智能型石墨烯/光敏剂/CpG纳米光致免疫复合药物的构建及其介导的高效抗肿瘤作用研究

项目名称： 智能型石墨烯/光敏剂/CpG纳米光致免疫复合药物的构建及其介导的高效抗肿瘤作用研究

项目编号： No.81471785

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 吴春惠

作者单位： 电子科技大学

项目金额： 70万元

中文摘要： 发展新型的纳米药物共递体系用于恶性肿瘤的多模治疗是药物控释与肿瘤纳米生物医学领域的研究热点。本项目主要利用光动力治疗(PDT)的免疫效应和树突状细胞(DC)的专职抗原呈递能力，以pH敏感的具有电荷转移功能的聚合物-纳米石墨烯为载体，以靶向线粒体的光敏剂(PS)和免疫辅剂CpG ODN为组装单元，构建一种智能的纳米光致免疫复合药物,实现PS和CpG ODN分别在线粒体和内涵体中定点释放，从增强PDT抗肿瘤免疫响应和CpG ODN的免疫刺激效应两方面高效诱导生成肿瘤抗原，并冲击致敏DC细胞形成疫苗；在此基础上，建立髓源DC离体培养体系和乳腺癌小鼠荷鼠模型，利用生物学、免疫学和医学研究方法研究DC疫苗的特异性、显著增强的抗肿瘤免疫治疗效应和机制，评价其临床应用的可能性。本项目将拓展石墨烯纳米复合材料的生物医学新应用，同时对探索利用纳米共递平台研制DC疫苗高效治疗恶性肿瘤的新模式具有重要意义。

中文关键词： 功能化纳米石墨烯；光敏剂；CpG；寡核苷酸；树突状细胞；肿瘤免疫治疗

英文摘要： Multimodal nanomedicines are rapidly emerging as promising approaches to effectively treat malignant cancer in the field of nanobiotechnology. Photodynamic therapy (PDT), a well-known noninvasive modality, had been demonstrated to induce the systemic anti-tumor immunity. By taking this advantage of PDT and the professional antigen-presenting ability of dendritic cells (DCs), the project proposes a novel strategy to design a kind of smart photo- & immuno-responsive nanocomplexes (termed as GN-PA-CpG/PS) in the combination of polymer functionlized graphene nanosheets(GN),mitochondrion-targeted photosensitizer (PS) and an adjuant unmethylated cytidine-guanosine-containing oligonucleotide (CpG ODN). The carrier GN conjugated with charge-conversional polymer through a pH-sensitive linker can deliver PS and CpG ODN to mitochonodiron and endosome respectively, and thus enhance the photo-killing efficiencies of PS and eventurally the immuno activiation. Based on this hyposis, tumor antigens generated from breast cancer cells (MDA-MB-468)treated with GN-PA-CpG/PS upon light stimulation will be utilized to activate DCs ex vivo and explore the immunogenic properties (including the mature status, the cytokine section and the induced cytotoxic T lymphocyte(CTL) toxocity). Furthermore, the syngerstic in vivo immune therapy efficiencies of DC vaccination pulsed with PDT tumor antigen aganst mammary MDA-MB-468 tumor model will be evaluated with various biological, immulogical and medical techniques. The specific CD8+ CTL responses, IFN γ-producing CD8+ T cell populations, the CD4+CD25+ Treg cell populations will be detected to reveal the mechanism behind the immunotherapy of GN-PA-CpG/PS. This project will inevitably show the novel biomedical applications of graphene nanomaterials and provide valuable information for the development of PDT-generated DC vaccine with nanomedicine in cancer treatment.

英文关键词： Charge-transfer polymer functionlized graphene nanosheets;Photosensitizer;CpG ODN;Dendritic Cells;Cancer Immunotherapy