Cerberus Nanoparticles: Cotargeting of Mitochondrial DNA and Mitochondrial Topoisomerase I in Breast Cancer Cells

The mitochondrion is an unorthodox target for developing chemotherapeutic strategies for cancer. Mitochondrion also contains circular DNA responsible for the protein synthesis for oxidative phosphorylation. Damaging mitochondrial DNA selectively, keeping nuclear DNA intact is currently a foremost hurdle. Here, triphenylphosphine-decorated mitochondria targeting positively charged Cerberus Nanoparticle (mt-CN) was engineered. These nanoparticles can contain cisplatin (DNA damaging agent) and SN38 or Topotecan (Topoisomerase I inhibitor) simultaneously in a single particle. Confocal laser scanning microscopy confirmed the homing of the mt-CNs into mitochondria in MCF7 breast cancer cells. We further confirmed mt-CN-mediated marked accumulation of mt-DNA damage in MCF7 cells using a combination of long-range polymerase-chain-reaction and gel electrophoresis. MCF7 cells treated with mt-CN exhibited a significant reduction in synthesis of mitochondria-encoded cytochrome c oxidase subunit 1 while keeping nuclear DNA unperturbed. The mt-CN damaged mitochondrial outer membrane, which leads to the release of cytochrome c and reactive oxygen species generation. Finally, mt-CNs induced apoptosis in MCF7 cells by cleavage of caspase-9 to trigger improved cell death. It can be anticipated that these Cerberus Nanoparticles can inhibit various targets specifically and spatially into mitochondria as next-generation chemotherapy.