279. A Novel Functionalized Polymeric Formulation for use in Delivering Therapeutic Genes for the Treatment of Solid Tumors

We have described the synthesis, physico-chemical properties and gene therapy application of a novel water soluble gene delivery system PEG-PEI-Chol (PPC). PPC is composed of a low molecular weight branched polyethyleneimine, cholesterol and polyethylene glycol and designed to promote DNA condensation into nanoparticles, enhance membrane uptake and improve biocompatibility and pharmacokinetics, respectively. The chemical composition and molar ratios between the individual components of the polymer were verified by NMR. Formulation of PPC with DNA produced particles of ∼100nm mean diameter and zeta potential of ∼20mV. In vitro optimization studies using a luciferase reporter gene were performed in order to evaluate the effects of varying amounts of PEG and increasing nitrogen to phosphorus ratio (N:P). Use of the PPC delivery system with a plasmid encoding for interleukin-12 (IL-12) for treatment of solid tumors was examined in mice. Significant inhibition in tumor growth rate and/or increased incidence of complete tumor rejection was seen in murine models of breast cancer and head and neck cancer following intratumoral injections. A combination therapy approach was evaluated where the IL-12/PPC treatment was combined with an investigative polymeric formulation of paclitaxel against 4T1 mammary tumors and it was shown that combined therapy led to a synergistic inhibition of tumor growth. This form of paclitaxel had little effect on SCCVII head and neck tumors however, cyclophosphamide strongly inhibited SCCVII tumor growth. Further, when IL-12/PPC intratumoral injections were combined with cyclophosphamide administration, there was a slight additional inhibition in tumor growth over the cyclophosphamide treatment alone and there was a significant increase in the rate of complete tumor rejection. Future studies will be aimed at optimizing dose and dosing regimens of combination therapies for the treatment of solid tumors.