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Hoffmann, Florian (2007): Decoy gelatin nanoparticles as a novel tool to elucidate the role of NF-kB in Kupffer cells on hepatic ischemia/reperfusion injury. Dissertation, LMU München: Fakultät für Chemie und Pharmazie



Kupffer cells, the resident macrophages of the liver, play an important role in host defense and immune system. Moreover, they are also involved in several pathological conditions, like the hepatic ischemia/reperfusion injury. The transcription factor NF-kB is activated during this event. However, to date it was not possible to evaluate the consequence of this upregulation, as NF-kB possesses both detrimental and beneficial properties, regarding of the liver cell type affected. An activation in Kupffer cells is thought to lead to an increased inflammatory response. This hypothesis could not be proven in vivo, as a selective inhibition of NF-kB in Kupffer cells was not possible due to technical difficulties. In this work, solid nanoparticles made of gelatin were chosen to deliver NF-kB inhibiting decoy oligonucleotides exclusively to Kupffer cells in order to block the activation of NF-kB. Confocal scanning laser microscopy showed selective uptake of gelatin nanoparticles into the Kupffer cells without affecting hepatocytes. An increase in NF-kB binding activity during postischemic reperfusion could be diminished by the delivery of decoy oligonucleotides to the resident liver macrophages. In addition, a rise in TNF-alpha mRNA expression assessed by real time RT-PCR was also reduced, thus providing evidence for the effectiveness of this selective targeting. Thus, this work established a novel carrier for a specific Kupffer cell targeting.