We have recently developed surface-shielded
transferrin-
polyethylenimine (Tf-PEI)/
DNA delivery systems that target reporter gene expression to distant
tumors after systemic application. In the present study, we used surface-shielded Tf-PEI/
DNA complexes for delivering the gene for a highly potent
cytokine,
tumor necrosis factor-alpha (
TNFalpha).
TNFalpha is known for its ability to induce hemorrhagic
tumor necrosis and
tumor regression. However, the therapeutic application of
TNFalpha is hampered by its high systemic toxicity dictating the need to target
TNFalpha activity to the
tumor. Systemic application of surface-shielded Tf-PEI complexes with the
TNFalpha gene resulted in preferential expression of
TNFalpha in the
tumor without detectable
TNFalpha serum levels, in contrast to the application of nontargeted complexes.
Tumor-targeted
TNFalpha gene delivery induced pronounced hemorrhagic
tumor necrosis and inhibition of
tumor growth in three murine
tumor models of different tissue origins, Neuro2a
neuroblastoma, MethA
fibrosarcoma, and M-3
melanoma, with complete
tumor regressions observed in the MethA model. No systemic TNF-related toxicity was observed due to the localization of the
TNFalpha activity to the
tumor. Targeted gene therapy may be an attractive strategy applicable to highly active, yet toxic, molecules such as
TNFalpha.