Development of an interactive tumor vascular suppression strategy to inhibit multidrug resistance and metastasis with pH/H2O2 responsive and oxygen-producing nanohybrids

An ideal cancer therapeutic strategy should not only reverse multidrug resistance (MDR), but also prevent cancer metastasis. In this study, bovine serum albumin (BSA) was hybridized with Mn(2+)via biomineralization to develop a hybrid protein oxygen nanocarrier, which contained doxorubicin (DOX) and small interfering RNA (siRNA). The nanohybrid has the function of producing oxygen and chemotherapy synergistic gene therapy. FA-BSA-MnO2/DOX/siRNA was favorable for increasing the sensitivity of MCF-7/ADR cells to DOX. Moreover, FA-BSA-MnO2/DOX/siRNA NPs were also able to generate oxygen (O-2) by reaction with endogenous hydrogen peroxide (H2O2) in tumor, thereby down-regulating the expression of hypoxia inducible factor-1 alpha (HIF-1 alpha), and then the expression of the vascular endothelial growth factor (VEGF) was down-regulated. At the same time, siRNA can directly or indirectly suppress the expression of the VEGF and HIF-1 alpha. Therefore, the combination of two pathways and the chemo-gene therapy strategy can interactively overcome tumor hypoxia-associated MDR and metastasis, which will enhance therapeutic efficacy in the future.