Effect of clinically relevant iron oxide nanoparticles on macrophage polarization, tumor growth and tumor microenvironment modulation.

Macrophages are key regulators of the tumor microenvironment (TME) and attractive targets for nanomedicine therapies. Because intracellular iron can promote pro-inflammatory macrophage polarization, superparamagnetic iron oxide nanoparticles (SPION) have been proposed as potential antitumor therapeutics. Nevertheless, their ability to remodel the TME and inhibit tumor growth has remained unclear. Here, we evaluated whether the commercially available SPION formulations Feraheme and Synomag can regulate macrophage polarization, modulate the microenvironment, affect tumor growth, and alter tumor-targeted drug delivery. In vitro, despite being internalized by macrophages highly efficiently, Feraheme and Synomag only elicited modest effects on macrophage polarization markers. In vivo, repeated intravenous administrations of Feraheme in an orthotopic and syngeneic 4 T1 triple-negative breast cancer model resulted in significant increases in intratumoral iron levels. However, they did not affect tumor growth nor statistically significant altered tumor-associated macrophage density and polarization, T-cell subsets, or the composition of the TME. Accordingly, pre-treatment with Feraheme did not alter tumor vascularization or collagen content, nor did it result in a statistically significant improvement in the delivery of a model polymeric nanocarrier. Together, these results support the use of SPION as tracers for macrophage-targeted imaging applications rather than as antitumor therapeutics and TME priming agents.