A systemic targetable vector system is extremely important for the success and broader application of nucleic acids based therapeutics such as gene therapy, antisense therapy, and the emerging field of RNA interference. Systemic targeting has been a challenge not only for macromolecular drugs such as DNA, but also for small molecules. For nucleic acid delivery, vector systems based on synthetic reagents are better suited compared to viral vectors because of their lower risk for immunological and safety problems. In addition, synthetic vectors can be administered repeatedly and they can accommodate diverse forms of nucleic acids including large plasmid DNA and short oligonucleotides (DNA and RNA). First generation synthetic vectors based on cationic lipids or polymers are not suitable for systemic targeting due to the lack of specificity in their interactions. Molecular conjugates that can incorporate multiple functional moieties are ideal candidates for the design and construction of a targetable vector system. We have developed a prototype trifunctional polymer that provides some of the multiple functions needed for an effective gene delivery vehicle. This polymer conjugate can condense nucleic acid into nanoparticles with a steric protective layer and a targeting ligand layer on its surface. This layered particle provides tumor targeted delivery of nucleic acid from iv administration through tail vein. Recently, RNA interference has been demonstrated to be very effective in gene down regulation. Short double stranded RNA (siRNA) is very effective in down regulating genes sequence specifically. Though this technology has been widely accepted for target validation, its therapeutic potential is unknown. We have for the first time demonstrated the feasibility of using this technology for cancer therapy. We have obtained tumor growth inhibition and blood vessel growth inhibition using an siRNA against VEGFR2 delivered intravenously using the trifunctional polymer in a Neuro2A tumor model. We propose to develop this technology for the treatment of colon carcinoma. ? ? ?
