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Special Issue "Advances on Chelation in Medicine"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: 30 June 2020.

Special Issue Editor

Prof. Dr. George J. Kontoghiorghes
Website
Guest Editor
Postgraduate Research Institute of Science, Technology, Environment and Medicine, CY-3021 Limassol, Cyprus
Interests: drug design development and clinical use; orphan drugs; orphan diseases; drug risk/benefit assessment; drug targeting; drug clinical protocol design; drug interactions; chelation therapies; metal complex therapies; antioxidant therapies; ADMET properties
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue aims to present the current state of knowledge and new developments in the clinical use, application and effects of chelating drugs. Many areas are covered, including the use of chelating drugs for metal detoxification, as antioxidants, anticancer and anti-infective agents, and as modulators of protein function or pathways associated with disease. In addition, we will cover the use of chelator–metal complexes for increasing essential metal absorption; in clinical diagnosis, e.g., Tc and Gd complexes; as anticancer agents, e.g., Pt, Cu and Ga complexes. Important areas also include recent advances on the molecular, pharmacological, toxicological and other properties of chelating drugs, as well as new mechanisms of action, posology and interactions with other drugs. Such information is pivotal for designing therapeutic strategies for the effective treatment of millions of patients with many diseases such as thalassaemia, cancer and neurodegenerative diseases. It is envisaged that chelation in multifactorial diseases can play a major role and be used as a main, alternative or adjuvant therapy. In this context, improved therapeutic strategies could be developed and adopted based on combination therapies, target-specific and prodrug design methods and other aspects that can fulfil personalised medicine characteristics.

Prof. George J. Kontoghiorghes
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • chelation therapy
  • metal detoxification
  • chelator antioxidants
  • chelator–metal complex applications
  • chelating drug effects
  • deferiprone
  • deferoxamine
  • deferasirox
  • mimosine
  • maltol iron treatments
  • EDTA
  • DTPA
  • penicillamine
  • triethylenetetramine
  • dexrazoxane
  • iron overload treatment
  • thalassaemia treatment
  • iron deficiency treatment
  • iron metabolic disorders treatment
  • copper overload treatment
  • heavy metal detoxification
  • cancer treatment
  • neurodegenerative disease treatment
  • tissue damage treatment
  • kidney disease treatment
  • ischaemia/reperfusion injury treatment
  • antimicrobial treatments
  • mitochondrial disease treatment
  • ageing treatment

Published Papers (5 papers)

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Editorial

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Open AccessEditorial
Advances on Chelation and Chelator Metal Complexes in Medicine
Int. J. Mol. Sci. 2020, 21(7), 2499; https://doi.org/10.3390/ijms21072499 - 03 Apr 2020
Abstract
Metal ions such as iron, copper and zinc are essential for life [...] Full article
(This article belongs to the Special Issue Advances on Chelation in Medicine)
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Research

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Open AccessArticle
Manipulating the In Vivo Behaviour of 68Ga with Tris(Hydroxypyridinone) Chelators: Pretargeting and Blood Clearance
Int. J. Mol. Sci. 2020, 21(4), 1496; https://doi.org/10.3390/ijms21041496 - 22 Feb 2020
Abstract
Pretargeting is widely explored in immunoPET as a strategy to reduce radiation exposure of non-target organs and allow the use of short-lived radionuclides that would not otherwise be compatible with the slow pharmacokinetic profiles of antibodies. Here we investigate a pretargeting strategy based [...] Read more.
Pretargeting is widely explored in immunoPET as a strategy to reduce radiation exposure of non-target organs and allow the use of short-lived radionuclides that would not otherwise be compatible with the slow pharmacokinetic profiles of antibodies. Here we investigate a pretargeting strategy based on gallium-68 and the chelator THPMe as a high-affinity pair capable of combining in vivo. After confirming the ability of THPMe to bind 68Ga in vivo at low concentrations, the bifunctional THPMe-NCS was conjugated to a humanised huA33 antibody targeting the A33 glycoprotein. Imaging experiments performed in nude mice bearing A33-positive SW1222 colorectal cancer xenografts compared pretargeting (100 μg of THPMe-NCS-huA33, followed after 24 h by 8–10 MBq of 68Ga3+) with both a directly labelled radioimmunoconjugate (89Zr-DFO-NCS-huA33, 88 μg, 7 MBq) and a 68Ga-only negative control (8–10 MBq of 68Ga3+). Imaging was performed 25 h after antibody administration (1 h after 68Ga3+ administration for negative control). No difference between pretargeting and the negative control was observed, suggesting that pretargeting via metal chelation is not feasible using this model. However, significant accumulation of “unchelated” 68Ga3+ in the tumour was found (12.9 %ID/g) even without prior administration of THPMe-NCS-huA33, though tumour-to-background contrast was impaired by residual activity in the blood. Therefore, the 68Ga-only experiment was repeated using THPMe (20 μg, 1 h after 68Ga3+ administration) to clear circulating 68Ga3+, producing a three-fold improvement of the tumour-to-blood activity concentration ratio. Although preliminary, these results highlight the potential of THPMe as a 68Ga clearing agent in imaging applications with gallium citrate. Full article
(This article belongs to the Special Issue Advances on Chelation in Medicine)
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Open AccessArticle
Associative Interactions among Zinc, Apolipoprotein E, and Amyloid-β in the Amyloid Pathology
Int. J. Mol. Sci. 2020, 21(3), 802; https://doi.org/10.3390/ijms21030802 - 25 Jan 2020
Abstract
Zinc and apolipoprotein E (apoE) are reportedly involved in the pathology of Alzheimer’s disease. To investigate the associative interaction among zinc, apoE, and amyloid-β (Aβ) and its role in amyloid pathogenesis, we performed various biochemical and immunoreactive analyses using brain tissues of Tg2576 [...] Read more.
Zinc and apolipoprotein E (apoE) are reportedly involved in the pathology of Alzheimer’s disease. To investigate the associative interaction among zinc, apoE, and amyloid-β (Aβ) and its role in amyloid pathogenesis, we performed various biochemical and immunoreactive analyses using brain tissues of Tg2576 mice and synthetic Aβ and apoE peptides. On amyloid plaques or in brain lysates of Tg2576 mice, apoE and Aβ immunoreactivities increased after zinc chelation and were restored by its subsequent replacement. Zinc depletion dissociated apoE/Aβ complexes or larger-molecular sizes of Aβ oligomers/aggregates into smaller-molecular sizes of apoE and/or Aβ monomers/complexes. In the presence of zinc, synthetic apoE and/or Aβ peptides aggregated into larger-molecular sizes of oligomers or complexes. Endogenous proteases or plasmin in brain lysates degraded apoE and/or Aβ complexes, and their proteolytic activity increased with zinc depletion. These biochemical findings suggest that zinc associates with apoE and Aβ to encourage the formation of apoE/Aβ complexes or large aggregates, raising the deposition of zinc-rich amyloid plaques. In turn, the presence of abundant zinc around and within apoE/Aβ complexes may block the access or activity of Aβ-degrading antibodies or proteases. These results support the plausibility of chelation strategy aiming at reducing amyloid pathology in Alzheimer’s disease. Full article
(This article belongs to the Special Issue Advances on Chelation in Medicine)
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Open AccessArticle
Deferoxamine Enhanced Mitochondrial Iron Accumulation and Promoted Cell Migration in Triple-Negative MDA-MB-231 Breast Cancer Cells Via a ROS-Dependent Mechanism
Int. J. Mol. Sci. 2019, 20(19), 4952; https://doi.org/10.3390/ijms20194952 - 08 Oct 2019
Cited by 2
Abstract
In our previous study, Deferoxamine (DFO) increased the iron concentration by upregulating the expression levels of TfR1 and DMT1 and exacerbated the migration of triple-negative breast cancer cells. However, the mechanisms of iron distribution and utilization in triple-negative breast cancer cells with a [...] Read more.
In our previous study, Deferoxamine (DFO) increased the iron concentration by upregulating the expression levels of TfR1 and DMT1 and exacerbated the migration of triple-negative breast cancer cells. However, the mechanisms of iron distribution and utilization in triple-negative breast cancer cells with a DFO-induced iron deficiency are still unclear. In this study, triple-negative MDA-MB-231 and estrogen receptor (ER)-positive MCF-7 breast cancer cells were used to investigate the mechanisms of iron distribution and utilization with a DFO-induced iron deficiency. We found that the mitochondrial iron concentration was elevated in MDA-MB-231 cells, while it was decreased in MCF-7 cells after DFO treatment. The cellular and mitochondrial reactive oxygen species (ROS) levels increased in both breast cancer cell types under DFO-induced iron-deficient conditions. However, the increased ROS levels had different effects on the different breast cancer cell types: Cell viability was inhibited and apoptosis was enhanced in MCF-7 cells, but cell viability was maintained and cell migration was promoted in MDA-MB-231 cells through the ROS/NF-κB and ROS/TGF-β signaling pathways. Collectively, this study suggests that under DFO-induced iron-deficient conditions, the increased mitochondrial iron levels in triple-negative MDA-MB-231 breast cancer cells would generate large amounts of ROS to activate the NF-κB and TGF-β signaling pathways to promote cell migration. Full article
(This article belongs to the Special Issue Advances on Chelation in Medicine)
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Review

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Open AccessReview
Current Biomedical Use of Copper Chelation Therapy
Int. J. Mol. Sci. 2020, 21(3), 1069; https://doi.org/10.3390/ijms21031069 - 06 Feb 2020
Abstract
Copper is an essential microelement that plays an important role in a wide variety of biological processes. Copper concentration has to be finely regulated, as any imbalance in its homeostasis can induce abnormalities. In particular, excess copper plays an important role in the [...] Read more.
Copper is an essential microelement that plays an important role in a wide variety of biological processes. Copper concentration has to be finely regulated, as any imbalance in its homeostasis can induce abnormalities. In particular, excess copper plays an important role in the etiopathogenesis of the genetic disease Wilson’s syndrome, in neurological and neurodegenerative pathologies such as Alzheimer’s and Parkinson’s diseases, in idiopathic pulmonary fibrosis, in diabetes, and in several forms of cancer. Copper chelating agents are among the most promising tools to keep copper concentration at physiological levels. In this review, we focus on the most relevant compounds experimentally and clinically evaluated for their ability to counteract copper homeostasis deregulation. In particular, we provide a general overview of the main disorders characterized by a pathological increase in copper levels, summarizing the principal copper chelating therapies adopted in clinical trials. Full article
(This article belongs to the Special Issue Advances on Chelation in Medicine)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Current biomedical use of copper chelation threrapy
Authors: Gabriele Toietta; et al.

Title: EDTA chelation therapy in the treatment of neurodegenerative diseases: an update
Authors: Maria Elena Ferrero; et al.

Title: Manipulating the in vivo behaviour of radiometals with chelators, from pretargeting to clearance agents
Authors: Cinzia Imberti; et al.

Title: Discovery of 3-hydroxyquinazoline-2,4(1H,3H)-dione Derivatives:
A Series of Metal Ions Chelators with Potent Anti-HCV Activities
Authors: Yang Cao; et al.

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