Targeting C-type lectins on dendritic cells using carbohydrate-analogs for the specific delivery of tumor vaccines

肿瘤微环境是免疫抑制的，因此免疫细胞对肿瘤细胞具有耐受性。为了开发能够激活免疫系统对抗肿瘤的抗癌疫苗，克服这种耐受性是必不可少的。树突状细胞是体内最重要的抗原提呈细胞，协调各种免疫细胞之间的相互作用。因此，树突状细胞是激活抗癌免疫反应的有吸引力的靶点。某些C型凝集素在树突状细胞的细胞表面有独特的表达。因此，原则上，这些受体是向树突状细胞输送免疫调节剂的理想靶点。这些凝集素受体的天然碳水化合物配体类似于非常适合的前体，以开发用于特定靶向的类似物。生物物理技术将与特定配体的计算机辅助设计相结合，然后通过化学合成。最后，这些配体被连接到脂质体上，脂质体是一种长寿的隐形载体，能够将肿瘤抗原作为货物运送到树突状细胞。这一设计过程的成功分三个阶段进行评估。首先，将测试脂质体与表达特定C型凝集素的哺乳动物模型细胞的结合。然后，分离的免疫细胞将用于分析肿瘤抗原在体外的有效传递。最后，靶向脂质体在体内应用，以确保在小鼠癌症模型中有效的传递和激活。

The tumor microenvironment is immune suppressive and as a consequence immune cells become tolerant over tumor cells. In order to develop anti-cancer vaccines that activate the immune system against the tumor, it is essential to overcome this tolerance. Dendritic cells are the most important antigen presenting cells in the body and orchestrate the interplay between various immune cells. Therefore, dendritic cells are attractive targets for the activation of the immune response against cancer. Certain C-type lectins are uniquely expressed on the cell surface of dendritic cells. Thus in principle, these receptors are ideal targets for delivery of immunomodulatory agents to dendritic cells. Natural carbohydrate ligands of these lectin receptors resemble well-suited precursors to develop analogs for specific targeting. Biophysical techniques will be combined with computer-aided design of specific ligands that are then chemically synthesized. Finally, these ligands are coupled to liposomes, which are long-lived stealth vehicles that are able to carry tumor antigens as cargo to dendritic cells. The success of this design process is evaluated in three stages. First, the liposomal vehicles will be tested for binding to mammalian model cells expressing specific C-type lectins. Then, isolated immune cells will serve to analyze the efficient delivery of tumor antigens in vitro. Finally, the targeted liposomes are applied in vivo to ensure effective delivery and activation in a murine cancer model.