Tumor-targeted gene delivery of tumor necrosis factor-[alpha] induces tumor necrosis and tumor regression without systemic toxicity

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.