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

Yi-Mei Zhang,Zhong-Zhu Chen,Li-Xia Gao,Yan Tang,Meng Xia,Ya-Fei Luo,Zheng Huang,Bo-Chu Wang,Rui Ao,Jiu-Hong Huang

doi:10.3390/nano11112875

Abstract

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 (TTCI) 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 (TTCI 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 IC50 values of TTCI 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 TTCI 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.

Highlights

IntroductionPancreatic cancer, known as the “king of cancers”, is the fourth leading cause of cancer mortality in the world and its prognosis is cruel: the five-year survival rate remains lower than 10% [1,2]
The target mitochondria-targeted prodrug 4 was obtained by coupling anticancer drug molecule CPI-613 to the other end of the linkage under the same conditions
CPI-613 and mitochondrial targeting ligand veloped by conjugating the drug CPI-613 and mitochondrial targeting ligand TPP

Summary

Introduction

Pancreatic cancer, known as the “king of cancers”, is the fourth leading cause of cancer mortality in the world and its prognosis is cruel: the five-year survival rate remains lower than 10% [1,2]. CPI-613, a member of a novel class of anti-cancer lipoate derivatives, is an anti-mitochondrial metabolism agent which strongly induces apoptosis by disrupting mitochondrial metabolism, such as by changing mitochondrial enzyme activities and redox status in several types of cancer cells, especially in pancreatic cancer and small lung cancer cells [3,4]. CPI-613 has exhibited prominent antitumor activity against human pancreatic cancer in xenograft models, with low side-effects thanks to its specificity and selectivity for tumor cells [5,6,7].

Methods

Results

Conclusion