A NOVEL APPROACH FOR TARGETING DNA TO DENDRITIC CELLS IN VIVO FOR VACCINE DEVELOPMENT AND CANCER IMMUNOTHERAPY

使用被称为DNA的遗传物质作为疫苗，是疫苗接种技术的一个相对较新的进步，有可能对抗许多传染病和癌症。使用DNA的好处是，它可以很容易地被操纵来开发具有预期的预防和/或免疫治疗效果的新疫苗。然而，为了达到最佳效果，用作疫苗的DNA需要针对体内的特定细胞类型。有证据表明，存在于血液和其他组织中的一小部分被称为树突状细胞的细胞，在诱导DNA疫苗的效果方面发挥了重要作用。然而，目前向这些细胞运送DNA的方法往往缺乏选择性，或者使用病毒来运送DNA。这可能会造成过敏性反应的风险，甚至可能导致肿瘤。使用由磷脂制成的称为脂质体的小膜囊作为DNA输送载体最近引起了相当大的兴趣，因为它们被认为是安全的，并有可能输送大量DNA。虽然DNA可以很容易地包装在脂质体中，但靶向脂质体及其内容物(例如。体内的特定细胞(如树突状细胞)。我们最近生产了一种新型的螯合脂质分子，它可以方便地附着在脂质体表面的特异性靶向分子上，例如工程形式的抗体片段，它可以靶向或引导脂质体及其有效载荷(例如。DNA)，直接进入树突状细胞。该项目将通过检测含有模式抗原DNA的脂质体是否可以用于疫苗接种来测试使用这种靶向脂质体作为DNA疫苗的可能性，以抑制小鼠高转移性肿瘤(黑色素瘤)的生长和转移。

The use of genetic material, known as DNA, as a vaccine, has been a relatively new advance in vaccination technology with potential for combating many infectious diseases and cancers. The use of DNA has the advantage that it can be easily manipulated to develop new vaccines that have the desired preventative and-or immunotherapeutic effect. For optimal effect, however, the DNA to be used as a vaccine needs to be targeted to specific cell types in the body. Evidence suggests that a minor population of cells known as dendritic cells, which are present in blood and other tissues, play an important role in eliciting the effects of DNA vaccines. However, current methods for delivering DNA to these cells often lack selectivity in delivery, and-or use viruses to deliver the DNA. This can pose the risk of allergic type reactions and-or possibly cause tumours. The use of small membranous vesicles known as liposomes, made of phospholipids, has recently attracted considerable interest as DNA delivery vehicles, since these are considered safe, and have the potential to deliver large quantities of DNA. Although DNA can easily be packaged inside liposomes, it is has not been easy to target the liposomes and their contents (eg. encapsulated DNA) to specific cells (such as dendritic cells) within the body. We have recently produced a novel chelator lipid molecule which can be used to conveniently attach onto the liposome surface specific targeting molecules, such as engineered forms of antibody fragments, that can target or steer the liposomes together with their payload (eg. the DNA), directly to dendritic cells. This project will test the potential for using such targeted liposomes as DNA vaccines by examining whether liposomes containing DNA for a model antigen can be used in vaccinations to inhibit the growth and metastasis of a highly metastatic tumour (melanoma) in mice.