A nano-system combines mitochondrial damage with microtubule stabilization for cancer metastasis suppression

Abstract

Mitochondria targeting has been extensively reported in cancer therapy. Nevertheless, damaging mitochondria alone does not yield excellent efficacy, making it a challenge in the effective treatment of cancer metastasis. Inspired by the close relationship between mitochondria and microtubules in location and function, we propose an active-targeting nano-system that consists of a mitochondrial-damaging drug and a microtubule stabilizer. The nano-system exhibits synergistic cytotoxicity and effectively inhibits the migration and invasion of tumor cells more than either damaging mitochondria or stabilizing microtubules alone in vitro. In vivo experiments also reveal a remarkable suppression of over 85% of lung metastasis by the nano-system. Further mechanism investigations unravel mitochondrial damage by up-regulated reactive oxygen species and down-regulated adenosine triphosphate. Along with microtubule stabilization, mitochondrial fission is suppressed, further promoting mitochondrial damage. Subsequently, the nano-system jointly suppresses the epithelial–mesenchymal transition process and reduces the expression of metastasis-associated proteins to exert the anti-metastasis effect. Overall, mitochondrial damage combined with microtubule stabilization scales new heights in anti-metastasis efficacy, indicating that this combination strategy is a potential therapy for cancer metastasis.