Iron Binding and Iron Removal Efficiency of Desferrioxamine Based Polymeric Iron Chelators: Influence of Molecular Size and Chelator Density.
Iron Binding and Iron Removal Efficiency of Desferrioxamine Based Polymeric Iron Chelators: Influence of Molecular Size and Chelator Density.
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DOI：
10.1002/mabi.201600244
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发表时间：
2017-03
影响因子：
4.6
通讯作者：
J. L. Hamilton;Muhammad Imran ul-haq;A. Creagh;C. Haynes;J. Kizhakkedathu
中科院分区：
文献类型：
--
作者：
J. L. Hamilton;Muhammad Imran ul-haq;A. Creagh;C. Haynes;J. Kizhakkedathu
去铁胺 (DFO) 是一种经临床批准的高亲和力铁螯合剂，用于治疗铁过载。由于其半衰期短且毒性大，DFO每天给药8-12小时，每周5-7天。在这篇手稿中，报告了超支化聚甘油 (HPG)-DFO 缀合物的分子特性对其铁结合的影响（通过等温滴定量热法）、存在和不存在低分子量 (MW) 铁螯合剂时铁蛋白的除铁效率以及对铁介导的蛋白质氧化的保护。 HPG-DFO 的铁结合特性随缀合物的大小和 DFO 密度而略有改变。较低分子量的缀合物在室温下显示出更高的除铁效率，然而，高分子量缀合物的功效在生理温度下增加。在低分子量螯合剂存在下，HPG-DFO 缀合物从铁蛋白中去除铁的效果显着增加，表明联合治疗的潜力。聚合物支架的分子特性也对防止缀合物引起的铁介导的蛋白质氧化有影响。因此，这些结果有助于定义 HPG-DFO 的铁结合热力学及其对 MW 的依赖性，并且可以扩展以提高对聚合螯合剂-铁原位相互作用的一般理解。
Desferrioxamine (DFO) is a clinically approved, high affinity iron chelator used for the treatment of iron overload. Due to its short half-life and toxicity, DFO is administered for 8-12 h per day, 5-7 d per week. In this manuscript, the influence of molecular properties of hyperbranched polyglycerol (HPG)-DFO conjugates on their iron binding by isothermal titration calorimetry, iron removal efficiency from ferritin in presence and absence of a low molecular weight (MW) iron chelator, and protection against iron mediated oxidation of proteins is reported. The iron binding properties of HPG-DFO are slightly altered with size and DFO density of conjugates. The lower MW conjugate shows greater iron removal efficiency at room temperature, however, the efficacy of high MW conjugates increases at physiological temperature. The iron removal from ferritin by HPG-DFO conjugates increases significantly in presence of a low MW chelator, suggesting the potential of combination therapy. The molecular properties of the polymer scaffold also have influence on the prevention of iron mediated oxidation of proteins by the conjugates. The results therefore help to define the iron binding thermodynamics of HPG-DFO and their dependence on MW, and can be extended to improve the general understanding of polymeric chelator-iron interactions in situ.