Journal
JOURNAL OF CONTROLLED RELEASE
Volume 283, Issue -, Pages 84-93Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2018.05.025
Keywords
Reactive oxygen species (ROS); Nanogel; Chelation therapy; Iron overload (IO); Deferoxamine (DFO)
Funding
- NIH [R01DK099596]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK099596] Funding Source: NIH RePORTER
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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.
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