The Construction and Application of Mn3O4/DOX@Lip Nano-drug Delivery System Based on Fenton-Like Reaction

The tumor microenvironment with low pH and high-level glutathione is different from other issues, which provides more possible strategies for designing drug delivery systems (DDSs). In this manuscript, we designed a microenvironmentresponsive Mn3O4/DOX@Lip nano-DDS. Mn3O4 nanoparticles were prepared by thermal decomposition. Based on coordination of the chemotherapy drug doxorubicin (DOX) with Mn atom, the Mn3O4 nanoparticles could load and deliver DOX. A layer of sensitive liposomes was assembled on the outermost layer to further effectively prevent the leakage of DOX during the delivery process. X-ray diffraction (XRD) and energy dispersive X-ray spectroscopy (EDX) analysis results showed the manganese oxide was Mn3O4. The morphology and particle size of Mn3O4 were characterized by transmission electron microscope (TEM) and dynamic light scattering (DLS). Results showed that the Mn3O4 nanoparticles were a relatively uniform polyhedron with a particle size of around 20 nm. The drug loading of particles was 100 mu g/mg. In weakly acidic microenvironment of tumor cells, the liposome membrane ruptured. In addition, the high-level glutathione microenvironment was also conducive to the decomposition of Mn3O4 and the DOX was released in cells. Confocal imaging results demonstrated that after co-incubation with the Mn3O4 particles, the fluorescence of reactive oxygen species (ROS) probe in cancer cells increased significantly, indicating that the DDS could trigger an increase of ROS in cells by down-regulating the content of glutathione. The amount of ROS depended on the concentration of added particles and the incubation time. MTT and flow cytometry experiment results showed that Mn3O4/DOX@Lip had more cell cytotoxic compared to the single chemotherapy drug. It might be ascribed to the Fenton-like reaction triggered by the reduction product Mn2+, which converted the H2O2 in the cell into the more toxic center dot OH and promoted apoptosis. The ROS-mediated apoptosis and chemotherapy played a synergistic effect to enhance the ability of cell apoptosis. This proposed Mn3O4/DOX@Lip nano-DDS uses exogenous substances to stimulate endogenous cytotoxicity and enhance the effect of chemotherapy drug, providing new research strategies for tumor treatment.