Novel prodrug supramolecular nanoparticles capable of rapid mitochondrial-targeting and ROS-responsiveness for pancreatic cancer therapy

Abstract

Mitochondrial dysfunction is a feature of cancer cells and targeting cancer mitochondria has emerged as a promising anticancer therapy. In this study, a novel mitochondria-targeted and ROS-responsive drug delivery nanoplatform was developed from the TPP-TK-Chlorambucil (TTCb) prodrug for effective pancreatic cancer therapy. Mitochondria targeting ligand TPP and DNA alkylating drug chlorambucil were connected by a linker containing ROS-cleave thioketal. DSPE-PEG2000 was utilized as the assisting component to increase the accumulation of nanoparticles in the tumor by the EPR effect. This smart nanoplatform showed effective mitochondrial targeting, ROS-cleaving capability and remarkable therapeutic performance in cells. The formulated nanoparticles (TTCb-NPs) rapidly revealed high cellular uptake, which demonstrated that higher accumulation in mitochondria facilitated chlorambucil targeted delivery to mitochondria where it acts on mtDNA and induces cell death. The results of in vitro antitumor activity demonstrated that the IC₅₀ values of TTCb-NPs in three pancreatic cancer cells were around 20–30 μM, which was lower than that of chlorambucil. 50 μM TTCb-NPs could significantly inhibit the growth of BxPC3 cells. Therefore, TTCb-NPs are promising as drug delivery systems with organelle targeting and ROS-stimulated control release. These results demonstrated that the synthesized TTCb-NPs exhibited therapeutic potential for the treatment of refractory pancreatic tumors.