Receptor-Induced Delivery of interfering RNA

This project addresses one of the major limitations of therapeutic agents, in particular of siRNA as a new, recently promoted class of drug: its delivery to the target organ, tissue or celltype. We will work out an in this context new delivery approach, termed "Receptor-Induced-Delivery" (RID). By covalently attaching siRNAs to hormone ligands, this cargo will be taken up exclusively by cells expressing the corresponding receptor. As a part of the down-regulation process of the endocytosed receptor-ligand complex the coupled siRNA will be hydrolyzed from the ligand in order to unfold its function in the cytoplasm by cleaving the complementary messenger RNA. This mechanism enables addressing of many diseases while minimizing side-effects. As a proof of concept human prolactin receptor (hPLR), which is overexpressed in many ovarian cancer cells will be used to internalize c-Met targeting siRNA, conjugated to human placental lactogen (hPL). Both visualization of the receptor-ligand internalization as well as linking interfering RNA to hPL has been worked out in preliminary experiments. Optimization of coupling strategies, proof of delivery of the fused molecules in vitro (ovarian cancer cell lines) and in vivo (ovarian cancer mouse model) as well as evaluation of various combined siRNAs are the direct aims. As a consequence of efficient delivery of functional c-Met siRNAs, knockdown of c-Met expression is expected to reduce dissemination of metastases in the peritoneal cavity in a mouse model.