Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského náměstí 2, 162 06, Prague 6, Czech Republic.
Department of Organic Chemistry, Faculty of Science, Charles University, Hlavova 8, 128 43, Prague 2, Czech Republic.
Macromol Biosci. 2020 Dec;20(12):e2000254. doi: 10.1002/mabi.202000254. Epub 2020 Sep 21.
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 I-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.
血色病（铁过载）包括一组以实质器官中铁的毒性过度积累为特征的疾病。目前，这种疾病仅有少数几种治疗方法获得批准；然而，所有这些治疗方法都有严重的副作用。在这项研究中，研究了一种维持/预防血色病的治疗模式：在胃肠道中，具有极低全身生物利用度的聚合物与铁离子形成稳定的配合物，从而降低铁的生物利用度。用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）合成了大孔聚合物珠。聚合物在体外几分钟内迅速从水溶液中螯合铁离子，且无细胞毒性和非促氧化剂。此外，体内分布和药代动力学研究表明，从胃肠道摄取量可忽略不计（使用 I 标记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。所制备的聚合物的治疗效果在体内得到了成功的测试，并表现出对从胃肠道摄取铁的显著抑制作用，而没有任何明显的毒性迹象。此外，还开发了一种用于预测螯合剂选择性的计算方法。因此，这种模式可以应用于下一代维持/预防血色病和/或其他具有类似病理生理学的疾病的治疗。
