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Iron-mediated generation of highly toxic Reactive Oxygen Species (ROS) plays a major role in the process leading to iron overload-related diseases. The long-term subcutaneous administration of Deferoxamine (DFO) is currently clinically-approved to improve patient symptoms and survival. However, non-specific toxicity and short circulation times of the drug in humans often leads to poor patient compliance. Herein, thioketal-based ROS-responsive polymeric nanogels containing DFO moieties (rNG-DFO) were designed to chelate iron and to degrade under oxidative stimuli into fragments <10 nm to enhance excretion of iron-bound chelates. Serum ferritin levels and iron concentrations in major organs of IO mice decreased following treatment with rNG-DFO, and fecal elimination of iron-bound chelates increased compared to free DFO. Furthermore, rNG-DFO decreased iron mediated oxidative stress levels in vitro and reduced iron-mediated inflammation in the liver of IO mice. The study confirms that ROS-responsive nanogels may serve as a promising alternative to DFO for safer and more efficient iron chelation therapy.ROS-triggered degradable polymeric nanogels post-functionalized with Deferoxamine (rNG-DFO) are prepared to chelate excess iron and improve elimination of iron-bound chelates.Degradable nanogels (rNG-DFO) are prepared for iron chelation.No sign of acute toxicity at 150 mg/kg/dose equivalent DFO (5 doses).There was less iron-overload related inflammation in the liver.Mice treated with rNG-DFO had decreased serum ferritin.Total fecal elimination of iron-bound chelates increased.