University of Georgia,
Keywords: deferoxamine, nanochelation, iron overload, polyrotaxane, disease model
Summary:Chronic blood transfusion in thalassemia and sickle cell patients eventually results in iron overload (IO), leading to severe oxidative stress in cells and tissues. Although clinically approved, the use of the iron chelator deferoxamine (DFO) is hindered by non-specific toxicity and poor pharmacokinetic properties in humans. Based on a clear understanding of the IO condition, a rationally-designed nanochelator system was prepared by incorporating DFO and reactive oxygen species (ROS)-sensitive thioketal groups into a polyrotaxane-based platform (rPR-DFO). ROS-induced degradation of these nanochelators significantly increased urine and fecal elimination of excess iron in vivo and successfully restored systemic and hepatic iron levels to normal. In addition to significantly improved pharmacokinetic parameters, rPR-DFO was well-tolerated in mice and no adverse side effects were noted in acute toxicity studies. All these favorable properties of rPR-DFO make it an attractive nanochelation strategy for the safe and efficient treatment of IO-related conditions.