Light-switchable diphtherin transgene system combined with losartan for triple negtative breast cancer therapy based on nano drug delivery system

Abstract

Breast cancer is a common malignancy in women. The abnormally dense collagen network in breast cancer forms a therapeutic barrier that hinders the penetration and anti-tumor effect of drugs. To overcome this hurdle, we adopted a therapeutic strategy to treat breast cancer which combined a light-switchable transgene system and losartan. The light-switchable transgene system could regulate expression of the diphtheria toxin A fragment (DTA) gene with a high on/off ratio under blue light and had great potential for spatiotemporally controllable gene expression. We developed a nanoparticle drug delivery system to achieve tumor microenvironment-responsive and targeted delivery of DTA-encoded plasmids (pDTA) to tumor sites via dual targeting to cluster of differentiation-44 and αvβ3 receptors. In vivo studies indicated that the combination of pDTA and losartan reduce the concentration of collagen type I from 5.9 to 1.9 µg/g and decreased the level of active transforming growth factor-β by 75.0% in tumor tissues. Moreover, deeper tumor penetration was achieved, tumor growth was inhibited, and the survival rate was increased. Our combination strategy provides a novel and practical method for clinical treatment of breast cancer.