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.

Keywords: carbohydrate; iron–carbohydrate complexes; nanomedicine.

Figure 1

Iron oxide nanoparticle uptake by monocytes and macrophages with different ligands; IgG, human serum albumin and no ligand. SPIO = superparamagnetic iron oxide, IgG = immunoglobulin G, HSA = human serum albumin [45].

Figure 2

Micrographs showing Prussian blue staining for iron deposits in (A) liver, (B) heart, and (C) kidney samples taken from the HMW iron dextran (a), LMW iron dextran (b), ferric gluconate (c), ferric carboxymaltose (d), iron sucrose (e), and control (f) groups on Day 29 [48].

Figure 3

Bar chart showing ferritin immunostaining for stored iron in liver, heart, and kidney samples taken from the HMW iron dextran, LMW iron dextran, ferric gluconate, ferric carboxymaltose, iron sucrose, and control groups on Day 29 [48].

Figure 4

Cumulative serum ferritin profiles for treatment groups, fitted using global fitting with a custom function (plateau followed by mono-exponential association followed by mono-exponential decay), FCM = ferric carboxymaltose, IIM = iron isomaltoside, IS = iron sucrose [43].