具有三重载药空间的中空介孔二氧化硅/磷脂复合载体的构建及其诱导肿瘤免疫治疗的研究

Tumor immunotherapy has attracted great interest in medical research area. The main strategy for clinic application is combined drug therapy, which is capable of inducing anti-tumor immune response as well as diminishing the immune suppression mediated by tumor microenvironment. Nevertheless, with traditional methods of drug administration, the combined drugs can hardly accumulate in tumor site to achieve synergistic effect. Consequently, it becomes quite necessary to develop safe and highly efficient drug co-delivery platforms for tumor immunotherapy. In this program, interleukin-2 (IL-2), cyclophosphamide (CTX) and α-galactosylceramide (KRN7000) are taken as model drugs; hollow mesoporous silica nanoparticles (HMSNs) and phospholipids are selected to be basic materials. The study focuses on the loading of model drugs and the complexation of basic materials. Relative research contents include: 1) Through modifing the material feature and the loading enviroment, to achieve the encapsulation of CTX and IL-2 within the hollow and mesoporous structure of HMSNs, respectively; 2) Inserting glycolipid KRN7000 into the phospholipid bilayer, achieve the coating of phospholipid-glycolipid hybrid bilayer on HMSNs surface through inducing the interaction between lipids and the external surface of HMSNs. 3) applying drugs-loaded hybrid vectors to induce tumor immunotherapy in animal model. This program will provide theoretical knowledge and experimental experiences for construction of hybrid vectors and its application in tumor immunotherapy.

免疫治疗是当前肿瘤研究的热点之一，其主要策略是通过联合用药诱导抗肿瘤免疫应答并减缓肿瘤的免疫抑制。目前的常规给药方式难以确保联用药物富集于肿瘤并发挥协同效应，因此需要构建共转运载体以实现多药诱导肿瘤免疫治疗。本项目拟以中空介孔二氧化硅纳米颗粒（HMSNs）与磷脂为基础，针对药物装载与材料复合展开研究，构建具有三重载药空间的复合载体，并实现对理化性质差异显著的三类药物的共载。将通过调控材料性质与装载环境，使细胞因子IL-2（诱导效应细胞活性）与化学药物CTX（减轻免疫抑制）分别装载于HMSNs的介孔孔道与中空空腔；拟利用磷脂双分子层融合免疫佐剂糖脂KRN7000（维持效应细胞活性），并通过诱导脂类分子与HMSNs表面间的相互作用，实现脂质结构在HMSNs表面的包覆；研究复合载体共载多药诱导肿瘤免疫治疗的效果。本项目预期为多药共转运复合载体的构建及将其用于肿瘤免疫治疗提供理论基础和实验依据。

免疫治疗是当前肿瘤研究的热点之一，其主要策略是通过联合用药诱导抗肿瘤免疫应答并减缓肿瘤的免疫抑制。目前的常规给药方式难以确保联用药物富集于肿瘤并发挥协同效应，因此需要构建共转运载体以实现多药诱导肿瘤免疫治疗。本项目拟以中空介孔二氧化硅纳米颗粒（HMSNs）与磷脂为基础，构建具有三重载药空间的复合载体（HMLB），并实现对理化性质差异显著的三类药物的共载——通过调控材料性质与装载环境，使细胞因子IL-2（诱导效应细胞活性）与化学药物PTX（减轻免疫抑制）分别装载于HMSNs 的介孔孔道与中空空腔；拟利用磷脂双分子层融合免疫佐剂糖脂KRN7000（维持效应细胞活性），并诱导脂类分子包覆于HMSNs的表面；在黑色素瘤皮下和转移模型中研究复合载体共载多药诱导肿瘤免疫治疗的效果，并开展深入的免疫学分析。本项目预期为多药联合进行肿瘤免疫治疗以及共转运复合载体的构建提供理论基础和实验依据。