乳酸三种纳米载体。体外细胞吞噬及体内血液循环研究结果显示，载荧光探针的仿细胞外层膜结构纳米颗粒具有显著的抗巨噬细胞吞噬及血液长循环性能。改性后纳米载体在新西兰白兔血液中循环的半衰期可长达20~80h，是对照样品的4~30倍。用接枝不同密度叶酸基团的仿细胞膜聚合物制备的纳米颗粒，被乳腺癌细胞摄取的量可增加2~8倍，表现出良好的靶向性能。.相关的研究结果已发表SCI论文3篇，国内及国际会议论文4篇，申请发明专利3项，培养博士生1名，硕士生3名。与项目计划相比，超额完成了各项任务指标，圆满结题。