Iron chelaton therapy using Fe (III) specific chelators is the most widely used treatment approach to improve survival and reduce the iron burden in patients suffering from iron overload. However, the current FDA approved iron chelators have limitations such as short vascular residence time, low excretion efficiency, toxicity, and non-compliance to therapy. In this report, we describe the synthesis of biodegradable long circulating macromolecular iron chelator that showed enhanced circulation times and iron sequestration with reduced toxicity compared to deferoxamine, the gold standard in the treatment of iron overload. We synthesized a series of ketal group incorporated biodegradable hyperbranched polyglycerols (BHPGs) with different molecular weights and degradation profile. The BHPGs showed pH and ketal group structure dependent degradation profiles in both in vitro and in vivo. The degradable polymers showed excellent biocompatibility and showed minimal accumulation in vital organs in mice upon intravenous injection. The optimized BHPGs were conjugated with different densities of deferoxamine via reductive amination chemistry. The obtained macrochelators showed minimal toxicity and similar iron binding profile as that of non-degradable macromolecular chelators. Extensive in vitro and in vivo characterizations of these novel macrochelators were performed, and confirmed that these macrochelators are highly biocompatible, non-toxic and exhibited high iron excretion in iron overload mice. The current macromolecular approach is novel and innovative, and we anticipate that this highly efficient and long acting therapeutic approach will significantly improve patience compliance to iron chelation therapy.

Biodegradable macromolecular iron chelating system for the treatment of iron overload

256th National Meeting (2018)

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