RESUMO
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.
RESUMO
Iron chelation therapy using iron (III) specific chelators such as desferrioxamine (DFO, Desferal), deferasirox (Exjade or ICL-670), and deferiprone (Ferriprox or L1) are the current standard of care for the treatment of iron overload. Although each chelator is capable of promoting some degree of iron excretion, these chelators are also associated with a wide range of well documented toxicities. However, there is currently very limited data available on their effects in developing embryos. In this study, we took advantage of the rapid development and transparency of the zebrafish embryo, Danio rerio to assess and compare the toxicity of iron chelators. All three iron chelators described above were delivered to zebrafish embryos by direct soaking and their effects on mortality, hatching and developmental morphology were monitored for 96 hpf. To determine whether toxicity was specific to embryos, we examined the effects of chelator exposure via intra peritoneal injection on the cardiac function and gene expression in adult zebrafish. Chelators varied significantly in their effects on embryo mortality, hatching and morphology. While none of the embryos or adults exposed to DFO were negatively affected, ICL -treated embryos and adults differed significantly from controls, and L1 exerted toxic effects in embryos alone. ICL-670 significantly increased the mortality of embryos treated with doses of 0.25 mM or higher and also affected embryo morphology, causing curvature of larvae treated with concentrations above 0.5 mM. ICL-670 exposure (10 µL of 0.1 mM injection) also significantly increased the heart rate and cardiac output of adult zebrafish. While L1 exposure did not cause toxicity in adults, it did cause morphological defects in embryos at 0.5 mM. This study provides first evidence on iron chelator toxicity in early development and will help to guide our approach on better understanding the mechanism of iron chelator toxicity.