TARGETING OF A CHOLECYSTOKININ-DNA COMPLEX TO PANCREATIC-CELLS IN-VITRO AND IN-VIVO

The carboxy terminal octapeptide of cholecystokinin (CCK8) is a hormon e that binds high affinity receptors in a number of tissues including pancreas and pancreatic tumours. As part of our studies to develop eff ective gene therapy for the treatment of pancreatic cancers, we have i nvestigated various gene delivery systems that depend on CCK8 receptor targeting. In this paper,we describe the synthesis of a CCK8-DNA comp lex designed to deliver foreign DNA to cholecystokinin receptor-positi ve cells. CCK8 was ligated to avidin and then complexed to linearis bi otinylated DNA (pSV-CAT). The uptake of P-32-labelled CCK8-DNA complex by rat pancreatic acini was linear with time over 4 h with 65-70% of uptake inhibited by 100 nM CCK8. The complex appeared to be internalis ed since it could not be removed by acid wash. When administered intra -arterially, the complex was rapidly removed from the circulation with no evidence of targeted delivery to the pancreas, However, following a single intraperitoneal dose, the pancreas accumulated-5- 8% of the t otal administered complex by 24 h. These results suggest that peptide- dependent gene delivery to CCK receptor positive cells in vivo is feas ible but, when administered directly into the circulation, diffusional barriers across the endothelium may limit distribution to peripheral tissues. Intraperitoneal administration therefore may be a useful alte rnative for targeting the pancreas.