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

Abstract

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 Mn2+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 (O2) by reaction with endogenous hydrogen peroxide (H2O2) in tumor, thereby down-regulating the expression of hypoxia inducible factor-1α (HIF-1α), 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-1α. 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.