Renal clearable nanochelators for iron overload therapy
Renal clearable nanochelators for iron overload therapy
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DOI：
10.1038/s41467-019-13143-z
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发表时间：
2019-11-13
影响因子：
16.6
通讯作者：
Kim, Jonghan
中科院分区：
文献类型：
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作者：
Kang, Homan;Han, Murui;Kim, Jonghan
铁螯合剂已被广泛用于清除继发性铁过载患者体内过量的有毒铁。然而，基于小分子的铁螯合剂可引起不良副作用，如感染、胃肠道出血、肾衰竭和肝纤维化。在这里，我们报告肾可清除纳米螯合剂铁超载疾病。首先，与天然去铁胺（DFO）相比，单剂量静脉注射后，纳米螯合剂显示出有利的药代动力学性质，例如肾脏特异性生物分布和快速肾脏排泄（在4小时内>80%注射剂量）。其次，皮下（SC）给药纳米螯合剂改善药效学，如通过与静脉内注射相比尿铁排泄效率增加7倍所证明的。第三，每日SC注射纳米螯合剂至铁过载小鼠和大鼠，持续5天，降低血清和肝脏中的铁水平。此外，纳米螯合剂显著降低了由铁过载引起的肾损伤，而没有证明DFO自身的肾毒性。这种肾可清除纳米螯合剂提供增强的功效和安全性。
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.