Targeting self-enhanced ROS-responsive artesunatum prodrug nanoassembly potentiates gemcitabine activity by down-regulating CDA expression in cervical cancer

Abstract

Prodrug self-delivery carriers with targeting that specifically responded to tumor microenvironments have good potential to improve the application dilemma of approved clinical therapeutic drugs (systemic distribution and side effects). It's noted the conversion of gemcitabine (GEM) to inactive ingredients under the action of cytidine deaminase (CDA) during metabolism in vivo limits its clinical effect. A high level of reactive oxygen species (ROS) results in a high level of oxidative stress in tumor cells, which changes the expression of CDA and optimizes the metabolism of GEM in vivo and overcome drug resistance. In this study, the ROS responsive and ROS self-supplied prodrug of artemisia (ART)-thioacetal bond (TK)-GEM was synthesized and self-vectors based on ART-TK-GEM (TK@FA NPs) was prepared by using nano precipitation. ROS responsive characteristics ensure specific release of prodrugs in tumor cells with high level of ROS thereby reducing side effects on normal cells and tissues. The endogenous ROS and newly generated ROS by ART can reduce the expression of CDA and optimizes the metabolism of GEM, and the accumulated ROS can also induce apoptosis of tumor cells, realizing synergistic anti-tumor effect of chemical drugs and traditional Chinese medicines. This paper proposes a simple method by using clinically approved drugs to improve the insufficient effect of existing chemotherapy and overcome resistance, which has potential to appropriately shorten the drug development cycle and accelerate the clinical investigation of drugs.