Macrophage-Mediated Delivery of Fe3O4-Nanoparticles: A Generalized Strategy to Deliver Iron to Tumor Microenvironment.

Abstract

Iron is used to alter macrophage phenotypes and induce tumor cell death. Iron oxide nanoparticles can induce macrophage polarization into the M1 phenotype, which inhibits tumor growth and can dissociate into iron ions in macrophages. In this study, we proposed to construct high expression of Ferroportin1 macrophages as carriers to deliver Fe3O4-nanoparticles and iron directly to tumor sites. Three sizes of Fe3O4-nanoparticles with gradient concentrations were used. The migration ability of iron-carrying macrophages was confirmed by an in vitro migration experiment and monocyte chemoattractant protein-1 detection. The release of iron from macrophages was confirmed by determining their levels in the cell culture supernatant, and we constructed a high expression of ferroportin strain of macrophage lines to increase intracellular iron efflux by increasing membrane transferrin expression. Fe3O4-NPs in Ana-1 cells were degraded in lysosomes, and the amount of iron released was correlated with the expression of ferroportin1. After Fe3O4-nanoparticles uptake by macrophages, not only polarized macrophages into M1 phenotype, but the nanoparticles also dissolved in the lysosome and iron were released out of the cell. FPN1 is the only known Fe transporter; we use a Lentiviral vector carrying the FPN1 gene transfected into macrophages, has successfully constructed Ana-1-FPN1 cells, and maintains high expression of FPN1. Ana-1-FPN1 cells increase intracellular iron release. Fe3O4-nanoparticles loaded with engineered Ana-1 macrophages can act as a "reservoir" of iron. Our study provides proof of strategy for Fe3O4-NPs target delivery to the tumor microenvironment. Moreover, increase of intracellular iron efflux by overexpression of FPN1, cell carriers can act as a reservoir for iron, providing the basis for targeted delivery of Fe3O4-NPs and iron ions in vivo.