Smart design of a therapeutic nanoplatform for mitochondria-targeted copper-depletion therapy combined with chemotherapy

Mitochondria-targeted copper-depletion is emerging as an attractive strategy to combat cancer. However, existing copper molecular chelators are non-specific, toxic and ineffective. Here, it is reported that multifunctional nanoparticles (MSN-TPP/BNA-DPA) can not only target mitochondria to deprive copper ions to trigger copper-depletion therapy, but also serve as nanocarriers to deliver anticancer drugs for chemotherapy, which are engineered by conjugating a fluorophore 4-bromo-1,8-naphthalicanhydride (BNA), a copper-depriving moiety dimethylpyridinamine (DPA) and a mitochondrial targeting ligand triphenylphosphonium (TPP) on the surface of mesoporous silica nanoparticles (MSN). BNA and the internal charge transfer of compound BNA-DPA endow MSN-TPP/BNA-DPA with green fluorescence emission upon UV excitation, which can be used to monitor the cellular uptake of nanoparticles. When copper ions bind to DPA, green fluorescence is quenched, providing visualization feedback of copper-depletion. Therapeutically, mitochondria-targeted copper-depletion effectively causes mitochondria damage, elevated oxidative stress and reduced ATP production to induce intensive cancer cell death. Moreover, the mesoporous structure enables MSN-TPP/BNA-DPA to deliver doxorubicin to mitochondria for chemotherapy and enhances copper-depletion therapy through H2O2 production. Together, the synergistic therapeutic effect of enhanced copper-depletion therapy and doxorubicin-mediated chemotherapy achieves a remarkable cancer cell-killing effect and significant tumor growth inhibition in 4T1 tumor-bearing mice. This work provides an efficacious strategy for copper-depletion based synergistic cancer therapy.

Automated summary

Multifunctional nanoparticles (MSN-TPP/BNA-DPA) have been developed to target mitochondria for copper-depletion therapy and deliver anticancer drugs for chemotherapy. These nanoparticles are constructed by conjugating a fluorophore (BNA), a copper-depriving moiety (DPA), and a mitochondrial targeting ligand (TPP) on the surface of mesoporous silica nanoparticles (MSN). The use of BNA-DPA enables visualization of copper-depletion through quenching of green fluorescence upon copper binding. Therapeutically, mitochondria-targeted copper-depletion causes mitochondria damage, oxidative stress, and reduced ATP production to induce cancer cell death.