新型脂质-多肽杂交纳米疫苗介导的多靶点可视化免疫治疗黑色素瘤研究

肿瘤疫苗治疗转移性黑色素瘤极具潜力。研究证实树突细胞（DC）和CD169+巨噬细胞（Mφ）均为重要的抗原递呈细胞（APCs），我们前期采用同步活体靶向抗原递送和促APC激活可提高T细胞激活效率，但仍缺乏能同时作用DC和CD169+Mφ并直接杀灭肿瘤细胞的疫苗。我们发现脂质-蜂毒肽杂交材料能高效杀伤肿瘤细胞并刺激DC成熟，采用磁力牵引能提高DC归巢效率而增强抗癌功效，且肿瘤细胞、成熟DC和Mφ均高表达清道夫受体（SR-B1）。据此本项目拟进一步研制同步负载黑色素瘤抗原肽、蜂毒肽和光学/核磁探针的纳米疫苗，并结合磁力牵引以实现：①在体高效经SR-B1靶向肿瘤细胞；②抗原靶向递送至DC和CD169+ Mφ；③激活APC；④直接杀伤肿瘤；⑤使用近红外/磁共振多模成像活体动态评价疫苗功效。本项目创新性地结合了多靶点免疫治疗、抗癌多肽、磁力牵引和多模成像手段，可为高效治疗转移性黑色素瘤提供可视化策略。

Tumor vaccine has great potential in the treatment of metastatic melanoma. Recent studies have shown that dendritic cells (DCs) and CD169+ macrophages（Mφ）are important antigen presenting cells (APCs).We have reported that synchronous in vivo targeted delivery of antigen to APCs and activation of APCs can significantly improve the T-cell activation efficacy. However, there is a lack of vaccine that can efficiently activate DC and CD169+ macrophages cells, targeting deliver antigens to these cells, and directly kill tumor cells. Previously, we have developed a lipid-melittin hybrid nanoparticle, which possess the ability to efficiently kill melanoma cells and in vitro stimulate DC maturation. Moreover, we reported that magnetic pull force can facilitate DC migration and resulted in enhanced antitumor efficacy. Taking advantage of the high expression of SR-B1 in melanoma cells, mDCs, and macrophages, the project aims to establish a nanovaccine with simultaneous loading of magnetic resonance and optical imaging contrast agents, melanoma antigen peptide as well as melittin. In combination with magnetic pull force, this study aims to achieve: 1) efficient targeting of melanoma cells and APCs in vivo; 2) targeting delivery of antigens to DCs and CD169+ macrophages; 3) effective activation of APCs；4) direct killing of melanoma cells. 5)Another advantage of this study is the ability to use the dual-modality imaging technique (near infrared and magnetic resonance imaging) to in vivo dynamically evaluate the anticancer efficiency of the developed nanovaccines. Taken together, the project establishes a new method of integration of multi APC-targeted immunotherapy, anti-tumor peptide, magnetic pull force, as well as dula-modality imaging, thus providing a novel strategy for treating metastatic melanoma.