Chelating Polymers for Hereditary Hemochromatosis Treatment

Abstract

Hemochromatosis (iron overload) encompasses a group of diseases that are characterized by a toxic hyperaccumulation of iron in parenchymal organs. Currently, only few treatments for this disease have been approved; however, all these treatments possess severe side effects. In this study, a paradigm for hemochromatosis maintenance/preventive therapy is investigated: polymers with negligible systemic biological availability form stable complexes with iron ions in the gastrointestinal tract, which reduces the biological availability of iron. Macroporous polymer beads are synthesized with three different iron‐chelating moieties (benzene‐1,2‐diol, benzene‐1,2,3‐triol, and 1,10‐phenanthroline). The polymers rapidly chelate iron ions from aqueous solutions in vitro in the course of minutes, and are noncytotoxic and nonprooxidant. Moreover, the in vivo biodistribution and pharmacokinetics show a negligible uptake from the gastrointestinal tract (using 125I‐labeled polymer and single photon emission computed tomography/computed tomography), which generally prevents them from having systemic side effects. The therapeutic efficacy of the prepared polymers is successfully tested in vivo, and exhibits a significant inhibition of iron uptake from the gastrointestinal tract without any noticeable signs of toxicity. Furthermore, an in silico method is developed for the prediction of chelator selectivity. Therefore, this paradigm can be applied to the next‐generation maintenance/preventive treatment for hemochromatosis and/or other diseases of similar pathophysiology.

Chelators for Treatment of Iron and Copper Overload: Shift from Low-Molecular-Weight Compounds to Polymers

“…Most oral polymer iron scavengers under development (see below) are phenolics, so this is a major issue. The interaction with the mucosa of the gastrointestinal tract may be beneficial to form a temporary barrier depot increasing efficacy of the treatment [134], but may potentially disturb the digestion process in long-term effects; however, this was not shown in (mostly short term) animal studies.…”

“…However, the introduction of hydrophobic ligands may together with this additional crosslinking lead to limitation in metal binding capacity [137]. Macroreticular resin microparticles [134,140,141] with double molecular porosity (gaining access to the chelated metal to the moieties) and meso/macropores (accelerating strongly metal chelation kinetics) have the main advantage of fast metal uptake kinetics, usually within a few minutes; metal is completely complexed from solution (see Figure 6, for example), even for larger particles, where diffusion would otherwise slow down the uptake.…”

“…The chelating iron ligands used for microparticles are mostly inspired by bacterial siderophores such as deferoxamines and enterobactin or plant phenolics, e.g., catechol, caffeic acid, 2,5-dihydroxybenzoic acid, [134,135] 3-hydroxypyridin-4-ones, [111,130,[143][144][145] 2,3-dihydroxybenzoic acid [137] or hydroxamic acid [136]. These groups efficiently complex iron(III) which is the most abundant form of iron in the diet, but not iron(II).…”

“…As the reduction of iron(III) to iron(II) is the prerequisite for iron uptake (Fe(III) as-is is not uptaken), binding also iron(II) brings additional benefits. Our group successfully utilized polymer-bound 9,10-phenantroline, as it readily complexes both iron (II) and iron (III) for this purpose [134].…”

“…In fact, DMT1 transporter inhibitors may be beneficial not only for treatment of iron overload, but also for treatment of Wilson's disease (copper(II) is also uptaken by DMT1 transporter; therapy with zinc(II) salts is based on this fact) and lead poisoning. There are also only rare cases of polymers complexing iron(II) [134].…”