Interferon-alpha (IFNa) has been shown to be effective in treating cancer. One of the limitations of IFNa therapy as well as all protein therapeutics is their short half-life in vivo that require them to be administered frequently and create difficulties in maintaining steady state plasma levels. Gene therapy approaches could be employed to provide a more sustained release of IFNa in treating cancer. Insert Therapeutics (Insert) is developing new non-viral systemic nucleic acid delivery systems that can be used to provide a constant in vivo source of IFNa. The Insert non-viral delivery system involves several components: cyclodextrin-containing polycations (CDP), and a modifying agent that has a terminal adamantane (AD) for forming inclusion complexes with cyclodextrins on the surface of the colloidal CDP/nucleic acid particles. The polycation interacts with nucleic acids of sizes from short single-stranded oligonucleotides to large plasmids and self-assembles with the nucleic acids via electrostatic interactions to form colloidal particles. The polycations can mediate the transfection of cultured cells with high efficiency and completely protects the nucleic acid from nuclease digestion. The adamantane component self-assembles with the particles to modify the surface properties, thereby adapting the particles to be more suitable for systemic delivery. An important application of this modification technology is the addition of a ligand to target nucleic acids to specific tissues or cell types. When fully developed, the nucleic acid delivery system will overcome many of the problems associated with current gene therapy technologies. It will be a generalized delivery system that is non-immunogenic, non-toxic, stable in vivo, and amenable to large-scale production. In this phase I SBIR grant, we propose to develop a systemic IFNa DNA delivery vehicle to provide a sustained plasma release of IFNa for treatment of metastatic cancer. We will develop a therapeutic formulation of the delivery system for in vivo testing, optimize the conditions for the systemic delivery of the IFNa gene and test for efficacy in tumor bearing animal models. In future studies (phase II SBIR), we will conduct pre-clinical development of the delivery system so that it can be tested in clinical trials as a more efficient means to administer IFNa to patients.