Mitochondria-targeted delivery of doxorubicin to enhance antitumor activity with HER-2 peptide-mediated multifunctional pH-sensitive DQAsomes

INTRODUCTION: Multidrug resistance (MDR) of breast cancer is the major challenge to successful chemotherapy while mitochondria-targeting therapy was a promising strategy to overcome MDR. MATERIALS AND METHODS: In this study, HER-2 peptide-PEG(2000)-Schiff base-cholesterol (HPSC) derivate was synthesized successfully and incorporated it on the surface of the doxorubicin (DOX)-loaded dequalinium (DQA) chloride vesicle (HPS-DQAsomes) to treat drug-resistant breast cancer. Evaluations were performed using human breast cancer cell and DOX-resistant breast cancer cell lines (MCF-7 and MCF-7/ADR). RESULTS: The particle size of HPS-DQAsomes was ~110 nm with spherical shape. In vitro cytotoxicity assay indicated that HPS-DQAsomes could increase the cytotoxicity against MCF-7/ADR cell line. Cellular uptake and mitochondria-targeting assay demonstrated that HPS-DQAsomes could target delivering therapeutical agent to mitochondria and inducing mitochondria-driven apoptosis process. In vivo antitumor assay suggested that HPS-DQAsomes could reach favorable antitumor activity due to both tumor targetability and sub-organelles’ targetability. Histological assay also indicated that HPS-DQAsomes showed a strong apoptosis-inducing effect. No obvious systematic toxicity of HPS-DQAsomes could be observed. CONCLUSION: In summary, multifunctional HPS-DQAsomes provide a novel and versatile approach for overcoming MDR via mitochondrial pathway in cancer treatment.