title: Chelating polymeric beads as potential therapeutics for Wilson's disease.
abstract: Wilson's disease is a genetic disorder caused by a malfunction of ATPase 7B that leads to high accumulation of copper in the organism and consequent toxic effects. We propose a gentle therapy to eliminate the excessive copper content with oral administration of insoluble non-resorbable polymer sorbents containing selective chelating groups for copper(II). Polymeric beads with the chelating agents triethylenetetramine, N,N-di(2-pyridylmethyl)amine, and 8-hydroxyquinoline (8HQB) were investigated. In a preliminary copper uptake experiment, we found that 8HQB significantly reduced copper uptake (using copper-64 as a radiotracer) after oral administration in Wistar rats. Furthermore, we measured organ radioactivity in rats to demonstrate that 8HQB radiolabelled with iodine-125 is not absorbed from the gastrointestinal tract after oral administration. Non-resorbability and the blockade of copper uptake were also confirmed with small animal imaging (PET/CT) in mice. In a long-term experiment with Wistar rats fed a diet containing the polymers, we have found that there were no signs of polymer toxicity and the addition of polymers to the diet led to a significant reduction in the copper contents in the kidneys, brains, and livers of the rats. We have shown that polymers containing specific ligands could potentially be novel therapeutics for Wilson's disease.
authors.affiliation: Institute of Biophysics and Informatics, First Faculty of Medicine, Charles University in Prague, Salmovska 1, 120 00 Prague 2, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Mattová
authors.affiliation: Institute of Biophysics and Informatics, First Faculty of Medicine, Charles University in Prague, Salmovska 1, 120 00 Prague 2, Czech Republic.
authors.forename: Pavla
authors.initials: P
authors.lastname: Poučková
authors.affiliation: Institute of Macromolecular Chemistry AS CR, v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Kučka
authors.affiliation: Institute of Macromolecular Chemistry AS CR, v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Skodová
authors.affiliation: Institute of Macromolecular Chemistry AS CR, v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Vetrík
authors.affiliation: Institute of Macromolecular Chemistry AS CR, v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Stěpánek
authors.affiliation: Institute of Biophysics and Informatics, First Faculty of Medicine, Charles University in Prague, Salmovska 1, 120 00 Prague 2, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Urbánek
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 5, 77900 Olomouc, Czech Republic.
authors.forename: Miloš
authors.initials: M
authors.lastname: Petřík
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 5, 77900 Olomouc, Czech Republic.
authors.forename: Zbyněk
authors.initials: Z
authors.lastname: Nový
authors.affiliation: Institute of Macromolecular Chemistry AS CR, v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic. Electronic address: mhruby@centrum.cz.
authors.forename: Martin
authors.initials: M
authors.lastname: Hrubý
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000378:metabolism; D002614:Chelating Agents / Q000737:chemistry / Q000627:therapeutic use*; D003300:Copper / Q000378:metabolism*; D005260:Female; D041981:Gastrointestinal Tract / Q000378:metabolism; D006527:Hepatolenticular Degeneration / Q000188:drug therapy* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008744:Methylamines / Q000737:chemistry / Q000627:therapeutic use; D008768:Methylmethacrylates / Q000737:chemistry / Q000627:therapeutic use*; D051379:Mice; D015125:Oxyquinoline / Q000737:chemistry / Q000627:therapeutic use; D011725:Pyridines / Q000737:chemistry / Q000627:therapeutic use; D017208:Rats, Wistar; D014266:Trientine / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D002614:Chelating Agents; D008744:Methylamines; D008768:Methylmethacrylates; D011725:Pyridines; C121054:bis(2-pyridyl)methylamine; C020347:GMA-EDMA; D015125:Oxyquinoline; D003300:Copper; D014266:Trientine
keywords: Chelators; Copper chelation; Polymer beads; Wilson’s disease