Criticality of Surface Characteristics of Intravenous Iron–Carbohydrate Nanoparticle Complexes: Implications for Pharmacokinetics and Pharmacodynamics

Abstract

Un-complexed polynuclear ferric oxyhydroxide cannot be administered safely or effectively to patients. When polynuclear iron cores are formed with carbohydrates of various structures, stable complexes with surface carbohydrates driven by multiple interacting sites and forces are formed. These complexes deliver iron in a usable form to the body while avoiding the serious adverse effects of un-complexed forms of iron, such as polynuclear ferric oxyhydroxide. The rate and extent of plasma clearance and tissue biodistribution is variable among the commercially available iron–carbohydrate complexes and is driven principally by the surface characteristics of the complexes which dictate macrophage opsonization. The surface chemistry differences between the iron–carbohydrate complexes results in significant differences in in vivo pharmacokinetic and pharmacodynamic profiles as well as adverse event profiles, demonstrating that the entire iron–carbohydrate complex furnishes the pharmacologic action for these complex products. Currently available physicochemical characterization methods have limitations in biorelevant matrices resulting in challenges in defining critical quality attributes for surface characteristics for this class of complex nanomedicines.

Probing Subcellular Iron Availability with Genetically Encoded Nitric Oxide Biosensors

“…These results are consistent with recent studies that suggest that IS and FCM [ 4 ] have different pharmacokinetic profiles, possibly owing to variations in the rate and amount of iron absorption and biodegradation to bioavailable iron. The current research aims to understand better the impact of the carbohydrate ligand of such iron (III)-containing complexes on their biological activity [ 5 ]. Different carbohydrates, including disaccharides, oligosaccharides, and polysaccharides, have been tested as an alternative pharmacological approach to improve iron nanoparticles’ safety and efficacy [ 4 , 5 ].…”

“…The current research aims to understand better the impact of the carbohydrate ligand of such iron (III)-containing complexes on their biological activity [ 5 ]. Different carbohydrates, including disaccharides, oligosaccharides, and polysaccharides, have been tested as an alternative pharmacological approach to improve iron nanoparticles’ safety and efficacy [ 4 , 5 ]. Considering that the geNOps technology even allows the detection of the distribution of intracellular iron levels ( Figure 4 ), this approach may potentially open new avenues in analytical nanomedicine to investigate subcellular drug-targeting and for application to bioequivalence evaluation strategies [ 5 , 37 ].…”

“…(ii) DMT1 channels are also on the cell surface, where iron can enter the cell in its reduced form through the cell plasma membrane into the cytosol, available as labile iron [ 3 ]. Cleverly designed nanoparticles of polynucleare iron carbohydrate complex were developed for intravenous iron therapy [ 4 , 5 ]. In contrast, upon therapeutic administration, these intravenous iron–carbohydrate complexes are opsonized by macrophages and delivered to the principal organs of the mononuclear phagocytic system, the liver, and the spleen [ 4 ].…”

“…In contrast, upon therapeutic administration, these intravenous iron–carbohydrate complexes are opsonized by macrophages and delivered to the principal organs of the mononuclear phagocytic system, the liver, and the spleen [ 4 ]. Iron is then delivered to the bone marrow via normal iron transport systems [ 5 ]. Cells have several biochemical strategies to control the labile ferrous iron pool [ 6 ].…”

Hypersensitivity to Intravenous Iron Preparations

“…Carbohydrates stabilize the gel, slow the release of iron and maintain the resulting particles in colloid suspension. The rate of release of bioactive iron is inversely related to the strengths of the complex: stronger complexes have a lower potential to saturate transferrin with subsequent lower free iron toxicity [ 1 , 2 , 19 ].…”