Sullivan 2015

Siderophore containing polymers as novel oral iron chelation therapeutics

Bradley P. Sullivan1, Jian Qian1, and Cory Berkland1,2

1Department of Pharmaceutical Chemistry, School of Pharmacy, and 2Department of Chemical and Petroleum Engineering, School of Engineering, The University of Kansas, Lawrence, Kansas.

Hematomachrosis, or iron overload, is a chronic disease that can cause several comorbidities including cardiac abnormalities and liver failure. Several iron chelation therapies exist to treat patients with hematomachrosis; however, many of the current therapies are associated with poor long term patient compliance and/or are associated with severe adverse reactions. We synthesized and characterized several crosslinked polyallylamine (PAAm) polymers that were conjugated with 2,3-dihydroxybenzoic acid (DHBA), a natural iron chelating siderophore. Control crosslinked PAAm showed limited iron binding capacity, whereas crosslinked DHBAconjugated polymers showed marked iron binding capacity that was correlated to the extent of DHBA conjugation. DHBA-conjugated polymers showed minimal binding capacity for other dietary metals, suggesting relatively high selectivity for iron. Interestingly, fecal elimination of iron was enhanced in mice fed a diet containing 5% DHBA-conjugated polymer compared to mice fed a diet containing 5% PAAm crosslinked control polymer. The data suggest that polymers conjugated with DHBA can selectively chelate iron and can enhance fecal elimination of iron in orally dosed rodents. This novel DHBA-based polymer platform may provide a safe and efficacious therapeutic option to treat patients with iron overload.