Zytokin-vermitteltes Targeting von Adenovirusvektoren zur effizienten Transduktion hematopoietischer Zellen

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Adenovirus (Ad) vector targeting aims for the efficient gene transfer to specific cell types and tissues. So far, targeting efforts have met with limited success. Recently, we developed a novel geneti-chemical targeting platform that allows for the flexible use of different ligands even in combination with polymer shielding for the generation of truly retargeted Ad particles. However, our data indicate that not only the type of ligand, but also its position on the capsid strongly influences the intracellular fate of the vector particle and, therefore, transduction efficiency. This is probably due to post-receptor restrictions at the level of particle disassembly and/or particle trafficking. We will use the geneti-chemical targeting platform to characterize post-receptor restrictions for Ad vectors at the molecular and cell biology level. We will analyze the influence of ligand positioning and ligand copy number for three ligands with different intracellular fates: transferrin, EGF, and mannans. In addition, the influence of shielding polymers on the post-receptor fate of Ad vector particles will be characterized. Further, we will investigate the effect of bioresponsive bonds on post-receptor fate when used to link ligands and shielding polymers to the vector particles. Detailed analysis at a molecular level may form a basis for rational design of targeted Ad vectors. The results obtained may likely be transferable to other gene delivery systems.