Abstract
Iron chelators have been widely used to remove excess toxic iron from patients with secondary iron overload. However, small molecule-based iron chelators can cause adverse side effects such as infection, gastrointestinal bleeding, kidney failure, and liver fibrosis. Here we report renal clearable nanochelators for iron overload disorders. First, after a singledose intravenous injection, the nanochelator shows favorable pharmacokinetic properties, such as kidney-specific biodistribution and rapid renal excretion (>80% injected dose in 4 h), compared to native deferoxamine (DFO). Second, subcutaneous (SC) administration of nanochelators improves pharmacodynamics, as evidenced by a 7-fold increase in efficiency of urinary iron excretion compared to intravenous injection. Third, daily SC injections of the nanochelator for 5 days to iron overload mice and rats decrease iron levels in serum and liver. Furthermore, the nanochelator significantly reduces kidney damage caused by iron overload without demonstrating DFO’s own nephrotoxicity. This renal clearable nanochelator provides enhanced efficacy and safety.
Highlights
Iron chelators have been widely used to remove excess toxic iron from patients with secondary iron overload
We have previously demonstrated that physicochemical properties such as size, shape, surface charges, and hydrophilicity/ lipophilicity control the fate of inorganic/organic hybrid NPs in the body[29,30,31,32,33]
We proved that zwitterionic NPs with smaller hydrodynamic diameter (HD) than the kidney threshold (
Summary
Iron chelators have been widely used to remove excess toxic iron from patients with secondary iron overload. The nanochelator significantly reduces kidney damage caused by iron overload without demonstrating DFO’s own nephrotoxicity This renal clearable nanochelator provides enhanced efficacy and safety. Iron is an essential metal nutrient, but excess iron increases oxidative stress and promotes tissue damage by catalysis of hydroxyl radicals to accelerate lipid peroxidation[1] It increases the risk of heart failure, liver cirrhosis and cancer, arthritis, dyslipidemia, diabetes, and gonadal dysfunction[2,3], and may be associated with several neurodegenerative diseases (e.g. Alzheimer’s and Parkinson’s diseases)[4,5,6,7]. Promoting renal clearance is important in chelation therapy because increased hepatic iron stores in many iron overload patients cause liver dysfunction and limit the capacity of biliary excretion[27]. We design ultrasmall nanochelators that circulate in the blood for a reasonable residence time during which they bind and remove excess iron exclusively via the urinary elimination while bypassing the immune system with negligible nonspecific tissue distribution
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