Hydroxamic Acid-Containing Hydrogels for Nonabsorbed Iron Chelation Therapy:  Synthesis, Characterization, and Biological Evaluation

Abstract

Iron overload is a severe clinical condition and can be largely prevented by the use of iron-specific chelating agents. A successful iron chelator needs to be orally active, nontoxic, and selective. In this study, hydrogels containing pendant hydroxamic acid groups have been synthesized as potential nonabsorbed chelators for iron in the gastrointestinal tract. The synthetic method employed to introduce hydroxamic acid groups to polymer chains involved reaction of polymer gels based on N-acryloxysuccinimide, acryloyl chloride, and (2-hydroxyethyl)acrylate monomers with hydroxylamine. These hydroxamic acid-functionalized polymer gels swell favorably in water and effectively sequester iron. In vitro iron-binding properties of these hydrogels were evaluated from their binding isotherms by use of iron(II) alone and in the presence of other competing metal ions. These polymers bind iron over a broad pH range. The iron-binding properties of the polymers were found to depend on the concentration of hydroxamate groups on polymer chains. The in vivo iron-binding efficacy of the polymers was evaluated in rat as the animal model. The polymers prevented an increase in serum hemoglobin and hematocrit levels in the animals, thus suggesting the prevention of systemic absorption of dietary iron from the gastrointestinal tract. The animals also maintained normal body weight during the treatment period, indicating the absence of any apparent toxicity associated with these polymers.

Activated Ester Containing Polymers: Opportunities and Challenges for the Design of Functional Macromolecules

“…Hydrogels prepared by chelating Fe 3+ ions with polymers containing pendent hydroxamic acid groups could act as potential chelators for excess iron in the gastrointestinal tract. 421 This approach was extended to polymers containing other metal binding ligands introduced by PPM. Terpyridine functional polyNIPAMs, obtained from precursor poly(NIPAM-co-NHSMA), was cross-linked with Mn 2+ or Co 2+ to produce supramolecular metal gels.…”

Non-Systemic Drugs: A Critical Review

“…These are derived from structures typical of siderophores (hexadentate chelates of catecholamide, hydroxamate, hydroxypyridonate, 2,3-dihydroxyterephthalamide) that are made insoluble by functionalization onto polymeric backbones [43]. However, there are few examples of non-systemic iron chelators demonstrating an effect in preclinical iron overload models [44] and no clinical development has been reported. One challenge encountered by this approach is the multiple pathways utilized by the intestinal mucosa to extract dietary iron, one of which is the selective transport of heme-iron [45].…”

In vitro chelating, cytotoxicity, and blood compatibility of degradable poly(ethylene glycol)-based macromolecular iron chelators

“…Hence, more than 30 years of research on alternative low molecular weight [9,18] and, to a lesser extent, high molecular weight chelators have been conducted. While low molecular weight chelators demonstrate some toxicity at near therapeutic dosing, the rather limited work concerning high molecular weight chelators is very promising [15,19,20].…”