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Chelating Polymers for Hereditary Hemochromatosis Treatment.
Macromolecular Bioscience ( IF 4.4 ) Pub Date : 2020-09-21 , DOI: 10.1002/mabi.202000254 Ondřej Groborz 1, 2, 3 , Lenka Poláková 1 , Kristýna Kolouchová 1, 4 , Pavel Švec 1, 4 , Lenka Loukotová 1 , Vijay Madhav Miriyala 5 , Pavla Francová 6 , Jan Kučka 1 , Jan Krijt 7 , Petr Páral 6 , Martin Báječný 6 , Tomáš Heizer 6 , Radek Pohl 5 , David Dunlop 5 , Jiří Czernek 1 , Luděk Šefc 6 , Jiří Beneš 3 , Petr Štěpánek 1 , Pavel Hobza 5 , Martin Hrubý 1
Macromolecular Bioscience ( IF 4.4 ) Pub Date : 2020-09-21 , DOI: 10.1002/mabi.202000254 Ondřej Groborz 1, 2, 3 , Lenka Poláková 1 , Kristýna Kolouchová 1, 4 , Pavel Švec 1, 4 , Lenka Loukotová 1 , Vijay Madhav Miriyala 5 , Pavla Francová 6 , Jan Kučka 1 , Jan Krijt 7 , Petr Páral 6 , Martin Báječný 6 , Tomáš Heizer 6 , Radek Pohl 5 , David Dunlop 5 , Jiří Czernek 1 , Luděk Šefc 6 , Jiří Beneš 3 , Petr Štěpánek 1 , Pavel Hobza 5 , Martin Hrubý 1
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Hemochromatosis (iron overload) encompasses a group of diseases that are characterized by a toxic hyperaccumulation of iron in parenchymal organs. Currently, only few treatments for this disease have been approved; however, all these treatments possess severe side effects. In this study, a paradigm for hemochromatosis maintenance/preventive therapy is investigated: polymers with negligible systemic biological availability form stable complexes with iron ions in the gastrointestinal tract, which reduces the biological availability of iron. Macroporous polymer beads are synthesized with three different iron‐chelating moieties (benzene‐1,2‐diol, benzene‐1,2,3‐triol, and 1,10‐phenanthroline). The polymers rapidly chelate iron ions from aqueous solutions in vitro in the course of minutes, and are noncytotoxic and nonprooxidant. Moreover, the in vivo biodistribution and pharmacokinetics show a negligible uptake from the gastrointestinal tract (using 125I‐labeled polymer and single photon emission computed tomography/computed tomography), which generally prevents them from having systemic side effects. The therapeutic efficacy of the prepared polymers is successfully tested in vivo, and exhibits a significant inhibition of iron uptake from the gastrointestinal tract without any noticeable signs of toxicity. Furthermore, an in silico method is developed for the prediction of chelator selectivity. Therefore, this paradigm can be applied to the next‐generation maintenance/preventive treatment for hemochromatosis and/or other diseases of similar pathophysiology.
中文翻译：
用于治疗遗传性血色病的螯合聚合物。
血色病（铁过载）包括一组以实质器官中铁的毒性超积累为特征的疾病。目前，这种疾病的治疗方法只有少数获得批准。然而，所有这些治疗都有严重的副作用。在这项研究中，研究了血色病维持/预防治疗的范例：全身生物利用度可忽略不计的聚合物与胃肠道中的铁离子形成稳定的复合物，这降低了铁的生物利用度。大孔聚合物珠粒由三种不同的铁螯合部分（苯-1,2-二醇、苯-1,2,3-三醇和1,10-菲咯啉）合成。该聚合物可在数分钟内迅速从体外水溶液中螯合铁离子，并且无细胞毒性和无促氧化作用。而且，125 I 标记的聚合物和单光子发射计算机断层扫描/计算机断层扫描），这通常可以防止它们产生全身副作用。所制备聚合物的治疗功效已在体内成功测试，并显示出对胃肠道铁吸收的显着抑制，而没有任何明显的毒性迹象。此外，开发了一种用于预测螯合剂选择性的计算机方法。因此，该范例可应用于血色病和/或其他类似病理生理疾病的下一代维持/预防治疗。
更新日期：2020-09-21
中文翻译：
用于治疗遗传性血色病的螯合聚合物。
血色病（铁过载）包括一组以实质器官中铁的毒性超积累为特征的疾病。目前，这种疾病的治疗方法只有少数获得批准。然而，所有这些治疗都有严重的副作用。在这项研究中，研究了血色病维持/预防治疗的范例：全身生物利用度可忽略不计的聚合物与胃肠道中的铁离子形成稳定的复合物，这降低了铁的生物利用度。大孔聚合物珠粒由三种不同的铁螯合部分（苯-1,2-二醇、苯-1,2,3-三醇和1,10-菲咯啉）合成。该聚合物可在数分钟内迅速从体外水溶液中螯合铁离子，并且无细胞毒性和无促氧化作用。而且，125 I 标记的聚合物和单光子发射计算机断层扫描/计算机断层扫描），这通常可以防止它们产生全身副作用。所制备聚合物的治疗功效已在体内成功测试，并显示出对胃肠道铁吸收的显着抑制，而没有任何明显的毒性迹象。此外，开发了一种用于预测螯合剂选择性的计算机方法。因此，该范例可应用于血色病和/或其他类似病理生理疾病的下一代维持/预防治疗。
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