FC-BBR/IND-induced glucose oxidase nanodrugs for targeted combination therapy

Targeted therapy from cells to mitochondria can improve the bioavailability and therapeutic effects of drugs. Combination therapy by combining two or more therapeutic methods comes to be seen a hopeful strategy to overcome the emergence of resistance. Ferrocene (FC) derivatives of the sandwich structure can not only directly inhibit the proliferation of cancer cells but also catalyze the Fenton reaction to enhance chemodynamic therapy. Berberine (BBR) is a Chinese herbal extract with mitochondria-targeted anticancer activity. In our work, glucose oxidase (GOD) was induced to self-assemble by ferrocene-berberine conjugate (FC-BBR) and indomethacin (IND), which was then encapsulated by hyaluronic acid (HA) and formed nanodrugs (FC-BBR/IND@GOD@HA NPs). Molecular simulation results showed that the drugs could be bound to multiple sites of GOD and induce its self-assembly. The prepared nanoassembly could inhibit the proliferation and induce the apoptosis of HepG2 cells, which might be the result of targeted chemodynamic therapy and starvation therapy. Moreover, the FC-BBR/IND@GOD@HA NPs could also promote the production of reactive oxygen species and the loss of mitochondrial membrane potential and block the cells in S phase. More importantly, it could inhibit the movement and migration of cancer cells, which gave it the potential to prevent tumor metastasis.