Systemic delivery of the tumor necrosis factor gene to tumors by a novel dual DNA-nanocomplex in a nanoparticle system.

ABSTRACT

Many cancers fail to respond to immunotherapy as a result of immune suppression by the tumor microenvironment. The exogenous expression of immune cytokines to reprogram the tumor microenvironment represents an approach to circumvent this suppression. The present studies describe the development of a novel dual nanoparticle (DNP) system for driving DNA expression vectors encoding inflammatory cytokines in tumor cells. The DNP system consists of a DNA expression vector-cationic peptide nanocomplex (NC) surrounded by a diblock polymeric NP. Tumor necrosis factor alpha (TNF) was selected as the prototype cytokine for this system, based on its pleotropic inflammatory and anti-cancer activities. Our results demonstrate that the DNP system is highly effective in driving expression of TNF in tumor cells. We also demonstrate that the DNPs are effective in inducing apoptosis and anti-tumor activity. These findings support a novel immunotherapeutic approach for the intratumoral delivery of DNA vectors that express inflammatory cytokines.