Use of Clofibrate to Bypass Nuclear Targeting in the Development of Non-Viral Gene Delivery Systems

Clofibrate is a commercially available chemical that has been found to induce increased cell division in the hepatocytes of rodents. Previous experiments in our lab have investigated the use of clofibrate to bypass the need for nuclear targeting in non-viral gene delivery systems, since the large size of the gene delivery vector limits its ability to enter the nucleus of hepatocytes. We decided to replicate these experiments, with the intention of seeing higher levels of gene expression by using targeted DNA nanoparticles that contained additional targeting for mice hepatocytes. Mice were dosed with corn oil, clofibrate, clofibrate and non-targeted DNA nanoparticle, or clofibrate and targeted DNA nanoparticle over the course of a 5-day clofibrate dosing protocol. Body weight gain, liver weight gain, and levels of luciferase gene expression was compared across treatment groups. It was found that only the treatment group dosed with non-targeted DNA nanoparticles exhibited a 10-fold increase in gene expression compared to the control group (p = 0.0108). Therefore, we decided to further explore this result by determining if a dose-dependent response would be seen from non-targeted DNA nanoparticles over the course of a 14-day clofibrate dosing protocol. Mice were dosed with clofibrate, clofibrate and 10 ug non-targeted DNA nanoparticle, or clofibrate and 100 ug non-targeted DNA nanoparticle with changes in body weight, liver weight, and luciferase gene expression being recorded. The data suggested that non-targeted DNA nanoparticles did not exhibit a dose-dependent response in luciferase gene expression when dosed in the presence of clofibrate.