A folic acid-modified non-viral vector combines gene therapy with chemotherapy to reverse cancer chemotherapy resistance

Abstract

Drug resistance limits the broader application of chemotherapy in cancer, which is currently a thorny clinical problem to be solved. The combined strategy of molecular targeted therapy and traditional chemotherapy has recently shown potential clinical benefits for overcoming chemoresistance. Herein, a folic acid (FA)-modified targeted drug/gene delivery system composed of FA-PEG-PCL-PEG-FA, MPEG-PCL-MPEG, and 1, 2-dioleoyl-3-trimethylammonium-propane (DOTAP) through a self-assembly approach, named F-DPA, is developed to co-deliver Paclitaxel (PTX) and plasmid shBCL-2. In vitro, compared to a single treatment, the combination of plasmid shBCL-2 with PTX induces cell apoptosis, inhibits cell proliferation, and arrests the cell cycle in the G2/M phase. In vivo experiments show that the FA-targeted combined treatment dramatically improves anti-tumor efficacy by decreasing neovascularization, suppressing proliferation, and increasing tumor cells apoptosis without toxicity. These results indicate that the FA-modified codelivery system of plasmid shBCL-2 and PTX can suppress the expression of BCL-2, thereby improving the sensitivity of cancer cells to chemotherapy drugs and significantly enhancing their therapeutic effect, which is a promising treatment option for chemoresistant ovarian cancer.