Comparing iron sucrose and ferric carboxymaltose interactions with murine and human macrophages: Focus on the lysosomal compartment

Intravenous iron drugs are commonly used in the treatment of iron deficiency/iron deficiency anaemia. However, the cellular mechanisms underlying the uptake of these complexes remain poorly understood. This study examines the interaction of two iron complexes, iron sucrose and ferric-carboxymaltose, with murine J774A.1 and human M2a macrophages, focusing on their uptake and localization within lysosomal compartments at various time points: 45 min, 6 h, 24 h, and 5 days. We employed multiple analytical methods, including Prussian blue staining and transmission electron microscopy, to assess the intracellular iron complexes. In addition, the stability of the two complexes in cell culture medium and artificial lysosomal fluid was assessed by dynamic light scattering and transmission electron microscopy. A formation of larger aggregates for both complexes in cell culture medium was observed, likely due to interactions with serum proteins. The analysis in artificial lysosomal fluid revealed a slight, but not statistically significant, decrease in hydrodynamic diameter. Upon interaction with macrophages, our results demonstrate that iron sucrose is internalized more rapidly by both macrophage cell types compared to ferric carboxymaltose. Furthermore, the detection of ferric ions within intracellular and intralysosomal compartments occurs at a later time point following macrophage exposure to ferric carboxymaltose, suggesting slower internalization in comparison to iron sucrose. Our findings suggest that the two complexes remain intact upon reaching macrophages and, after internalization, are localized within intracellular vesicles, indicating endocytosis as the primary uptake mechanism. Iron sucrose was internalized more rapidly in comparison to ferric carboxymaltose by both macrophage types, whereas a decrease in metabolic activity was only observed for the J774A.1 macrophages in the presence of high iron sucrose concentration, i.e., 1mg/mL iron. These findings provide new insights into the dynamics of different iron-carbohydrate complexes on cellular uptake and may contribute to optimizing future drug designs.