Novel Mitochondria-Targeted NIR Cyanine Cy750M-C1 Nanoparticles for Chemotherapy against Triple-Negative Breast Cancer.

Abstract

Mitochondrial metabolism plays an important role in promoting cancer development, making mitochondria a novel promising target for cancer therapy. Current mitochondria-targeted fluorescent agents can specifically accumulate in the mitochondria of cancer cells and can be applied for cancer imaging and therapy. However, their clinical application is still limited due to the poor solubility and lower tumor-specific distribution. In the present study, we synthesized a novel NIR small-molecule dye, Cy750M-C1, and evaluated its optical properties, mitochondrial distribution, and anticancer activity. We also synthesized nanoparticles loading Cy750M-C1 (Cy750M-C1-FA-NPs) and demonstrated that Cy750M-C1-FA-NPs are specifically targeted to the tumor and dramatically inhibited tumor growth in vivo. The mechanistic study revealed that Cy750M-C1 specifically targeted mitochondria of TNBC cells, subsequently promoting ROS production through inhibition of mitochondrial complexes (complexes I, III, and IV) and OXPHOS and depletion of ATP, leading, in turn, to AMPK activation and Drp1 dephosphorylation mediating the mitochondrial translocation of Drp1 and BAX and ultimately inducing mitochondrial fission, caspase activation, as well as apoptosis. Overall, our data implicate that Cy750M-C1 could be developed as a novel anticancer agent with mitochondria-targeting ability and NIR fluorescence imaging and that Cy750M-C1-FA-NPs could also be considered as promising drug delivery carriers for antitumor agents.