Smart Design of Mitochondria-Targeted and ROS-Responsive CPI-613 Delivery Nanoplatform for Bioenergetic Pancreatic Cancer Therapy.

Mitochondria, as the powerhouse of most cells, are not only responsible for the generation of adenosine triphosphate (ATP) but also play a decisive role in the regulation of apoptotic cell death, especially of cancer cells. Safe potential delivery systems which can achieve organelle-targeted therapy are urgently required. In this study, for effective pancreatic cancer therapy, a novel mitochondria-targeted and ROS-triggered drug delivery nanoplatform was developed from the TPP-TK-CPI-613 () prodrug, in which the ROS-cleave thioketal functions as a linker connecting mitochondrial targeting ligand TPP and anti-mitochondrial metabolism agent CPI-613. DSPE-PEG2000 was added as an assistant component to increase accumulation in the tumor via the EPR effect. This new nanoplatform showed effective mitochondrial targeting, ROS-cleaving capability, and robust therapeutic performances. With active mitochondrial targeting, the formulated nanoparticles ( NPs) demonstrate much higher accumulation in mitochondria, facilitating the targeted delivery of CPI-613 to its acting site. The results of in vitro antitumor activity and cell apoptosis revealed that the IC values of NPs in three types of pancreatic cancer cells were around 20~30 µM, which was far lower than those of CPI-613 (200 µM); 50 µM NPs showed an increase in apoptosis of up to 97.3% in BxPC3 cells. Therefore, this mitochondria-targeted prodrug nanoparticle platform provides a potential strategy for developing safe, targeting and efficient drug delivery systems for pancreatic cancer therapy.