Abstract
There are several options available for intravenous application of iron supplements, but they all have a similar structure:—an iron core surrounded by a carbohydrate coating. These nanoparticles require processing by the reticuloendothelial system to release iron, which is subsequently picked up by the iron-binding protein transferrin and distributed throughout the body, with most of the iron supplied to the bone marrow. This process risks exposing cells and tissues to free iron, which is potentially toxic due to its high redox activity. A new parenteral iron formation, ferric pyrophosphate citrate (FPC), has a novel structure that differs from conventional intravenous iron formulations, consisting of an iron atom complexed to one pyrophosphate and two citrate anions. In this study, we show that FPC can directly transfer iron to apo-transferrin. Kinetic analyses reveal that FPC donates iron to apo-transferrin with fast binding kinetics. In addition, the crystal structure of transferrin bound to FPC shows that FPC can donate iron to both iron-binding sites found within the transferrin structure. Examination of the iron-binding sites demonstrates that the iron atoms in both sites are fully encapsulated, forming bonds with amino acid side chains in the protein as well as pyrophosphate and carbonate anions. Taken together, these data demonstrate that, unlike intravenous iron formulations, FPC can directly and rapidly donate iron to transferrin in a manner that does not expose cells and tissues to the damaging effects of free, redox-active iron.
Highlights
Iron supplements for intravenous (IV) application contain polymeric iron hydroxyl/oxy nanoparticles, often of mixed iron electrovalence, with a carbohydrate coating to control particle size and toxicity (Gupta 2016)
The primary means by which iron is transported in the circulation is bound to the protein transferrin, which contains two iron-binding sites that bind tightly, but not covalently, to iron (III) and deliver it to cells and tissues throughout the body. (Aisen et al 1978; Luck and Mason 2012) Labile plasma iron (LPI) is an indicator of redox-active iron and is believed to be a toxic species
Iron bound to transferrin does not contribute to LPI, and LPI is not present in the bloodstream until transferrin iron binding capacity is exceeded. (Esposito et al 2003; Pratt et al 2017)
Summary
Iron supplements for intravenous (IV) application contain polymeric iron hydroxyl/oxy nanoparticles, often of mixed iron electrovalence, with a carbohydrate coating to control particle size and toxicity (Gupta 2016). These include the iron carbohydrate complexes iron dextran, iron sucrose, sodium ferric gluconate, and ferumoxytol; these complexes all contain an iron-oxyhydroxide/oxide central core with a carbohydrate shell (Girelli 2018). These nanoparticles require uptake by macrophages over a period of 4–17 h in the reticuloendothelial system to release the iron In a prospective study in patients on hemodialysis receiving IV iron, currently approved IV iron products were associated with increased exposure to NTBI as well as increased pro-inflammatory cytokines and ROS (Pai et al 2011)
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