Abstract

Mitochondria play a central role in cancer progression and tumor metastasis, and nanomedicines targeting mitochondria have emerged as a promising strategy for tumor therapy. However, mitochondria targeting strategies have not been widely explored in the inhibition of tumor metastasis, and they have disadvantages of complicated preparation, low drug loading, systemic toxicity of the carriers and poor accumulation at tumor sites. Here we firstly developed self-assembled nanodrugs with a high drug loading (∼68%) comprised of a berberine derivative (Ber) and doxorubicin (Dox) by a simple nano-precipitation method, which successfully altered the target location of Dox from the nucleus to mitochondria and therefore inhibited the proliferation, invasion and migration of MDA-MB-231 cells by triggering cell apoptosis. The surface of nanodrugs was modified with DSPE-PEG-folic acid (DSPE-PEG-FA) and hyaluronic acid (HA) for precise tumor recognition and enhanced accumulation (HA-FA-BD NDs). Upon arrival at the tumor site with the help of the enhanced permeability and retention (EPR) effect, the partial degradation of HA by hyaluronidase (HAase) at the tumor site allowed the partial exposure of the positively charged FA-BD NDs to the cells, then nanodrugs would accumulate and enter tumor cells by dual binding to both folic acid (FA) and CD-44 receptors. Once internalized into lysosomes, both the HA outer shell and DSPE-PEG-FA of nanodrugs were degraded or decomposed completely to expose positively charged BD NDs. Driven by delocalized lipophilic cations, nanodrugs could escape from lysosomes and reach mitochondria to induce a cascade reaction and finally cell apoptosis, as well as suppressing matrix metalloprotease (MMP)-2 and -9 activities and finally cell migration and invasion. In a xenograft mice model of MDA-MB-231 breast cancer cells, the nanodrugs repaired the defects in Mfn 1/Drp 1 mitochondrial proteins, suppressed the activity of MMP-2 and -9, and significantly inhib