Targeting of Mitochondria in Triple-Negative Breast Cancer Cells Using Berberine Derivative Self-Assembled Micelles Coated with Erythrocyte-Cancer Hybrid Membranes

Systemic chemotherapy remains the most frequent treatment for triple-negative breast cancer (TNBC) because the tumors do not express any of the three surface receptors targeted by selected treatments. A more selective alternative may be delivering drugs such as the well established anti-tumor drug as well as mitochondrial toxin doxorubicin to mitochondria in tumor cells by carriers containing TNBC surface proteins and delocalized lipophilic cations such as berberine derivatives that can target TNBC tumors and mitochondria, respectively. Once they enter tumor cells, the drug-loaded carriers will target to the mitochondria and inactivate them in the presence of cations. Here we synthesized amphiphilic 9- O -cetyl-berberine, which retained the anti-tumor activity of berberine, through a method involving microwave irradiation, then allowed the molecules to co-assemble spontaneously with doxorubicin into micelles. The micelles were coated with membranes derived from erythrocytes and the TNBC cell line MDA-MB-231 to shield their cytotoxic and hemolytic positive charge. The resulting nanovesicles showed good stability in the short term and good safety, and synergistically inhibited proliferation and migration of TNBC cells by reducing mitochondrial membrane potential and promoting the generation of reactive oxygen species and activating apoptotic signaling. These results establish the potential of this system to co-deliver doxorubicin and delocalized lipophilic cations to treat TNBC.