Centre for Blood Research, Department of Pathology and Laboratory Medicine, and ‡Department of Chemistry, University of British Columbia , Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
ACS Nano. 2013 Dec 23;7(12):10704-16. doi: 10.1021/nn4035074. Epub 2013 Nov 25.
Patients requiring chronic red blood cell (RBC) transfusions for inherited or acquired anemias are at risk of developing transfusional iron overload, which may impact negatively on organ function and survival. Current iron chelators are suboptimal due to the inconvenient mode of administration and/or side effects. Herein, we report a strategy to engineer low molecular weight iron chelators with long circulation lifetime for the removal of excess iron in vivo using a multifunctional dendritic nanopolymer scaffold. Desferoxamine (DFO) was conjugated to hyperbranched polyglycerol (HPG) and the plasma half-life (t1/2) in mice is defined by the structural features of the scaffold. There was a 484 fold increase in t1/2 between the DFO (5 min) versus the HPG-DFO (44 h). In an iron overloaded mouse model, efficient iron excretion by HPG-DFO in the urine and feces was demonstrated (p = 0.0002 and 0.003, respectively) as was a reduction in liver, heart, kidney, and pancreas iron content, and plasma ferritin level (p = 0.003, 0.001, 0.001, 0.001, and 0.003, respectively) compared to DFO. Conjugates showed no apparent toxicity in several analyses including body weight, serum lactate dehydrogenase level, necropsy analysis, and by histopathological examination of organs. These findings were supported by in vitro biocompatibility analyses, including blood coagulation, platelet activation, complement activation, red blood cell aggregation, hemolysis, and cell viability. This nanopolymer-based chelating system would potentially benefit patients suffering from transfusional iron overload.
需要长期输注红细胞（RBC）治疗遗传性或获得性贫血的患者有发生输血性铁过载的风险，这可能对器官功能和生存产生负面影响。由于给药方式不方便和/或副作用，目前的铁螯合剂并不理想。在此，我们报告了一种使用多功能树枝状纳米聚合物支架工程化具有长循环寿命的低分子量铁螯合剂的策略，用于体内去除多余的铁。去铁胺（DFO）与超支化聚甘油（HPG）偶联，其在小鼠中的血浆半衰期（t1/2）由支架的结构特征决定。DFO（5 分钟）与 HPG-DFO（44 小时）相比，t1/2 增加了 484 倍。在铁过载小鼠模型中，HPG-DFO 可有效从尿液和粪便中排出铁（分别为 p = 0.0002 和 0.003），并且肝脏、心脏、肾脏和胰腺铁含量以及血浆铁蛋白水平降低（分别为 p = 0.003、0.001、0.001、0.001 和 0.003）与 DFO 相比。与 DFO 相比，几种分析包括体重、血清乳酸脱氢酶水平、尸检分析以及对器官的组织病理学检查均未显示出明显的毒性。这些发现得到了体外生物相容性分析的支持，包括凝血、血小板激活、补体激活、红细胞聚集、溶血和细胞活力。这种基于纳米聚合物的螯合系统可能使输血性铁过载的患者受益。
