Design of Polymeric Iron Chelators for Treating Iron Overload in Cooley's Anemia

1982 ◽  
pp. 107-117 ◽  
Author(s):  
ANTHONY WINSTON ◽  
JAMES ROSTHAUSER ◽  
DAVID FAIR ◽  
JAMSHED BAPASOLA ◽  
WEERASAK LERDTHUSNEE
Keyword(s):  
Iron Overload ◽  
Iron Chelators ◽  
Cooley's Anemia

Therapeutic Macromolecular Iron Chelators

2019 ◽  
Vol 26 (2) ◽  
pp. 323-334 ◽  
Author(s):  
Upendra Bulbake ◽  
Alka Singh ◽  
Abraham J. Domb ◽  
Wahid Khan
Keyword(s):  
Iron Overload ◽  
Chelation Therapy ◽  
Iron Chelator ◽  
Therapeutic Agents ◽  
Iron Chelators ◽  
Low Molecular Weight ◽  
Research Findings ◽  
Pharmaceutical Properties ◽  
Single Living ◽  
Living Process

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.

scholarly journals Treatment of iron overload syndrome: a general review

2019 ◽  
Vol 65 (9) ◽  
pp. 1216-1222 ◽  
Author(s):  
Tadeu Gonçalves de Lima ◽  
Fernanda Luna Neri Benevides ◽  
Flávio Lima Esmeraldo Filho ◽  
Igor Silva Farias ◽  
Diovana Ximenes Cavalcante Dourado ◽  
...  
Keyword(s):  
Life Expectancy ◽  
Oxidative Damage ◽  
Iron Overload ◽  
Hereditary Hemochromatosis ◽  
Treatment Strategies ◽  
Iron Chelators ◽  
Pharmacological Targets ◽  
Pubmed Database ◽  
Toxic Drugs ◽  
Oral Chelators

SUMMARY INTRODUCTION Iron overload is a broad syndrome with a large spectrum of causative etiologies that lead to iron deposition. When iron exceeds defenses, it causes oxidative damage and tissular disfunction. Treatment may prevent organ dysfunction, leading to greater life expectancy. METHODS Literature from the last five years was reviewed through the use of the PubMed database in search of treatment strategies. DISCUSSION Different pharmacological and non-pharmacological strategies are available for the treatment of iron overload and must be used according to etiology and patient compliance. Therapeutic phlebotomy is the basis for the treatment of hereditary hemochromatosis. Transfusional overload patients and those who cannot tolerate phlebotomy need iron chelators. CONCLUSION Advances in the understanding of iron overload have lead to great advances in therapies and new pharmacological targets. Research has lead to better compliance with the use of oral chelators and less toxic drugs.

scholarly journals A Novel Star Like Eight-Arm Polyethylene Glycol-Deferoxamine Conjugate for Iron Overload Therapy

Pharmaceutics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 329
Author(s):  
Bohong Yu ◽  
Yinxian Yang ◽  
Qi Liu ◽  
Aiyan Zhan ◽  
Yang Yang ◽  
...  
Keyword(s):  
Polyethylene Glycol ◽  
Iron Overload ◽  
Iron Chelator ◽  
Iron Chelators ◽  
Iron Binding ◽  
Binding Ability ◽  
Amide Bonds ◽  
Plasma Half Life ◽  
Iron Chelator Deferoxamine

The traditional iron chelator deferoxamine (DFO) has been widely used in the treatment of iron overload disease. However, DFO has congenital disadvantages, including a very short circular time and non-negligible toxicity. Herein, we designed a novel multi-arm conjugate for prolonging DFO duration in vivo and reducing cytotoxicity. The star-like 8-arm-polyethylene glycol (8-arm-PEG) was used as the macromolecular scaffold, and DFO molecules were bound to the terminals of the PEG branches via amide bonds. The conjugates displayed comparable iron binding ability to the free DFO. Furthermore, these macromolecule conjugates could significantly reduce the cytotoxicity of the free DFO, and showed satisfactory iron clearance capability in the iron overloaded macrophage RAW 246.7. The plasma half-life of the 8-arm-PEG-DFO conjugate was about 190 times than that of DFO when applied to an intravenously administered rat model. In conclusion, research indicated that these star-like PEG-based conjugates could be promising candidates as long circulating, less toxic iron chelators.

Iron Chelation by Deferoxamine Induces Autophagy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 117-117 ◽  
Author(s):  
Ivana De Domenico ◽  
Diane McVey Ward ◽  
James P. Kushner ◽  
Jerry Kaplan
Keyword(s):  
Molecular Weight ◽  
Iron Overload ◽  
Iron Chelation ◽  
Iron Chelators ◽  
Immunochemical Analysis ◽  
Alternate Route ◽  
High Affinity ◽  
Secondary Iron Overload ◽  
Proteosomal Degradation ◽  
Permeable Iron

Abstract Deferoxamine (DFO) is a high affinity Fe (III) chelator produced by Streptomyces pilosus that is used clinically to remove systemic iron in secondary iron overload disorders. DFO cannot be absorbed through the intestine and must be injected. As shown previously, De Domenico et al. EMBO J (2006), expression of Ferroportin (Fpn), the only mammalian iron exporter, can deplete cells of ferritin by lowering cytosolic iron and by exporting iron from cells. Fpn-mediated iron loss induces ferritin degradation by the proteosome. In this study we show that permeable iron chelators, desferirax or deferriprone also induce the proteosomal degradation of ferritin. In contrast, DFO-mediated iron chelation at clinically useful concentrations, leads to ferritin degradation in lysosomes. Immunochemical analysis revealed that DFO-treated cells show increased levels of LC3B, a protein required for autophagy, suggesting that DFO induces autophagy. Treatment of cells with desferasirox or deferriprone did not lead to accumulation of LC3B. Studies using high molecular weight conjugates of DFO or inhibitors of endocytosis showed that the presence of DFO in lysosomes was responsible for the induction of autophagy. Incubation of DFO-treated cells with 3-methyladenine, an autophagy inhibitor, does not, however, prevent ferritin loss suggesting there may be an alternate route for ferritin degradation. This hypothesis was confirmed by examining the effect of the proteosome inhibitor, MG132, on DFOinduced autophagy in cells treated with DFO and 3-methyladenine. Addition of MG132 to 3-methyladenine treated cells prevents ferritin degradation. These results indicate that ferritin degradation occurs by two routes: a DFO-induced entry of ferritin into lysosomes and a cytosolic route in which iron is extracted from ferritin prior to degradation by the proteosome.

Significant Impact Of Iron Chelation After Allogeneic Hematopoetic Stem Cell Transplantation On Disease Recurrence: Potential Anti-Leukemic Activity

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 180-180 ◽  
Author(s):  
Mauricette Michallet ◽  
Mohamad Sobh ◽  
Stephane Morisset ◽  
Helene Labussiere ◽  
Marie Y. Detrait ◽  
...  
Keyword(s):  
Stem Cell ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Serum Ferritin Level ◽  
Ferritin Level ◽  
Iron Chelation ◽  
Disease Recurrence ◽  
Hazard Ratio ◽  
Iron Chelators ◽  
Myeloid Leukemias

Abstract Iron overload (IO), primarily related to multiple red blood cell transfusions, is a relatively common complication in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Elevated pre-transplant ferritin level, a surrogate marker of iron overload, was demonstrated to be an important cause of mortality and morbidity in patients who have undergone allo-HSCT. Excessive iron accumulation results in tissue damage and organ failure, mainly as a result of the generation of free radicals that cause oxidative damage and organ dysfunction. Iron chelators have been widely used leading to normalisation for ferritine level and lower IO-related complications. As iron has a fundamental role in cell survival affecting pathways involved in DNA synthesis, cell differentiation, and apoptosis, some studies evaluated the anti-proliferative activity of iron chelators in cancer and leukemia patients on disease recurrence. The objective of this study was to determine at a first time the impact of serum ferritin level measured at time of allogeneic HSCT in adult patients with hematological disorders on the different outcomes and to investigate at a second time the role of iron chelation on relapse incidence. We included 158 patients, 100 males and 58 females with a median age of 45 years (18-67) who underwent allo-HSCT between 2002 and 2010. There were 83 acute myeloid leukemias, 10 chronic myeloid leukemias, 11 myelodysplastic syndromes, 7 myeloproliferative disorders, 19 myelomas, 9 non-Hodgkin lymphomas, 6 Hodgkin diseases, 5 aplastic anemias and 3 hemoglobinopathies. Sixty-seven (42%) patients were sex mismatched (F→M:37; M→F:30); for ABO compatibility, 61% were compatible, 18% had minor incompatibility and 21% had major incompatibility. Concerning the HSCT procedures, 60 patients (38%) received peripheral blood stem cell and 98 (62%) received bone marrow from 97 (61%) HLA related donors [matched, n=76; mismatched, n=21], and 61 (39%) HLA unrelated donors [matched, n=36; mismatched, n=25] after myeloablative [n=64, (41%)] or reduced intensity conditioning [n=94, (59%)]. At transplantation, 91 (58%) were in complete remission (CR) or chronic phase [CR1: n=61 (67%); ≥CR2: n=30 (33%)]. The median serum ferritin level at HSCT was 1327 microg./l (26-14136); 31(20%) patients had a level 26-500, 33 (21%) had a level 500-2500, and 94 (59%) >2500. There was no significant correlation between the different ferritin levels, disease kind and status at HSCT. After transplantation, 23 patients received iron chelating agents after a serum ferritin level of 1000 microg/l and stopped when the level decreased below 1000. The cumulative incidence of acute GVHD ≥ II at 3 months was 14% (11-16.5) with 10.5% (8-13) for grade III and 7% (5-9) for grade IV; the 1 year cumulative incidence of limited and extensive chronic GVHD were 4% (2-6) and 12.4% (9-16) respectively. After a median follow-up of 18 months (1-106), the 5 years OS probability was 65% for patients with ferritin level below 500 microg./l, 39% for level between 500 and 2500 microg./l and 28% for level > 2500 micog./l, [Hazard ratio= 3.5 (1.5-8.1), p=0.002]; this was explained by a significant higher TRM in patients with level >2500 [Hazard ratio= 4.3 (1.02-18), p=0.04]. Interestingly, we found in multivariate analysis that patients receiving iron chelators had significantly better OS [5 years OS= 59% vs. 34% for non-chelated patients, Hazard ratio= 0.34 (0.15-0.76), p=0.008], (Figure 1a), and experienced less disease relapse [5 years relapse incidence= 18% vs. 41% for non-chelated patients, Hazard ratio= 0.22 (0.07-0.73), p=0.012], (Figure 1b). In conclusion, we confirmed the negative impact of iron overload on the outcomes allo-HSCT recipients. More importantly, we demonstrated that iron chelators have a positive impact in reducing disease relapse by the possible mechanism of iron deprivation in leukemic cells. This clinical observation needs to be confirmed by prospective randomized trials.Figure 1a: Overall survival probability and b: relapse incidence in patients with or without iron chelationFigure 1. a: Overall survival probability and b: relapse incidence in patients with or without iron chelation Disclosures: Michallet: Novartis: Honoraria, Research Funding. Nicolini:Novartis: Consultancy, Honoraria, Research Funding.

Impact of Treatment with Iron Chelators in Lower-Risk MDS Patients Participating in the European Leukemianet MDS (EUMDS) Registry

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3186-3186 ◽  
Author(s):  
Saskia Langemeijer ◽  
Louise De Swart ◽  
Ge Yu ◽  
Alex Smith ◽  
Simon Crouch ◽  
...  
Keyword(s):  
Iron Overload ◽  
Treatment Period ◽  
Median Time ◽  
Lower Risk ◽  
Research Funding ◽  
Iron Chelation ◽  
Iron Chelators ◽  
Control Group ◽  
Inclusion Criteria ◽  
National Guidelines

Abstract Background Overall survival (OS) of lower-risk myelodysplastic syndrome (LR-MDS) patients treated with red blood cell transfusions (RBCT) is inferior to that of untransfused patients. RBCTs are associated with iron toxicity. Therefore, many transfused LR-MDS patients receive iron chelation according to (inter)national guidelines. The value of iron chelation in LR-MDS remains unproven. The aim of this study is to assess in a prospective, observational setting the efficacy of iron chelation to counteract the effects of iron overload in LR-MDS. Methods Three iron chelators are available in Europe for treatment of iron overload, but availability varies from country to country. We first assessed the impact of treatment of the 3 iron chelators on survival among the 195 patients treated with iron chelation. Secondly, we developed a model of a contemporary, observational control within the EU-MDS registry of patients who met the inclusion criteria, but who did not receive iron chelation. Results The EUMDS registry has accrued 2084 patients as of July 21, 2016. At this point, 195 patients had received chelation therapy (table). 82 (42%) Patients had died (22 after progressing to AML) and 34 alive patients had progressed to AML. The median time on chelation for all 195 patients was 15 months. Still-living patients had a median time on chelation of 18 months. Of the chelated patients, 149 received deferasirox as the initial chelator, 36 deferoxamine and 10 deferiprone. Treatment duration of the 3 different chelators and the use of the 3 chelators per country is given in table. Twenty patients switched from one chelator to another, but usually the treatment period of the 2nd chelator was short compared to the treatment period of the 1st chelator (data not shown). The Kaplan-Meier estimate showed a significantly better OS for the 149 patients initially treated with deferasirox compared to the 36 patients treated with desferoxamine (log rank p = 0.0021). Multivariate analysis of the 2 groups showed a hazard ratio (HR) of 2.2 (95% CI: 1.3-3.6) and after adjustment a HR of 1.9 (95% CI: 1.1-3.3). We compared the outcome of a non-chelated control group of 573 transfusion dependent patients with 192 chelated patients who achieved one of the following inclusion criteria, recommended to start iron chelation according to (inter)national guidelines: >15 units of RBCT or >1 unit/month during a 6-month period between visits or ferritin >1000 mg/L. Patients were analysed from time of reaching the criteria using receipt of chelation as the time-varying covariate. The unadjusted HRs and 95% CIs were: 1.2 (0.92 - 1.5) and 1.3 (0.95 - 1.7) after adjustment for relevant factors (p = 0.10). The corresponding risk estimates for the analyses restricted to the 149 patients initially treated with deferasirox were 1.5 (1.1 - 2.0) and 1.6 (1.2 - 2.3) respectively (p = 0.006). Interpretation Clinical practice of iron chelation in LR-MDS varied considerably in the 17 European countries participating in the EUMDS Registry. The most frequently used chelator is deferasirox. Use of this chelator varied from 0% to 25% per country. OS was significantly better after treatment with deferasirox when compared to the classical chelator deferoxamine. OS was also significantly better when compared with a large control group of 573 patients, even after adjustment for all relevant prognostic factors. Figure Figure. Disclosures Fenaux: Celgene, Janssen, Novartis, Astex, Teva: Research Funding; Celgene, Novartis, Teva: Honoraria. Symeonidis:Genesis: Honoraria; Roche: Honoraria; Amgen: Honoraria; Takeda: Consultancy, Honoraria. Almeida:Alexion: Speakers Bureau; BMS: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Shire: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Savic:Novo Nordisk: Other: Investigator. de Witte:Incyte: Consultancy; Celgene: Consultancy; Novartis: Honoraria, Research Funding.

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