Iron and copper are essential micronutrients needed for the proper function of every cell. However, in excessive amounts, these elements are toxic, as they may cause oxidative stress, resulting in damage to the liver and other organs. This may happen due to poisoning, as a side effect of thalassemia infusion therapy or due to hereditary diseases hemochromatosis or Wilson's disease. The current golden standard of therapy of iron and copper overload is the use of low-molecular-weight chelators of these elements. However, these agents suffer from severe side effects, are often expensive and possess unfavorable pharmacokinetics, thus limiting the usability of such therapy. The emerging concepts are polymer-supported iron- and copper-chelating therapeutics, either for parenteral or oral use, which shows vivid potential to keep the therapeutic efficacy of low-molecular-weight agents, while avoiding their drawbacks, especially their side effects. Critical evaluation of this new perspective polymer approach is the purpose of this review article.

Helmholtz Zentrum Dresden Rossendorf Institute of Radiopharmaceutical Cancer Research Bautzner Landstraße 400 01328 Dresden Germany

Institute of Biophysics and Informatics 1st Faculty of Medicine Charles University Prague Salmovska 1 120 00 Prague Czech Republic

Institute of Macromolecular Chemistry Academy of Sciences of the Czech Republic Heyrovského Náměstí 2 162 06 Prague Czech Republic

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Vest K.E., Paskavitz A.L., Lee J.B., Padilla-Benavides T. Dynamic changes in copper homeostasis and post-transcriptional regulation ofAtp7aduring myogenic differentiation. Metallomics. 2018;10:309–322. doi: 10.1039/C7MT00324B. PubMed DOI PMC

Cadet E., Gadenne M., Capron D., Rochette J. Advances in iron metabolism: A transition state. Rev. Med. Internet. 2005;26:315–324. doi: 10.1016/j.revmed.2004.09.024. PubMed DOI

Rishi G., Subramaniam V.N. The liver in regulation of iron homeostasis. Am. J. Physiol. Liver Physiol. 2017;313:G157–G165. doi: 10.1152/ajpgi.00004.2017. PubMed DOI

Vallerio L.G. Mammalian iron metabolism. Toxicol. Mech. Methods. 2007;17:497–517. doi: 10.1080/15376510701556690. PubMed DOI

Saboor M., Zehra A., Hamali H., Mobarki A. Revisiting Iron Metabolism, Iron Homeostasis and Iron Deficiency Anemia. Clin. Lab. 2021;67 doi: 10.7754/Clin.Lab.2020.200742. PubMed DOI

Bi Y., Ajoolabady A., Demillard L.J., Yu W., Hilaire M.L., Zhang Y., Ren J. Dysregulation of iron metabolism in cardiovascular diseases: From iron deficiency to iron overload. Biochem. Pharmacol. 2021;190:114661. doi: 10.1016/j.bcp.2021.114661. PubMed DOI

Barry N.P.E., Sadler P.J. Exploration of the medical periodic table: Towards new targets. Chem. Commun. 2013;49:5106–5131. doi: 10.1039/c3cc41143e. PubMed DOI

Palermo G., Spinello A., Saha A., Magistrato A. Frontiers of metal-coordinating drug design. Expert Opin. Drug Discov. 2020;16:497–511. doi: 10.1080/17460441.2021.1851188. PubMed DOI PMC

Mjos K.D., Orvig C. Metallodrugs in Medicinal Inorganic Chemistry. Chem. Rev. 2014;114:4540–4563. doi: 10.1021/cr400460s. PubMed DOI

Loginova N.V., Harbatsevich H.I., Osipovich N.P., Ksendzova G.A., Koval’Chuk T.V., Polozov G.I. Metal Complexes as Promising Agents for Biomedical Applications. Curr. Med. Chem. 2020;27:5213–5249. doi: 10.2174/0929867326666190417143533. PubMed DOI

Werner A. Beitrag zur Konstitution anorganischer Verbindungen. Z. Anorg. Chem. 1893;3:267–330. doi: 10.1002/zaac.18930030136. DOI

Pearson R.G. The HSAB Principle—more quantitative aspects. Inorganica Chim. Acta. 1995;240:93–98. doi: 10.1016/0020-1693(95)04648-8. DOI

Schwarzenbach G. DER CHELATEFFEKT. Helv. Chim. Acta. 1952;35:2344–2363. doi: 10.1002/hlca.19520350721. DOI

Ma Y., Zhou T., Kong X., Hider R. Chelating Agents for the Treatment of Systemic Iron Overload. Curr. Med. Chem. 2012;19:2816–2827. doi: 10.2174/092986712800609724. PubMed DOI

Grady R.W., Graziano J.H., Akers H.A., Cerami A. The development of new iron-chelating drugs. J. Pharmacol. Exp. Ther. 1976;196 PubMed

Nunez M.T., Chana-Cuevas P. New Perspectives in Iron Chelation Therapy for the Treatment of Neurodegenerative Diseases. Pharmaceuticals. 2018;11:109. doi: 10.3390/ph11040109. PubMed DOI PMC

Turnquis T.D., Sandell E.B. Stability constants of iron(III)-8-hydroxyquinoline complexes. Anal. Chim. Acta. 1968;42:239–245. doi: 10.1016/S0003-2670(01)80304-4. DOI

Zhou T., Ma Y., Kong X., Hider R.C. Design of iron chelators with therapeutic application. Dalton Trans. 2012;41:6371–6389. doi: 10.1039/c2dt12159j. PubMed DOI

Prachayasittikul V., Prachayasittikul V., Prachayasittikul S., Ruchirawat S. 8-Hydroxyquinolines: A review of their metal chelating properties and medicinal applications. Drug Des. Dev. Ther. 2013;7:1157–1178. doi: 10.2147/DDDT.S49763. PubMed DOI PMC

Bareggi S.R., Cornelli U. Clioquinol: Review of its Mechanisms of Action and Clinical Uses in Neurodegenerative Disorders. CNS Neurosci. Ther. 2010;18:41–46. doi: 10.1111/j.1755-5949.2010.00231.x. PubMed DOI PMC

Ritchie C.W., Bush A.I., Mackinnon A., Macfarlane S., Mastwyk M., MacGregor L., Kiers L., Cherny R., Li Q.X., Tammer A., et al. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting A beta amyloid deposition and toxicity in Alzheimer disease—A pilot phase 2 clinical trial. Arch. Neurol. 2003;60:1685–1691. doi: 10.1001/archneur.60.12.1685. PubMed DOI

Lannfelt L., Blennow K., Zetterberg H., Batsman S., Ames D., Hrrison J., Masters C.L., Targum S., Bush A.I., Murdoch R., et al. Safety, efficacy, and biomarker findings of PBT2 in targeting A beta as a modifying therapy for Alzheimer’s disease: A phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2008;7:779–786. doi: 10.1016/S1474-4422(08)70167-4. PubMed DOI

Kim J.-J., Kim Y.-S., Kumar V. Heavy metal toxicity: An update of chelating therapeutic strategies. J. Trace Elements Med. Biol. 2019;54:226–231. doi: 10.1016/j.jtemb.2019.05.003. PubMed DOI

Nurchi V.M., Crisponi G., Pivetta T., Donatoni M., Remelli M. Potentiometric, spectrophotometric and calorimetric study on iron(III) and copper(II) complexes with 1,2-dimethyl-3-hydroxy-4-pyridinone. J. Inorg. Biochem. 2008;102:684–692. doi: 10.1016/j.jinorgbio.2007.10.012. PubMed DOI

Cilibrizzi A., Abbate V., Chen Y.-L., Ma Y., Zhou T., Hider R. Hydroxypyridinone Journey into Metal Chelation. Chem. Rev. 2018;118:7657–7701. doi: 10.1021/acs.chemrev.8b00254. PubMed DOI

Hershko C., Konijn A.M., Nick H.P., Breuer W., Cabantchik Z.I., Link G. ICL670A: A new synthetic oral chelator: Evalu-ation in hypertransfused rats with selective radioiron probes of hepatocellular and reticuloendothelial iron stores and in iron-loaded rat heart cells in culture. Blood. 2001;97:1115–1122. doi: 10.1182/blood.V97.4.1115. PubMed DOI

Steinhauser S., Heinz U., Bartholomä M., Weyhermüller T., Nick H., Hegetschweiler K. Complex Formation of ICL670 and Related Ligands with FeIII and FeII. Eur. J. Inorg. Chem. 2005;2005:2262. doi: 10.1002/ejic.200500302. DOI

Dhungana S., White P.S., Crumbliss A.L. Crystal structure of ferrioxamine B: A comparative analysis and implications for molecular recognition. JBIC J. Biol. Inorg. Chem. 2001;6:810–818. doi: 10.1007/s007750100259. PubMed DOI

Wadas T.J., Wong E.H., Weisman G.R., Anderson C.J. Copper chelation chemistry and its role in copper radiopharmaceu-ticals. Curr. Pharm. Design. 2007;13:3–16. doi: 10.2174/138161207779313768. PubMed DOI

Jahn H.A., Teller E. Stability of polyatomic molecules in degenerate electronic states. I. Orbital degeneracy. Proc. R. Soc. Lond. A-Math. Phys. Sci. 1937;161:220–235.

Meares C.F., Wensel T. Metal chelates as probes of biological systems. Accounts Chem. Res. 1984;17:202–209. doi: 10.1021/ar00102a001. DOI

Hnatowich D.J., Layne W.W., Childs R.L., Lanteigne D., Davis M.A., Griffin T.W., Doherty P.W. Radioactive Labeling of Antibody: A Simple and Efficient Method. Science. 1983;220:613–615. doi: 10.1126/science.6836304. PubMed DOI

Delgado R., Felix V., Lima L.M.P., Price D.W. Metal complexes of cyclen and cyclam derivatives useful for medical appli-cations: A discussion based on thermodynamic stability constants and structural data. Dalton Trans. 2007;26:2734–2745. doi: 10.1039/B704360K. PubMed DOI

Joshi T., Kubeil M., Nsubuga A., Singh G., Gasser G., Stephan H. Harnessing the Coordination Chemistry of 1,4,7-Triazacyclononane for Biomimicry and Radiopharmaceutical Applications. ChemPlusChem. 2018;83:554–564. doi: 10.1002/cplu.201800103. PubMed DOI

Parker D. Tumor targeting with radiolabeled antibody conjugates. Chem. Soc. Rev. 1990;19:271–291. doi: 10.1039/CS9901900271. DOI

Donnelly P.S. The role of coordination chemistry in the development of copper and rhenium radiopharmaceuticals. Dalton Trans. 2011;40:999–1010. doi: 10.1039/c0dt01075h. PubMed DOI

Anderson C., Welch M.J. Radiometal-Labeled Agents (Non-Technetium) for Diagnostic Imaging. Chem. Rev. 1999;99:2219–2234. doi: 10.1021/cr980451q. PubMed DOI

Lukes I., Kotek J., Vojtisek P., Hermann P. Complexes of tetraazacycles bearing methylphosphinic/phosphonic acid pendant arms with copper(II), zinc(II) and lanthanides(III). A comparison with their acetic acid analogues. Coord. Chem. Rev. 2001;216:287–312. doi: 10.1016/S0010-8545(01)00336-8. DOI

Sargeson A.M. Developments in the synthesis and reactivity of encapsulated metal ions. Pure Appl. Chem. 1986;58:1511–1522. doi: 10.1351/pac198658111511. DOI

Voloshin Y.Z., Novikov V.V., Nelyubina Y.V. Recent advances in biological applications of cage metal complexes. RSC Adv. 2015;5:72621–72637. doi: 10.1039/C5RA10949C. DOI

Hancock R.D. The pyridyl group in ligand design for selective metal ion complexation and sensing. Chem. Soc. Rev. 2012;42:1500–1524. doi: 10.1039/C2CS35224A. PubMed DOI

Ma D., Lu F., Overstreet T., E Milenic D., Brechbiel M.W. Novel chelating agents for potential clinical applications of copper. Nucl. Med. Biol. 2002;29:91–105. doi: 10.1016/S0969-8051(01)00287-6. PubMed DOI

Gasser G., Tjioe L., Graham B., Belousoff M., Juran S., Walther M., Künstler J.-U., Bergmann R., Stephan H., Spiccia L. Synthesis, Copper(II) Complexation, 64Cu-Labeling, and Bioconjugation of a New Bis(2-pyridylmethyl) Derivative of 1,4,7-Triazacyclononane. Bioconjugate Chem. 2008;19:719–730. doi: 10.1021/bc700396e. PubMed DOI

Park G., Przyborowska A.M., Ye N., Tsoupas N.M., Bauer C.B., Broker G.A., Rogers R.D., Brechbiel M.W., Planalp R.P. Steric effects caused by N-alkylation of the tripodal chelator N,N′,N″-tris(2-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane (tachpyr): Structural and electronic properties of the Mn(ii), Co(ii), Ni(ii), Cu(ii) and Zn(ii) complexes. Dalton Trans. 2002:318–324. doi: 10.1039/b209228j. DOI

Price E.W., Orvig C. Matching chelators to radiometals for radiopharmaceuticals. Chem. Soc. Rev. 2013;43:260–290. doi: 10.1039/C3CS60304K. PubMed DOI

Ramogida C.F., Orvig C. Tumour targeting with radiometals for diagnosis and therapy. Chem. Commun. 2013;49:4720–4739. doi: 10.1039/c3cc41554f. PubMed DOI

Boros E., Packard A.B. Radioactive Transition Metals for Imaging and Therapy. Chem. Rev. 2018;119:870–901. doi: 10.1021/acs.chemrev.8b00281. PubMed DOI

Heroux K.J., Woodin K.S., Tranchemontagne D.J., Widger P.C.B., Southwick E., Wong E.H., Weisman G.R., Tomellini S.A., Wadas T.J., Anderson C.J., et al. The long and short of it: The influence of N-carboxyethyl versusN-carboxymethyl pendant arms on in vitro and in vivo behavior of copper complexes of cross-bridged tetraamine macrocycles. Dalton Trans. 2007:2150–2162. doi: 10.1039/b702938a. PubMed DOI PMC

Boswell C.A., Sun X., Niu W., Weisman G.R., Wong E.H., Rheingold A.L., Anderson C.J. Comparative in Vivo Stability of Copper-64-Labeled Cross-Bridged and Conventional Tetraazamacrocyclic Complexes. J. Med. Chem. 2004;47:1465–1474. doi: 10.1021/jm030383m. PubMed DOI

Juran S., Walther M., Stephan H., Bergmann R., Steinbach J., Kraus W., Emmerling F., Comba P. Hexadentate Bispidine Derivatives as Versatile Bifunctional Chelate Agents for Copper(II) Radioisotopes. Bioconjugate Chem. 2009;20:347–359. doi: 10.1021/bc800461e. PubMed DOI

Bleiholder C., Börzel H., Comba P., Ferrari R., Heydt M., Kerscher M., Kuwata S., Laurenczy G., Lawrance G.A., Lienke A., et al. Coordination Chemistry of a New Rigid, Hexadentate Bispidine-Based Bis(amine)tetrakis(pyridine) Ligand. Inorg. Chem. 2005;44:8145–8155. doi: 10.1021/ic0513383. PubMed DOI

Stephan H., Walther M., Fähnemann S., Ceroni P., Molloy J.K., Bergamini G., Heisig F., Müller C.E., Kraus W., Comba P. Bispidines for Dual Imaging. Chem.—A Eur. J. 2014;20:17011–17018. doi: 10.1002/chem.201404086. PubMed DOI

Singh G., Zarschler K., Hunoldt S., Martinez I.I.S., Ruehl C.L., Matterna M., Bergmann R., Mathe D., Hegedus N., Bachmann M., et al. Versatile Bispidine-Based Bifunctional Chelators for Cu-64(II)-Labelling of Biomolecules. Chem. Eur. J. 2020;26:1989–2001. doi: 10.1002/chem.201904654. PubMed DOI PMC

Comba P., Kerscher M., Schiek W. Bispidine Coordination Chemistry. Prog. Inorg. Chem. 2007:613–704. doi: 10.1002/9780470144428.ch9. DOI

Southcott L., Wang X.Z., Choudhary N., Wharton L., Patrick B.O., Yang H., Zarschler K., Kubeil M., Stephan H., Jara-quemada-Pelaez M.D., et al. H(2)pyhox—Octadentate Bis(pyridyloxine) Inorg. Chem. 2021;60:12186–12196. doi: 10.1021/acs.inorgchem.1c01412. PubMed DOI

Keramidas K.G., Rentzeperis P.I. The crystal structure of triethylenetetraamine copper(II) fluorophosphate, Cu(TRIEN)(PF6) Z. Kristallogr. 1992;201:171–176. doi: 10.1524/zkri.1992.201.3-4.171. DOI

Nurchi V.M., Crisponi G., Crespo-Alonso M., Lachowicz J.I., Szewczuk Z., Cooper G.J.S. Complex formation equilibria of Cu-II and Zn-II with triethylenetetramine and its mono- and di-acetyl metabolites. Dalton Trans. 2013;42:6161–6170. doi: 10.1039/C2DT32252H. PubMed DOI

Wu D.X., Hong M.C., Cao R., Liu H.Q. Synthesis and characterization of (Et(4)N)(4) MoS4Cu10Cl12: A polynuclear mo-lybdenum-copper cluster containing a central tetrahedral MoS4 encapsulated by octahedral Cu-6 and tetrahedral Cu-4 arrays. Inorg. Chem. 1996;35:1080–1082. doi: 10.1021/ic9410304. PubMed DOI

Birker P.J.M.W.L., Freeman H.C. Metal-binding in chelation therapy: X-ray crystal structure of a copper(I)–copper(II) complex ofD-penicillamine. J. Chem. Soc. Chem. Commun. 1976;9:312–313. doi: 10.1039/C39760000312. DOI

Milman N.T. Managing Genetic Hemochromatosis: An Overview of Dietary Measures, Which May Reduce Intestinal Iron Absorption in Persons with Iron Overload. Gastroenterol. Res. 2021;14:66–80. doi: 10.14740/gr1366. PubMed DOI PMC

Yanatori I., Kishi F. DMT1 and iron transport. Free. Radic. Biol. Med. 2018;133:55–63. doi: 10.1016/j.freeradbiomed.2018.07.020. PubMed DOI

Shayeghi M., Latunde-Dada G.O., Oakhill J., Laftah A.H., Takeuchi K., Halliday N., Khan Y., Warley A., McCann F., Hider R., et al. Identification of an Intestinal Heme Transporter. Cell. 2005;122:789–801. doi: 10.1016/j.cell.2005.06.025. PubMed DOI

Kikuchi G., Yoshida T., Noguchi M. Heme oxygenase and heme degradation. Biochem. Biophys. Res. Commun. 2005;338:558–567. doi: 10.1016/j.bbrc.2005.08.020. PubMed DOI

Engle-Stone R., Yeung A., Welch R., Glahn R. Meat and Ascorbic Acid Can Promote Fe Availability from Fe−Phytate but Not from Fe−Tannic Acid Complexes. J. Agric. Food Chem. 2005;53:10276–10284. doi: 10.1021/jf0518453. PubMed DOI

He W., Li X., Ding K., Li Y., Li W. Ascorbic Acid can Reverse the Inhibition of Phytic Acid, Sodium Oxalate and Sodium Silicate on Iron Absorption in Caco-2 cells. Int. J. Vitam. Nutr. Res. 2018;88:65–72. doi: 10.1024/0300-9831/a000503. PubMed DOI

Garcia-Casal M.N., Leets I., Layrisse M. beta-carotene and inhibitors of iron absorption modify iron uptake by Caco-2 cells. J. Nutr. 2000;130:5–9. doi: 10.1093/jn/130.1.5. PubMed DOI

Christides T., Amagloh F.K., Coad J. Iron Bioavailability and Provitamin A from Sweet Potato- and Cereal-Based Comple-mentary Foods. Foods. 2015;4:463–476. doi: 10.3390/foods4030463. PubMed DOI PMC

Kristan A., Gaspersic J., Rezen T., Kunej T., Kolic R., Vuga A., Fink M., Zula S., Doma S.A., Zupan I.P., et al. Genetic analysis of 39 erythrocytosis and hereditary hemochromatosis-associated genes in the Slove-nian family with idiopathic erythrocytosis. J. Clin. Lab. Anal. 2021;35:1–10. doi: 10.1002/jcla.23715. PubMed DOI PMC

Roemhild K., von Maltzahn F., Weiskirchen R., Knüchel R., von Stillfried S., Lammers T. Iron metabolism: Pathophysiology and pharmacology. Trends Pharmacol. Sci. 2021;42:640–656. doi: 10.1016/j.tips.2021.05.001. PubMed DOI PMC

Murphree C.R., Nguyen N.N., Raghunathan V., Olson S.R., Deloughery T., Shatzel J.J. Diagnosis and management of hereditary haemochromatosis. Vox Sang. 2020;115:255–262. doi: 10.1111/vox.12896. PubMed DOI

Milman N.T., Schioedt F.V., Junker A.E., Magnussen K. Diagnosis and Treatment of Genetic HFE-Hemochromatosis: The Danish Aspect. Gastroenterol. Res. 2019;12:221–232. doi: 10.14740/gr1206. PubMed DOI PMC

Griffiths W.J.H., Besser M., Bowden D.J., A Kelly D. Juvenile haemochromatosis. Lancet Child Adolesc. Health. 2021;5:524–530. doi: 10.1016/S2352-4642(20)30392-8. PubMed DOI

Wu L.Y., Song Z.Y., Li Q.H., Mou L.J., Yu Y.Y., Shen S.S., Song X.X. Iron chelators reverse organ damage in type 4B hereditary hemochromatosis Case reports. Medicine. 2021;100:e25258. doi: 10.1097/MD.0000000000025258. PubMed DOI PMC

Brissot P., Loreal O. Iron metabolism and related genetic diseases: A cleared land, keeping mysteries. J. Hepatol. 2016;64:505–515. doi: 10.1016/j.jhep.2015.11.009. PubMed DOI

Vos T., Allen C., Arora M., Barber R.M., Bhutta Z.A., Brown A., Carter A., Casey D.C., Charlson F.J., Chen A.Z., et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1789–1858. doi: 10.1016/S0140-6736(18)32279-7. PubMed DOI PMC

E Radford-Smith D., Powell E.E., Powell L.W. Haemochromatosis: A clinical update for the practising physician. Intern. Med. J. 2018;48:509–516. doi: 10.1111/imj.13784. PubMed DOI

D’Anna M.C., Roque M.E. Physiological focus on the erythropoietin-hepcidin-ferroportin axis. Can. J. Physiol. Pharmacol. 2013;91:338–345. doi: 10.1139/cjpp-2012-0214. PubMed DOI

Grech L., Borg K., Borg J. Novel therapies in beta-thalassaemia. Br. J. Clinic. Pharmaco. 2021;2021:1–16. PubMed

Franchini M., Forni G.L., Liumbruno G.M. Is there a standard-of-care for transfusion therapy in thalassemia? Curr. Opin. Hematol. 2017;24:558–564. doi: 10.1097/MOH.0000000000000373. PubMed DOI

Taher A.T., Saliba A., Harb A.R. Iron chelation therapy in transfusion-dependent thalassemia patients: Current strategies and future directions. J. Blood Med. 2015;6:197–209. doi: 10.2147/JBM.S72463. PubMed DOI PMC

Espinoza A., Le Blanc S., Olivares M., Pizarro F., Ruz M., Arredondo M. Iron, Copper, and Zinc Transport: Inhibition of Divalent Metal Transporter 1 (DMT1) and Human Copper Transporter 1 (hCTR1) by shRNA. Biol. Trace Element Res. 2011;146:281–286. doi: 10.1007/s12011-011-9243-2. PubMed DOI

Wang X., Flores S.R., Ha J.-H., Doguer C., Woloshun R.R., Xiang P., Grosche A., Vidyasagar S., Collins J.F. Intestinal DMT1 Is Essential for Optimal Assimilation of Dietary Copper in Male and Female Mice with Iron-Deficiency Anemia. J. Nutr. 2018;148:1244–1252. doi: 10.1093/jn/nxy111. PubMed DOI PMC

Linder M.C. Copper Homeostasis in Mammals, with Emphasis on Secretion and Excretion. A Review. Int. J. Mol. Sci. 2020;21:4932. doi: 10.3390/ijms21144932. PubMed DOI PMC

Vetrik M., Mattova J., Mackova H., Kucka J., Pouckova P., Kukackova O., Brus J., Eigner-Henke S., Sedlacek O., Sefc L., et al. Biopolymer strategy for the treatment of Wilson’s disease. J. Control. Release. 2018;273:131–138. doi: 10.1016/j.jconrel.2018.01.026. PubMed DOI

Poujois A., Woimant F. Wilson’s disease: A 2017 update. Clin. Res. Hepatol. Gas. 2018;42:512–520. doi: 10.1016/j.clinre.2018.03.007. PubMed DOI

Liu J., Luan J., Zhou X.Y., Cui Y.Z., Han J.X. Epidemiology, diagnosis, and treatment of Wilson’s disease. Intract. Rare Disease. Res. 2017;6:249–255. doi: 10.5582/irdr.2017.01057. PubMed DOI PMC

Maung M.T., Carlson A., Olea-Flores M., Elkhadragy L., Schachtschneider K.M., Navarro-Tito N., Padilla-Benavides T. The molecular and cellular basis of copper dysregulation and its relationship with human pathologies. FASEB J. 2021;35:e21810. doi: 10.1096/fj.202100273RR. PubMed DOI

Hedera P. Update on the clinical management of Wilson’s disease. Appl. Clini. Gen. 2017;10:9–19. doi: 10.2147/TACG.S79121. PubMed DOI PMC

Baldari S., Di Rocco G., Toietta G. Current Biomedical Use of Copper Chelation Therapy. Int. J. Mol. Sci. 2020;21:1069. doi: 10.3390/ijms21031069. PubMed DOI PMC

Vilensky J.A., Redman K. British anti-Lewisite (dimercaprol): An amazing history. Ann. Emerg. Med. 2003;41:378–383. doi: 10.1067/mem.2003.72. PubMed DOI

Ni W., Dong Q.-Y., Zhang Y., Wu Z.-Y. Zinc Monotherapy and a Low-copper Diet are Beneficial in Patients with Wilson Disease After Liver Transplantation. CNS Neurosci. Ther. 2013;19:905–907. doi: 10.1111/cns.12167. PubMed DOI PMC

Squitti R., Siotto M., Polimanti R. Low-copper diet as a preventive strategy for Alzheimer’s disease. Neurobiol. Aging. 2014;35:S40–S50. doi: 10.1016/j.neurobiolaging.2014.02.031. PubMed DOI

Kissel M., Peschke P., Subr V., Ulbrich K., Schuhmacher J., Debus J., Friedrich E. Synthetic macromolecular drug carriers: Biodistribution of poly[(N-2-hydroxypropyl)methacrylamide] copolymers and their accumulation in solid rat tumors. PDA J. Pharm. Sci. Technol. 2001;55:191–201. PubMed

Jagur-Grodzinski J. Polymers for targeted and/or sustained drug delivery. Polym. Adv. Technol. 2008;20:595–606. doi: 10.1002/pat.1304. DOI

Fox M.E., Szoka F.C., Fréchet J.M.J. Soluble Polymer Carriers for the Treatment of Cancer: The Importance of Molecular Architecture. Accounts Chem. Res. 2009;42:1141–1151. doi: 10.1021/ar900035f. PubMed DOI PMC

Abbina S., Abbasi U., Gill A., Wong K., Kalathottukaren M.T., Kizhakkedathu J.N. Design of Safe Nanotherapeutics for the Excretion of Excess Systemic Toxic Iron. ACS Central Sci. 2019;5:917–926. doi: 10.1021/acscentsci.9b00284. PubMed DOI PMC

Ul-Haq M.I., Hamilton J.L., Lai B.F.L., Shenoi R.A., Horte S., Constantinescu I., Leitch H.A., Kizhakkedathu J.N. Design of Long Circulating Nontoxic Dendritic Polymers for the Removal of Iron in Vivo. ACS Nano. 2013;7:10704–10716. doi: 10.1021/nn4035074. PubMed DOI

Rossi N.A., Mustafa I., Jackson J.K., Burt H.M., Horte S.A., Scott M.D., Kizhakkedathu J.N. In vitro chelating, cytotoxicity, and blood compatibility of degradable poly(ethylene glycol)-based macromolecular iron chelators. Biomaterials. 2009;30:638–648. doi: 10.1016/j.biomaterials.2008.09.057. PubMed DOI

Hamilton J.L., Ul-Haq M.I., Abbina S., Kalathottukaren M.T., Lai B.F., Hatef A., Unniappan S., Kizhakkedathu J.N. In vivo efficacy, toxicity and biodistribution of ultra-long circulating desferrioxamine based polymeric iron chelator. Biomaterials. 2016;102:58–71. doi: 10.1016/j.biomaterials.2016.06.019. PubMed DOI

Tian M., Chen X., Li H., Ma L., Gu Z.P., Qi X., Li X., Tan H., You C. Long-term and oxidative-responsive algi-nate-deferoxamine conjugates with a low toxicity for iron overload. RSC Adv. 2016;6:32471–32479. doi: 10.1039/C6RA02674E. DOI

Tian M., Chen X., Gu Z.P., Li H., Ma L., Qi X., Tan H., You C. Synthesis and evaluation of oxidation-responsive algi-nate-deferoxamine conjugates with increased stability and lowtoxicity. Carbohydr. Polym. 2016;144:522–530. doi: 10.1016/j.carbpol.2016.03.014. PubMed DOI

Jones G., Goswami S.K., Kang H.M., Choi H.S., Kim J. Combating iron overload: A case for deferoxamine-based nano-chelators. Nanomedicine. 2020;15:1341–1356. doi: 10.2217/nnm-2020-0038. PubMed DOI PMC

Liu Z., Lin T.-M., Purro M., Xiong M.P. Enzymatically Biodegradable Polyrotaxane–Deferoxamine Conjugates for Iron Chelation. ACS Appl. Mater. Interfaces. 2016;8:25788–25797. doi: 10.1021/acsami.6b09077. PubMed DOI PMC

Hallaway P.E., Eaton J.W., Panter S.S., Hedlund B.E. Modulation of deferoxamine toxicity and clearance by covalent at-tachment to biocompatible polymers. Proc. Natl. Acad. Sci. USA. 1989;86:10108–10112. doi: 10.1073/pnas.86.24.10108. PubMed DOI PMC

Dragsten P.R., Hallaway P.E., Hanson G.J., Berger A.E., Bernard B., Hedlund B.E. First human studies with a high-molecular-weight iron chelator. J. Lab. Clin. Med. 2000;135:57–65. doi: 10.1016/S0022-2143(00)70021-7. PubMed DOI

Hamilton J.L., Ul-Haq M.I., Creagh A.L., Haynes C.A., Kizhakkedathu J.N. Iron Binding and Iron Removal Efficiency of Desferrioxamine Based Polymeric Iron Chelators: Influence of Molecular Size and Chelator Density. Macromol. Biosci. 2016;17:1600244. doi: 10.1002/mabi.201600244. PubMed DOI

Guo S., Liu G., Frazer D.M., Liu T., You L., Xu J., Wang Y., Anderson G.J., Nie G. Polymeric Nanoparticles Enhance the Ability of Deferoxamine to Deplete Hepatic and Systemic Iron. Nano Lett. 2018;18:5782–5790. doi: 10.1021/acs.nanolett.8b02428. PubMed DOI

Harmatz P., Grady R.W., Dragsten P., Vichinsky E., Giardina P., Madden J., Jeng M., Miller B., Hanson G., Hedlund B. Phase Ib clinical trial of starch-conjugated deferoxamine (40SD02): A novel long-acting iron chelator. Br. J. Haematol. 2007;138:374–381. doi: 10.1111/j.1365-2141.2007.06651.x. PubMed DOI

Ang M.T.C., Gumbau-Brisa R., Allan D.S., McDonald R., Ferguson M.J., Holbein B.E., Bierenstiel M. DIBI, a 3-hydroxypyridin-4-one chelator iron-binding polymer with enhanced antimicrobial activity. MedChemComm. 2018;9:1206–1212. doi: 10.1039/C8MD00192H. PubMed DOI PMC

Kang H., Han M., Xue J., Baek Y., Chang J., Hu S., Nam H., Jo M.J., El Fakhri G., Hutchens M.P., et al. Renal clearable nanochelators for iron overload therapy. Nat. Commun. 2019;10:5134. doi: 10.1038/s41467-019-13143-z. PubMed DOI PMC

Zhou T., Le Kong X., Liu Z.D., Liu D.Y., Hider R.C. Synthesis and Iron(III)-Chelating Properties of Novel 3-Hydroxypyridin-4-one Hexadentate Ligand-Containing Copolymers. Biomacromolecules. 2008;9:1372–1380. doi: 10.1021/bm701122u. PubMed DOI

Skodova M., Hruby M., Filippov S.K., Karlsson G., Mackova H., Spirkova M., Kankova D., Steinhart M., Stepanek P., Ulbrich K. Novel Polymeric Nanoparticles Assembled by Metal Ion Addition. Macromol. Chem. Phys. 2011;212:2339–2348. doi: 10.1002/macp.201100431. DOI

Skodova M., Cernoch P., Stepanek P., Chanova E., Kucka J., Kalalova Z., Kankova D., Hruby M. Self-Assembled Poly-meric Chelate Nanoparticles as Potential Theranostic Agents. ChemPhysChem. 2012;13:4244–4250. doi: 10.1002/cphc.201200681. PubMed DOI

Winston A., Varaprasad D.V., Metterville J.J., Rosenkrantz H. Evaluation of polymeric hydroxamic acid iron chelators for treatment of iron overload. J. Pharmacol. Exp. Ther. 1985;232:644–649. PubMed

Lim J., Venditto V.J., Simanek E.E. Synthesis and characterization of a triazine dendrimer that sequesters iron(III) using 12 desferrioxamine B groups. Bioorganic Med. Chem. 2010;18:5749–5753. doi: 10.1016/j.bmc.2010.05.039. PubMed DOI PMC

Liu Z., Wang Y., Purro M., Xiong M.P. Oxidation-Induced Degradable Nanogels for Iron Chelation. Sci. Rep. 2016;6:20923. doi: 10.1038/srep20923. PubMed DOI PMC

Ergun B., Baydemir G., Andac M., Yavuz H., Denizli A. Ion imprinted beads embedded cryogels for in vitro removal of iron from beta-thalassemic human plasma. J. Appl. Polym. Sci. 2012;125:254–262. doi: 10.1002/app.35537. DOI

Wang Y., Liu Z., Lin T.M., Chanana S., Xiong M.P. Nanogel-DFO conjugates as a model to investigate pharmacokinetics, biodistribution, and iron chelation in vivo. Int. J. Pharm. 2018;538:79–86. doi: 10.1016/j.ijpharm.2018.01.004. PubMed DOI PMC

Liu Z., Qiao J., Nagy T., Xiong M.P. ROS-triggered degradable iron-chelating nanogels: Safely improving iron elimination in vivo. J. Control. Release. 2018;283:84–93. doi: 10.1016/j.jconrel.2018.05.025. PubMed DOI PMC

Golenser J., Domb A.J., Teomim D., Tsafack A., Nisim O., Ponka P., Eling W., I Cabantchik Z. The treatment of animal models of malaria with iron chelators by use of a novel polymeric device for slow drug release. J. Pharmacol. Exp. Ther. 1997;281 PubMed

Tran D.T., Hayes M.E., O Noble C., Dai Z., Working P.K., Szoka F.C. Twice Monthly Liposome Encapsulated Deferoxamine (LDFO) Has a High Molar Efficiency in Removing Total Body Iron in an Iron Dextran-Overloaded Mouse Model. Blood. 2016;128:2322. doi: 10.1182/blood.V128.22.2322.2322. DOI

Kozempel J., Hruby M., Novakova M., Kucka J., Leseticky L., Lebeda O. Novel polymer vectors of Cu-Radiochim. Acta. 2009;97:747–752.

Niculae D., Dusman R., Leonte R.A., Chilug L.E., Dragoi C.M., Nicolae A., Serban R.M., Niculae D.A., Dumitrescu I.B., Draganescu D. Biological Pathways as Substantiation of the Use of Copper Radioisotopes in Cancer Theranostics. Front. Phys. 2021;8 doi: 10.3389/fphy.2020.568296. DOI

Pant K., Sedlacek O., Nadar R.A., Hruby M., Stephan H. Radiolabelled Polymeric Materials for Imaging and Treatment of Cancer: Quo Vadis? Adv. Healthc. Mater. 2017;6:1–31. doi: 10.1002/adhm.201601115. PubMed DOI

Capriotti G., Varani M., Lauri C., Franchi G., Pizzichini P., Signore A. Copper-64 labeled nanoparticles for positron emis-sion tomography imaging: A review of the recent literature. Q. J. Nucl. Med. Mol. Im. 2020;64:346–355. PubMed

Mendonca P.V., Serra A.C., Silva C.L., Simoes S., Coelho J.F.J. Polymeric bile acid sequestrants-Synthesis Using conven-tional methods and new approaches based on “controlled”/living radical polymerization. Progr. Polym. Sci. 2013;38:445–461. doi: 10.1016/j.progpolymsci.2012.09.004. DOI

Feng Y., Li Q., Ou G., Yang M., Du L. Bile acid sequestrants: A review of mechanism and design. J. Pharm. Pharmacol. 2021;73:855–861. doi: 10.1093/jpp/rgab002. PubMed DOI

Aaseth J., Nurchi V.M., Andersen O. Medical Therapy of Patients Contaminated with Radioactive Cesium or Iodine. Biomolecules. 2019;9:856. doi: 10.3390/biom9120856. PubMed DOI PMC

Kontoghiorghes G.J., Eracleous E., Economides C., Kolnagou A. Advances in Iron Overload Therapies. Prospects for Effective Use of Deferiprone (L1), Deferoxamine, the New Experimental Chelators ICL670, GT56-252, L1NAll and their Combinations. Curr. Med. Chem. 2005;12:2663–2681. doi: 10.2174/092986705774463003. PubMed DOI

Zhou T., Neubert H., Liu D.Y., Liu Z.D., Ma Y.M., Le Kong X., Luo W., Mark A.S., Hider R.C. Iron Binding Dendrimers: A Novel Approach for the Treatment of Haemochromatosis. J. Med. Chem. 2006;49:4171–4182. doi: 10.1021/jm0600949. PubMed DOI

Das A.K., Islam M.N., Faruk M.O., Ashaduzzaman M., Dungani R. Review on tannins: Extraction processes, applications and possibilities. S. Afr. J. Bot. 2020;135:58–70. doi: 10.1016/j.sajb.2020.08.008. DOI

Adamczyk B., Simon J., Kitunen V., Adamczyk S., Smolander A. Tannins and Their Complex Interaction with Different Organic Nitrogen Compounds and Enzymes: Old Paradigms versus Recent Advances. ChemistryOpen. 2017;6:610–614. doi: 10.1002/open.201700113. PubMed DOI PMC

Florez I.D., Sierra J.M., Niño-Serna L.F. Gelatin tannate for acute diarrhoea and gastroenteritis in children: A systematic review and meta-analysis. Arch. Dis. Child. 2019;105:141–146. doi: 10.1136/archdischild-2018-316385. PubMed DOI

Groborz O., Poláková L., Kolouchová K., Švec P., Loukotová L., Miriyala V.M., Francová P., Kučka J., Krijt J., Páral P., et al. Chelating Polymers for Hereditary Hemochromatosis Treatment. Macromol. Biosci. 2020;20:2000254. doi: 10.1002/mabi.202000254. PubMed DOI

Brzonova I., Steiner W., Zankel A., Nyanhongo G.S., Guebitz G.M. Enzymatic synthesis of catechol and hydroxyl-carboxic acid functionalized chitosan microspheres for iron overload therapy. Eur. J. Pharm. Biopharm. 2011;79:294–303. doi: 10.1016/j.ejpb.2011.04.018. PubMed DOI

Polomoscanik S.C., Cannon C.P., Neenan T.X., Holmes-Farley S.R., Mandeville W.H., Dhal P.K. Hydroxamic acidcontaining hydrogels for nonabsorbed iron chelation therapy: Synthesis, characterization, and biological evaluation. Biomacromolecules. 2005;6:2946–2953. doi: 10.1021/bm050036p. PubMed DOI

Qian J., Sullivan B.P., Peterson S.J., Berkland C. Nonabsorbable Iron Binding Polymers Prevent Dietary Iron Absorption for the Treatment of Iron Overload. ACS Macro Lett. 2017;6:350–353. doi: 10.1021/acsmacrolett.6b00945. PubMed DOI

Mohammadi Z., Xie S.-X., Peltier E., Veisi M., Berkland C. Enhancing the selectivity of an iron binding hydrogel. Eur. Polym. J. 2011;47:1485–1488. doi: 10.1016/j.eurpolymj.2011.04.007. DOI

Huang X.L., Lu D., Ma Y.M., Zhang L.M., Wang L.N., Deng J., Wang Z., Zhao Y.J. From small deferiprone to macro-molecular micelles: Self-assembly enhances iron chelation. J. Colloid Interface Sci. 2019;533:375–384. doi: 10.1016/j.jcis.2018.08.086. PubMed DOI

Mattová J., Poučková P., Kucka J., Skodova M., Vetrik M., Štěpánek P., Urbánek P., Petrik M., Novy Z., Hrubý M. Chelating polymeric beads as potential therapeutics for Wilson’s disease. Eur. J. Pharm. Sci. 2014;62:1–7. doi: 10.1016/j.ejps.2014.05.002. PubMed DOI

Skodova M., Kucka J., Vetrik M., Skopal J., Walterová Z., Sedláček O., Štěpánek P., Mattová J., Poučková P., Urbánek P., et al. Chelating polymeric particles intended for the therapy of Wilson’s disease. React. Funct. Polym. 2013;73:1426–1431. doi: 10.1016/j.reactfunctpolym.2013.07.010. DOI

Mohammadi Z., Xie S.-X., Golub A.L., Gehrke S.H., Berkland C. Siderophore-Mimetic hydrogel for iron chelation therapy. J. Appl. Polym. Sci. 2011;121:1384–1392. doi: 10.1002/app.33562. DOI

Ghisalberti C.A., Falletta E., Lammi C., Facchetti G., Bucci R., Erba E., Pellegrino S. Nonabsorbable Iron(III) binding polymers: Synthesis and evaluation of the chelating properties. Polym. Test. 2020;90:106693. doi: 10.1016/j.polymertesting.2020.106693. DOI

Zhou T., Winkelmann G., Dai Z.-Y., Hider R.C. Design of clinically useful macromolecular iron chelators. J. Pharm. Pharmacol. 2011;63:893–903. doi: 10.1111/j.2042-7158.2011.01291.x. PubMed DOI

Saghaie L., Liu D., Hider R.C. Synthesis of polymers containing 3-hydroxypyridin-4-one bidentate ligands for treatment of iron overload. Res. Pharm. Sci. 2015;10:364–377. PubMed PMC

Andrews M., Briones L., Jaramillo A., Pizarro F., Arredondo M. Effect of Calcium, Tannic Acid, Phytic Acid and Pectin over Iron Uptake in an In Vitro Caco-2 Cell Model. Biol. Trace Element Res. 2014;158:122–127. doi: 10.1007/s12011-014-9911-0. PubMed DOI

Milman N.T. A Review of Nutrients and Compounds, Which Promote or Inhibit Intestinal Iron Absorption: Making a Platform for Dietary Measures That Can Reduce Iron Uptake in Patients with Genetic Haemochromatosis. J. Nutr. Metab. 2020;2020:1–15. doi: 10.1155/2020/7373498. PubMed DOI PMC

Zhang H., Onning G., Oste R., Gramatkovski E., Hulthen L. Improved iron bioavailability in an oat-based beverage: The combined effect of citric acid addition, dephytinization and iron supplementation. Eur. J. Nutr. 2007;46:95–102. doi: 10.1007/s00394-006-0637-4. PubMed DOI

Aguilar-De-Leyva A., Gonçalves-Araújo T., Daza V., Caraballo I. A new deferiprone controlled release system obtained by ultrasound-assisted compression. Pharm. Dev. Technol. 2013;19:728–734. doi: 10.3109/10837450.2013.829091. PubMed DOI

Inman R.S., Coughlan M.M., Wesslingresnick M. Extracellular ferrireductase activity of K562 cells is coupled to transfer-rin-dependent iron transport. Biochemistry. 1994;33:11850–11857. doi: 10.1021/bi00205a022. PubMed DOI

Manatschal C., Pujol-Giménez J., Poirier M., Reymond J.-L., A Hediger M., Dutzler R. Author response: Mechanistic basis of the inhibition of SLC11/NRAMP-mediated metal ion transport by bis-isothiourea substituted compounds. Elife. 2019;8:e51913. doi: 10.7554/eLife.51913. PubMed DOI PMC

Coraça-Huber D.C., Dichtl S., Steixner S., Nogler M., Weiss G. Iron chelation destabilizes bacterial biofilms and potentiates the antimicrobial activity of antibiotics against coagulase-negative Staphylococci. Pathog. Dis. 2018;76:fty052. doi: 10.1093/femspd/fty052. PubMed DOI

Zhao X.K., Li X., Huang X.P., Liang S.Y., Cai P.G., Wang Y.H., Cui Y.M., Chen W., Dong X.W. Development of lacto-bionic acid conjugated-copper chelators as anticancer candidates for hepatocellular carcinoma. Arab. J. Chem. 2021;14:103241. doi: 10.1016/j.arabjc.2021.103241. DOI

Argenziano M., Di Paola A., Tortora C., Di Pinto D., Pota E., Di Martino M., Perrotta S., Rossi F., Punzo F. Effects of Iron Chelation in Osteosarcoma. Curr. Cancer Drug Targets. 2020;20:443–455. doi: 10.2174/1568009620666201230090531. PubMed DOI

Lipinski B., Pretorius E. Iron-Induced Fibrin in Cardiovascular Disease. Curr. Neurovascular Res. 2013;10:269–274. doi: 10.2174/15672026113109990016. PubMed DOI PMC

Lipinski B., Pretorius E. Novel pathway of iron-induced blood coagulation: Implications for diabetes mellitus and its com-plications. Pol. Arch. Med. Wewn. 2012;122:115–122. doi: 10.20452/pamw.1201. PubMed DOI

Ramadori G. Albumin Infusion in Critically Ill COVID-19 Patients: Hemodilution and Anticoagulation. Int. J. Mol. Sci. 2021;22:7126. doi: 10.3390/ijms22137126. PubMed DOI PMC

Potentiometric Performance of Ion-Selective Electrodes Based on Polyaniline and Chelating Agents: Detection of Fe2+ or Fe3+ Ions