Multi-functionalized Nano-conjugate for combating multidrug resistant breast Cancer via starvation-assisted chemotherapy

The multi-drug resistance (MDR) is the leading reason resulting in the failure of cancer treatment. Decreasing the development chance of MDR and fighting against the MDR cancer are still facing severe challenges. In order to overcome MDR via disrupting the original metabolic pathway of cancer cells, we designed a multi-functionalized nano-conjugate based on the starvation therapy to make cancer cells availably sensitized to chemotherapy. The nano-conjugate constitutes of the nano-carrier (AuNP-PEG-RGD) and glucose oxidase (GOx, activity equivalent), which not only can specifically target cancer cells with the help of the cancer-targeting peptide (RGD) laid on the surface, but also can deplete glucose and O2 with the simultaneous generation of H2O2. Insufficient glucose, excess H2O2, and hypoxia microenvironments can suppress cell proliferation and induce cell apoptosis. With the hypothesis that the specific damage induced by the nano-conjugate can make cancer cells much vulnerable to chemotherapy, we further evaluated the therapeutic effect of an anti-cancer drug (doxorubicin, Dox) with the assistance of the low dose of nano-conjugate for the breast cancer cell. The results indicate that 0.2 mu g/mL of Dox in the combination of 22.5 pM of the nano-conjugate can kill 80% cancer cells, which effectively improves the treatment efficiency compared with the nano-conjugate or Dox alone based on the synergism effect (the combination index < 1). More importantly, our developed strategy can be used for sensitizing the MDR cancer cells to the traditional ineffective drugs, which owns potential applications in decreasing the chance of MDR development and overcoming drug-resistant cancers.