Nonviral Delivery of GRIM-19 Gene Inhibits Tumor Growth with Reduced Local and Systemic Complications.

Abstract

Chemotherapy causes inflammation, which promotes cancer development and results in complications such as hemorrhages and thrombosis. Development of new therapeutic strategies to limit inflammatory responses will potentially reduce these side effects in cancer patients. Gene therapy is an attractive cancer treatment because of its high specificity and limited side effects. A tumor suppressor gene associated with retinoid-interferon-induced mortality-19 (GRIM-19) was delivered by an amphiphilic copolymer poly(ɛ-caprolactone) and ethanolamine-functionalized poly (glycidyl methacrylate) (PCG). The transfection outcome of PCG/pGRIM-19 complexes was studied both in vitro and in vivo. The antitumor therapeutic effects were evaluated in a well-vascularized Neuro-2a neuroblastoma tumor mouse model in comparison with that of cisplatin. The PCG/pGRIM-19 nanocomplex showed high transfection efficiency and low toxicity. In vitro transfection of PCG/pGRIM-19 in Neuro-2a cells reduced the expression levels of Cyclin D1, BCL-2, and MMPs 2 and 9, and inhibited cell proliferation, migration, and stimulated apoptosis. In vivo experiments indicated that PCG/pGRIM-19 therapy downregulated signal transducer activator of transcription 3, nuclear factor-κB, and MMP9 expression in tumor tissues. Compared with cisplatin treatment, gene therapy with PCG/pGRIM-19 significantly inhibited local complications of intratumor hemorrhages, and systemic complications such as anemia and pulmonary embolism, thereby effectively prolonged mouse survival. Our results highlight the potential of PCG/pGRIM-19 gene therapy in reducing tumor burden and complications, providing novel strategies to enhance clinical cancer therapy.