Local and Systemic Delivery of Interleukin-12 Gene by Cationic Micelles for Cancer Immunogene Therapy

摘要

Immunogene therapy is an alternative strategy for cancer gene therapy. By stimulating the activities of immune cells in the tumor microenvironment, the genetic materials boost the immune response to attack cancer cells resulting in therapeutic effects. Interleukin-12 is an important regulator with great potential in modulating both innate and adaptive immunities. Here, a cancer immunogene therapy strategy was established and evaluated by delivering the IL-12 gene with a novel non-viral gene vector DMP. The DMP cationic micelles were prepared by modifying monomethoxy poly(ethylene glycol)poly(epsilon-caprolactone) with the DOTAP lipid via self-assembly. The anti-cancer efficacy of the DMP/IL-12 complex was studied on multiple murine cancer models via both local and systemic administration. Our results demonstrated that the secretory expressed IL-12 cytokine effectively enhanced lymphocytes activities resulting in strong inhibition of cancer cell growth in vitro. Meanwhile, there were obvious tumor regressions achieved in tumor models of C26 colon carcinoma and LL/2 lung cancer in vivo. Multiple anti-cancer mechanisms including T cell infiltration, TNF-alpha secretion, apoptosis induction and angiogenesis inhibition are involved; no pathology changes were observed in healthy tissues. These results suggest that the DMP/IL-12 complex is a potential candidate for cancer immunogene therapy.