Abstract
Desferrioxamine (DFO), deferiprone (L1) and desferasirox (ICL-670) are clinically approved iron chelators used to treat secondary iron overload. Although iron chelators have been utilized since the 1960s and there has been much improvement in available therapy, there is still the need for new drug candidates due to limited long-term efficacy and drug toxicity. Moreover, all currently approved iron chelators are of low molecular weight (MW) (<600 Da) and the objectives reported for the “ideal” chelator of low MW, including possessing the ability to promote iron excretion without causing toxic side effects, has proven difficult to realize in practice. With prolonged iron chelator use, patients may develop toxicities or become insensitive. In contrast, the limited research that has been geared towards developing higher MW, polymeric, long circulating iron chelators has shown promise. The inherent potential of polymeric iron chelators toward longer plasma half-lives and reduction in toxicity provides optimism and may be a significant addition to the currently available low MW iron chelators. This article reviews knowledge pertaining to this theme, highlights some unique advantages that these nanomedicines have in treating systemic iron overload as well as their potential utility in the treatment of other disease states.
Highlights
Reversible kidney failureHigh prolonged infusions and widespread DFO toxicity that has hindered the achievement of safe iron levels in many iron overloaded patients undergoing iron chelation therapy Figure 7
Desferrioxamine (DFO), deferiprone (L1) and desferasirox (ICL-670) are clinically approved iron chelators used to treat secondary iron overload
Current iron chelation therapy requires the daily administration of virtually the maximum tolerated doses of DFO, L1 and ICL-670 in order to ensure that the rates of transfusional iron loading and iron excretion in transfusion dependent patients are well matched
Summary
High prolonged infusions and widespread DFO toxicity that has hindered the achievement of safe iron levels in many iron overloaded patients undergoing iron chelation therapy Figure 7. In a 1989 report, Hallaway et al described the advantages associated with attaching DFO covalently to dextran and hydroxyethyl starch (HES) [44] This resulted in a significant increase in the plasma half-life and reduction in toxicity of DFO with no apparent loss in the iron chelating properties. In 2005 Polomoscanik et al reported the generation of a non-toxic formulation of DFO hydroxamic acid based iron chelating hydrogels and evaluated utility to prevent iron absorption in the gut [45] These gels were effective in preventing gastric iron absorption and did not cause any change in hemoglobin and hematocrit. In 2009, our group reported the development of welldefined, blood compatible and degradable PEG based
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