仿红细胞长循环和癌细胞高效靶向涂层构建及性能优化研究

Long circulation and tumor targeting are two essential requirements for nano-drug to concentrate onto tumor in safe and efficient chemotherapy. A representative nano-drug is micelle system formed with amphiphilic block-copolymers bearing folate and PEG. However, the slightly hydrophobic folate group is easily buried by the hydrophilic shell. Moreover, the micelle system can be dissociated by extreme dilution after intravenous injection. These two problems limit the improvement of the long circulation and tumor targeting performance. This project plans to improve long circulation and tumor targeting properties of nanoparticles by coating fabrication via a easy step-by-step method. Firstly, nanoparticles will be coated with polydopamine to provide active amino groups for further chemical modification. Secondly, small amount of HOOC-PEG-COOH is grafted on the surface by amidation for subsequent binding with ethanediamine folate (FA-NH2). Thirdly, the remaining surface amino groups are fully reacted with active ester groups linked on partial side-chains of phosphorylcholine polymers, forming erythrocyte mimetic surface to confer long circulation property. Finally, FA-NH2 is grafted at the PEG end carboxyl forming out-extended and number controllable folate receipt targeting coating. The proposed idea and method can be applied in different nanoparticles with different targeting systems. Therefore, the results, idea and method of this project can be used to reduce the toxicity and side effects of chemotherapy, and thus promote the development of nanomedicine.

靶向性和长循环性能兼具是纳米药物高选择性富集在肿瘤部位实现安全高效诊疗的基础。目前用含叶酸及PEG两亲性嵌段聚合物混合胶束为代表的靶向性诊疗药物，由于稀释解离及叶酸容易被包埋等原因，其靶向性和长循环性能不佳。本项目拟通过以下四步简单、温和的改性处理实现对不同类型纳米载体的长循环和靶向性高效修饰。①利用多巴胺的仿贻贝万能粘附作用在纳米颗粒表面构建聚多巴胺介导层提供化学修饰位点；②将少量的羧基化PEG用酰胺键接枝在介导层表面获得可靶向修饰的末端羧基；③在介导层表面剩余氨基上用酰胺键固定含大量两性离子的活性酯聚合物，获得仿红细胞膜结构的长循环性能；④将肿瘤靶向配体接枝在两性离子亲水壳层外长链PEG末端羧基，形成靶向配体向外伸展、数量可优化，靶向性和长循环性能俱佳的改性涂层。本项目的研究思路及方法途径适用于多种纳米载体及不同靶向体系，为解决癌症诊疗的毒副作用、促进纳米药物发展提供新思路及新方法。

癌症化疗是具有普遍性的临床治疗方法，因药物血液循环半衰期短和靶向性差导致的毒副作用严重影响治疗效果。项目以血液红细胞膜外表面的磷酰胆碱两性离子组装层结构为血液长循环表界面，耦合叶酸及RGD肽链为癌细胞靶向配体，建立了可用于不同纳米载体及诊疗药剂表面构建仿红细胞膜长循环及癌细胞靶向性涂层的共性方法。研究获得了具有血液长循环及肿瘤主动靶向性能的聚合物纳米胶束药物体系和肿瘤微环境释药的介孔二氧化硅纳米药物新体系。研究的载阿霉素纳米药物对HeLa细胞的靶向性能由常规研究水平的2~4倍大幅度提升到8-12倍，对正常细胞L929的毒性降低到1/2000。本项目的研究思路及其技术方法对解决化疗药物毒副作用难题开辟了更为有效的新途径。相关研究工作的部分研究结果已发表专业主流期刊SCI论文9篇，其中影响因子9~12的论文3篇；获授权发明专利8项；参加国际及国内学术论文交流10人次；培养博士研究生3名，硕士生6名；项目的主要研究成果“仿细胞膜聚合物抗污染涂层构建新策略及应用”获2021年陕西高等学校科学技术奖一等奖。