The development and biological evaluation of Octreotide contatining peptides for receptor mediated non-viral gene delivery

Chapter 1 describes the barriers that have hindered the effective use of gene delivery and a literature review of methods designed to overcome those barriers. Areas of gene delivery that will be discussed include viral, physical, and non-viral methods of gene delivery. A special focus will be on methods to target gene delivery vehicles and more specifically the somatostatin receptor 2 (SSTR2) targeting ligand, octreotide, to improve site specific non-viral gene delivery of DNA polyplexes Barriers to Gene Delivery Gene delivery offers the potential to deliver a therapeutic gene to a malfunctioning cell to create a healthy cell [1]. Yet, achieving therapeutic levels of expression of a desired gene is a multifaceted challenge. First, the delivery system and formulation of the DNA must be carefully considered or the DNA will not remain transfection competent and could be rapidly cleared from the body. In vitro incubation of plasmid DNA in serum has a half-life of 30 minutes. In vivo, dosed plasmid DNA has a half-life of less than five minutes as it is immediately degraded by circulating blood cells, proteins, DNA transporting molecules, and endonucleases leading to premature metabolism [2, 3]. Second, stabilized DNA particles must avoid being trapped within small capillaries, like those of the lungs, or removal by the reticulo-endothelial system [4]. Finally, the plasmid DNA must still specifically bind the cells of interest in order to increase the effective intracellular dose delivered. In this dissertation, I attempt to synthesize a non-viral molecule to create therapeutic DNA targeting. Targeting of plasmid DNA is necessary to create therapeutic effects by gene delivery systems. Without targeting, stabilized DNA will circulate through the body, and with no method of accumulation in specific tissues, be cleared by the liver. Circulating DNA has no therapeutic gain. Once appropriately targeted to the cells of interest, the