Therapeutic Macromolecular Iron Chelators

Author(s): Upendra Bulbake , Alka Singh , Abraham J. Domb* , Wahid Khan* .

Journal Name: Current Medicinal Chemistry

Volume 26 , Issue 2 , 2019

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Abstract:

Iron is a key element for every single living process. On a fundamental level, targeting iron is a valuable approach for the treatment of disorders caused by iron overload. Utilizing iron chelators as therapeutic agents has received expanding consideration in chelation therapy. Approved low molecular weight (MW) iron chelators to treat iron overload may experience short half-lives and toxicities prompting moderately high adverse effects. In recent years, polymeric/macromolecular iron chelators have received attention as therapeutic agents. Polymeric iron chelators show unique pharmaceutical properties that are different to their conventional small molecule counterparts. These polymeric iron chelators possess longer plasma half-lives and reduced toxicities, thus exhibiting a significant supplement to currently using low MW iron chelator therapy. In this review, we have briefly discussed polymeric iron chelators and factors to be considered when designing clinically valuable iron chelators. We have also discussed applications of polymeric iron chelators in the diseases caused by iron overload associated with transfusional hemosiderosis, neurodegenerative disorders, malaria and cancer. With this, research findings for new polymeric iron chelators are also covered.

Keywords: Polymeric iron chelators, iron chelators, deferoxamine, deferiprone, deferasirox.

[1]
Crichton, R.R.; Boelaert, J.R. Inorganic biochemistry of iron metabolism: from molecular mechanisms to clinical consequences; John Wiley & Sons, 2001, pp. 190-197.
[2]
Aisen, P.; Enns, C.; Wessling-Resnick, M. Chemistry and biology of eukaryotic iron metabolism. Int. J. Biochem. Cell Biol., 2001, 33(10), 940-959.
[3]
Koppenol, W.H. The Haber-Weiss cycle--70 years later. Redox Rep., 2001, 6(4), 229-234.
[4]
Crisponi, G.; Remelli, M. Iron chelating agents for the treatment of iron overload. Coord. Chem. Rev., 2008, 252(10), 1225-1240.
[5]
Chaston, T.B.; Richardson, D.R. Iron chelators for the treatment of iron overload disease: relationship between structure, redox activity, and toxicity. Am. J. Hematol., 2003, 73(3), 200-210.
[6]
Hamilton, J.L.J. Innovative polymeric iron chelators with iron binding affinity and biocompatibility for the treatment of transfusional iron overlo. Doctoral disseration, University of British Columbia: Vancouver, April, 2015.
[7]
Golenser, J.; Domb, A.; Teomim, D.; Tsafack, A.; Nisim, O.; Ponka, P.; Eling, W.; Cabantchik, Z.I. 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(3), 1127-1135.
[8]
Pearson, R.G. Hard and soft acids and bases. J. Am. Chem. Soc., 1963, 85(22), 3533-3539.
[9]
Richardson, D.; Bernhardt, P.V.; Becker, E.M. Iron chelators and uses thereof., US Patent 698939-7B1, 2006.
[10]
Hershko, C.; Graham, G.; Bates, G.W.; Rachmilewitz, E.A. Non-specific serum iron in thalassaemia: an abnormal serum iron fraction of potential toxicity. Br. J. Haematol., 1978, 40(2), 255-263.
[11]
Hoffbrand, A.V.; Taher, A.; Cappellini, M.D. How I treat transfusional iron overload. Blood, 2012, 120(18), 3657-3669.
[12]
Manning, T.; Kean, G.; Thomas, J.; Thomas, K.; Corbitt, M.; Gosnell, D.; Ware, R.; Fulp, S.; Jarrard, J.; Phillips, D. Iron chelators in medicinal applications - chemical equilibrium considerations in pharmaceutical activity. Curr. Med. Chem., 2009, 16(19), 2416-2429.
[13]
Morehouse, L.A.; Thomas, C.E.; Aust, S.D. Superoxide generation by NADPH-cytochrome P-450 reductase: the effect of iron chelators and the role of superoxide in microsomal lipid peroxidation. Arch. Biochem. Biophys., 1984, 232(1), 366-377.
[14]
Porter, J.B.; Garbowski, M. The pathophysiology of transfusional iron overload. Hematol. Oncol. Clin. North Am., 2014, 28(4), 683-701. [vi.].
[15]
Brittenham, G.M. Iron-chelating therapy for transfusional iron overload. N. Engl. J. Med., 2011, 364(2), 146-156.
[16]
Borgna-Pignatti, C.; Rugolotto, S.; De Stefano, P.; Zhao, H.; Cappellini, M.D.; Del Vecchio, G.C.; Romeo, M.A.; Forni, G.L.; Gamberini, M.R.; Ghilardi, R.; Piga, A.; Cnaan, A. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica, 2004, 89(10), 1187-1193.
[17]
Liu, Z.D.; Hider, R.C. Design of iron chelators with therapeutic application. Coord. Chem. Rev., 2002, 232(1), 151-171.
[18]
Hershko, C.; Link, G.; Konijn, A.M.; Cabantchik, Z.I. Objectives and mechanism of iron chelation therapy. Ann. N. Y. Acad. Sci., 2005, 1054(1), 124-135.
[19]
Modell, B.; Khan, M.; Darlison, M. Survival in β-thalassaemia major in the UK: data from the UK Thalassaemia Register. Lancet, 2000, 355(9220), 2051-2052.
[20]
Lee, P.; Mohammed, N.; Marshall, L.; Abeysinghe, R.D.; Hider, R.C.; Porter, J.B.; Singh, S. Intravenous infusion pharmacokinetics of desferrioxamine in thalassaemic patients. Drug Metab. Dispos., 1993, 21(4), 640-644.
[21]
Porter, J.B.; Faherty, A.; Stallibrass, L.; Brookman, L.; Hassan, I.; Howes, C. A trial to investigate the relationship between DFO pharmacokinetics and metabolism and DFO-related toxicity. Ann. N. Y. Acad. Sci., 1998, 850(1), 483-487.
[22]
Levine, J.E.; Cohen, A.; MacQueen, M.; Martin, M.; Giardina, P.J. Sensorimotor neurotoxicity associated with high-dose deferoxamine treatment. J. Pediatr. Hematol. Oncol., 1997, 19(2), 139-141.
[23]
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, L1NA11 and their combinations. Curr. Med. Chem., 2005, 12(23), 2663-2681.
[24]
Kontoghiorghes, G.J.; Aldouri, M.A.; Hoffbrand, A.V.; Barr, J.; Wonke, B.; Kourouclaris, T.; Sheppard, L. Effective chelation of iron in beta thalassaemia with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one. Br. Med. J. (Clin. Res. Ed.), 1987, 295(6612), 1509-1512.
[25]
Hoffbrand, A.V.; Cohen, A.; Hershko, C. Role of deferiprone in chelation therapy for transfusional iron overload. Blood, 2003, 102(1), 17-24.
[26]
Hoffbrand, A.V. AL-Refaie, F.; Davis, B.; Siritanakatkul, N.; Jackson, B.F.; Cochrane, J.; Prescott, E.; Wonke, B. Long-term trial of deferiprone in 51 transfusion-dependent iron overloaded patients. Blood, 1998, 91(1), 295-300.
[27]
Galanello, R. Deferiprone in the treatment of transfusion-dependent thalassemia: a review and perspective. Ther. Clin. Risk Manag., 2007, 3(5), 795-805.
[28]
Nisbet-Brown, E.; Olivieri, N.F.; Giardina, P.J.; Grady, R.W.; Neufeld, E.J.; Séchaud, R.; Krebs-Brown, A.J.; Anderson, J.R.; Alberti, D.; Sizer, K.C.; Nathan, D.G. Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet, 2003, 361(9369), 1597-1602.
[29]
Cappellini, M.D. Iron-chelating therapy with the new oral agent ICL670 (Exjade). Best Pract. Res. Clin. Haematol., 2005, 18(2), 289-298.
[30]
Nick, H.; Allegrini, P.R.; Fozard, L.; Junker, U.; Rojkjaer, L.; Salie, R.; Niederkofler, V.; O’Reilly, T. Deferasirox reduces iron overload in a murine model of juvenile hemochromatosis. Exp. Biol. Med. (Maywood), 2009, 234(5), 492-503.
[31]
Galanello, R.; Piga, A.; Alberti, D.; Rouan, M.C.; Bigler, H.; Séchaud, R. Safety, tolerability, and pharmacokinetics of ICL670, a new orally active iron-chelating agent in patients with transfusion-dependent iron overload due to β-thalassemia. J. Clin. Pharmacol., 2003, 43(6), 565-572.
[32]
Sánchez-González, P.D.; López-Hernandez, F.J.; Morales, A.I.; Macías-Nuñez, J.F.; López-Novoa, J.M. Effects of deferasirox on renal function and renal epithelial cell death. Toxicol. Lett., 2011, 203(2), 154-161.
[33]
Galanello, R.; Campus, S.; Origa, R. Deferasirox: pharmacokinetics and clinical experience. Expert Opin. Drug Metab. Toxicol., 2012, 8(1), 123-134.
[34]
Kontoghiorghes, G.J. A record number of fatalities in many categories of patients treated with deferasirox: loopholes in regulatory and marketing procedures undermine patient safety and misguide public funds? Expert Opin. Drug Saf., 2013, 12(5), 605-609.
[35]
Riva, A. A record number of fatalities in many categories of patients treated with deferasirox: loopholes in regulatory and marketing procedures undermine patient safety and misguide public funds? Expert Opin. Drug Saf., 2013, 12(5), 793-794.
[36]
Zhou, T.; Kong, X.L.; 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(5), 1372-1380.
[37]
Zhou, T.; Winkelmann, G.; Dai, Z.Y.; Hider, R.C. Design of clinically useful macromolecular iron chelators. J. Pharm. Pharmacol., 2011, 63(7), 893-903.
[38]
Mahoney, J.R., Jr; Hallaway, P.E.; Hedlund, B.E.; Eaton, J.W. Acute iron poisoning. Rescue with macromolecular chelators. J. Clin. Invest., 1989, 84(4), 1362-1366.
[39]
Feng, M.H.; van der Does, L.; Bantjes, A. Iron (III)-chelating resins. 3. Synthesis, iron (III)-chelating properties, and in vitro antibacterial activity of compounds containing 3-hydroxy-2-methyl-4(1H)-pyridinone ligands. J. Med. Chem., 1993, 36(19), 2822-2827.
[40]
Horowitz, D.; Margel, S.; Shimoni, T. Iron detoxification by haemoperfusion through deferoxamine-conjugated agarose-polyacrolein microsphere beads. Biomaterials, 1985, 6(1), 9-16.
[41]
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(4), 638-648.
[42]
Imran ul-haq, M. Design of long circulating nontoxic dendritic polymers for the removal of iron in vivo. ACS Nano, 2013, 7(12), 10704-10716.
[43]
Hauser, C.; Renfrow, W. Benzohydroxamic acid. Org. Synth., 1939, 1(2), 15-15.
[44]
Nishino, N.; Powers, J.C. Peptide hydroxamic acids as inhibitors of thermolysin. Biochemistry, 1978, 17(14), 2846-2850.
[45]
Kurzak, B.; Kozłowski, H.; Farkas, E. Hydroxamic and aminohydroxamic acids and their complexes with metal ions. Coord. Chem. Rev., 1992, 114(2), 169-200.
[46]
Huang, L.; Pardee, A.B. Suberoylanilide hydroxamic acid as a potential therapeutic agent for human breast cancer treatment. Mol. Med., 2000, 6(10), 849-866.
[47]
Holmes, M.A.; Matthews, B.W. Binding of hydroxamic acid inhibitors to crystalline thermolysin suggests a pentacoordinate zinc intermediate in catalysis. Biochemistry, 1981, 20(24), 6912-6920.
[48]
Parvathy, S.; Hussain, I.; Karran, E.H.; Turner, A.J.; Hooper, N.M. Alzheimer’s amyloid precursor protein α-secretase is inhibited by hydroxamic acid-based zinc metalloprotease inhibitors: similarities to the angiotensin converting enzyme secretase. Biochemistry, 1998, 37(6), 1680-1685.
[49]
Polomoscanik, S.C.; Cannon, C.P.; Neenan, T.X.; Holmes-Farley, S.R.; Mandeville, W.H.; Dhal, P.K. Hydroxamic acid-containing hydrogels for nonabsorbed iron chelation therapy: synthesis, characterization, and biological evaluation. Biomacromolecules, 2005, 6(6), 2946-2953.
[50]
Halliwell, B. Lipid peroxidation: A radical chain reaction. ‎. Free Radic. Biol. Med., 1989, 112-137.
[51]
Andrews, N.C. Disorders of iron metabolism. N. Engl. J. Med., 1999, 341(26), 1986-1995.
[52]
Brittenham, G. Disorders of iron metabolism: iron deficiency and overload. ematology: basic principles and practice,, 2000. 115-146.
[53]
Liu, Z.; Wang, Y.; Purro, M.; Xiong, M.P. Oxidation-induced degradable nanogels for iron chelation. Sci. Rep., 2016, 6, 20923.
[54]
Qian, J. Nonabsorbable iron binding polymers prevent dietary iron absorption for the treatment of iron overload. ACS Macro Lett., 2017, 6(4), 350-353.
[55]
Tyagi, P.; Kumar, A.; Gupta, D.; Singh, H. Decorporation of iron metal using dialdehyde cellulose-deferoxamine microcarrier. AAPS PharmSciTech, 2017, 18(1), 156-165.
[56]
Wang, N.; Jin, X.; Guo, D.; Tong, G.; Zhu, X. Iron chelation nanoparticles with delayed saturation as an effective therapy for Parkinson disease. Biomacromolecules, 2017, 18(2), 461-474.
[57]
Liu, G.; Men, P.; Kudo, W.; Perry, G.; Smith, M.A. Nanoparticle-chelator conjugates as inhibitors of amyloid-β aggregation and neurotoxicity: A novel therapeutic approach for Alzheimer disease. Neurosci. Lett., 2009, 455(3), 187-190.
[58]
Başar, I.; Ayhan, A.; Bircan, K.; Ergen, A.; Taşar, C. Transferrin receptor activity as a marker in transitional cell carcinoma of the bladder. Br. J. Urol., 1991, 67(2), 165-168.
[59]
Keer, H.N.; Kozlowski, J.M.; Tsai, Y.C.; Lee, C.; McEwan, R.N.; Grayhack, J.T. Elevated transferrin receptor content in human prostate cancer cell lines assessed in vitro and in vivo. J. Urol., 1990, 143(2), 381-385.
[60]
Faulk, W.P.; Hsi, B-L.; Stevens, P.J. Transferrin and transferrin receptors in carcinoma of the breast. Lancet, 1980, 2(8191), 390-392.
[61]
Buss, J.L.; Greene, B.T.; Turner, J.; Torti, F.M.; Torti, S.V. Iron chelators in cancer chemotherapy. Curr. Top. Med. Chem., 2004, 4(15), 1623-1635.
[62]
Theerasilp, M. Imidazole-modified deferasirox encapsulated polymeric micelles as pH-responsive iron-chelating nanocarrier for cancer chemotherapy. RSC Advances, 2017, 7(18), 11158-11169.
[63]
Hallaway, P.E.; Eaton, J.W.; Panter, S.S.; Hedlund, B.E. Modulation of deferoxamine toxicity and clearance by covalent attachment to biocompatible polymers. Proc. Natl. Acad. Sci. USA, 1989, 86(24), 10108-10112.
[64]
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(3), 374-381.
[65]
Hamilton, J.L.; Imran Ul-Haq, M.; 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.
[66]
Li, J. Macromolecular iron-chelators via RAFT-polymerization for the inhibition of methicillin-resistant Staphylococcus aureus growth. Polymer (Guildf.), 2016, 87, 64-72.
[67]
Power Coombs, M.R.; Grant, T.; Greenshields, A.L.; Arsenault, D.J.; Holbein, B.E.; Hoskin, D.W. Inhibitory effect of iron withdrawal by chelation on the growth of human and murine mammary carcinoma and fibrosarcoma cells. Exp. Mol. Pathol., 2015, 99(2), 262-270.


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Article Details

VOLUME: 26
ISSUE: 2
Year: 2019
Page: [323 - 334]
Pages: 12
DOI: 10.2174/0929867325666180904104318
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