{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:28:51Z","timestamp":1787164131706,"version":"build-2736575974"},"reference-count":37,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,20]],"date-time":"2025-12-20T00:00:00Z","timestamp":1766188800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-2022-03625"],"award-info":[{"award-number":["RGPIN-2022-03625"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Babcocks Synthetics Ltd."},{"DOI":"10.13039\/100011858","name":"Concordia University of Edmonton","doi-asserted-by":"publisher","award":["CSG-PROJ-2311-12"],"award-info":[{"award-number":["CSG-PROJ-2311-12"]}],"id":[{"id":"10.13039\/100011858","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Mitacs Globalink"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The most widely used chelating agent, ethylenediaminetetraacetic acid (EDTA), can cause mild to serious side effects when used for clinical applications. Introducing a polyethylene glycol (PEG) moiety into the molecular structure of EDTA has been shown to lower its toxicity; however, it is unclear whether this could affect EDTA chelation efficiency due to the steric hindrance and the loss of a coordination site caused by the PEGylation reaction. This research aimed to determine if PEGylation could reduce EDTA toxicity without affecting its chelation efficiency. To this end, effective formation constants were determined for EDTA and PEG-EDTA rare earth metal ion complexes using spectrophotometric and titrimetric methods. The stability of PEG-EDTA complexes with the target metal ions was assessed under different conditions using Fourier-transform infrared spectroscopy. The cytotoxicity and metal detoxification capacity of EDTA, PEG-EDTA, and their zinc(II) complexes were determined in two selected human cell types exposed to toxic heavy metal ions. This study suggests that PEG-EDTA has lower toxicity than EDTA, especially when complexed with a nontoxic metal ion, such as zinc(II), while only slightly losing chelation efficiency, potentially making PEG-EDTA a more favourable metal detoxification reagent for clinical applications.<\/jats:p>","DOI":"10.3390\/ijms27010044","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T11:30:18Z","timestamp":1766489418000},"page":"44","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Protective Effect of PEG-EDTA and Its Zinc(II) Complex on Human Cells"],"prefix":"10.3390","volume":"27","author":[{"given":"Tashneet","family":"Dhaliwal","sequence":"first","affiliation":[{"name":"Metals in Environment and Health (MEH) Research Cluster, Concordia University of Edmonton, Edmonton, AB T5B 4E4, Canada"},{"name":"Department of Environmental and Physical Sciences, Faculty of Science, Concordia University of Edmonton, Edmonton, AB T5B 4E4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1774-7886","authenticated-orcid":false,"given":"Cole","family":"Babcock","sequence":"additional","affiliation":[{"name":"Metals in Environment and Health (MEH) Research Cluster, Concordia University of Edmonton, Edmonton, AB T5B 4E4, Canada"},{"name":"Department of Environmental and Physical Sciences, Faculty of Science, Concordia University of Edmonton, Edmonton, AB T5B 4E4, Canada"},{"name":"Babcocks Synthetics Ltd., Wainwright, AB T9W 1PS, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brynmar","family":"Degenhardt","sequence":"additional","affiliation":[{"name":"Metals in Environment and Health (MEH) Research Cluster, Concordia University of Edmonton, Edmonton, AB T5B 4E4, Canada"},{"name":"Department of Biological Sciences, Faculty of Science, Concordia University of Edmonton, Edmonton, AB T5B 4E4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac","family":"Osorio Passos","sequence":"additional","affiliation":[{"name":"School of Engineering, Faculty of Nanotechnology Engineering, Universidad Pontificia Bolivariana, Medell\u00edn 050031, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tigran","family":"Stepanyan","sequence":"additional","affiliation":[{"name":"Metals in Environment and Health (MEH) Research Cluster, Concordia University of Edmonton, Edmonton, AB T5B 4E4, Canada"},{"name":"Department of Biological Sciences, Faculty of Science, Concordia University of Edmonton, Edmonton, AB T5B 4E4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7746-5533","authenticated-orcid":false,"given":"Makan","family":"Golizeh","sequence":"additional","affiliation":[{"name":"Metals in Environment and Health (MEH) Research Cluster, Concordia University of Edmonton, Edmonton, AB T5B 4E4, Canada"},{"name":"Department of Environmental and Physical Sciences, Faculty of Science, Concordia University of Edmonton, Edmonton, AB T5B 4E4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3477","DOI":"10.1021\/es9601301","article-title":"Copper Speciation and Binding by Organic Matter in Copper-Contaminated Streamwater","volume":"30","author":"Breault","year":"1996","journal-title":"Environ. Sci. Technol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"120","DOI":"10.15414\/jmbfs.2015.5.2.120-126","article-title":"Evaluating the Efficacy of EDTA, Grapefruit Seed Extract, Lysozyme and Sodium Benzoate Incorporated in Starch-Glycerol Based Antimicrobial Food Packaging Film","volume":"5","author":"Bhatia","year":"2015","journal-title":"J. Microbiol. Biotechnol. Food Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"8274504","DOI":"10.1155\/2016\/8274504","article-title":"Rationale for the Successful Management of EDTA Chelation Therapy in Human Burden by Toxic Metals","volume":"2016","author":"Ferrero","year":"2016","journal-title":"Biomed. Res. Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s40557-015-0085-9","article-title":"Evaluation and Management of Lead Exposure","volume":"27","author":"Kim","year":"2015","journal-title":"Ann. Occup. Environ. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1002\/jbm.a.30076","article-title":"Biodegradable Radiation Delivery System Utilizing Glass Microspheres and Ethylenediaminetetraacetate Chelation Therapy","volume":"70","author":"Conzone","year":"2004","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Seely, D.M., Wu, P., and Mills, E.J. (2005). EDTA Chelation Therapy for Cardiovascular Disease: A Systematic Review. BMC Cardiovasc. Disord., 5.","DOI":"10.1186\/1471-2261-5-32"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"315","DOI":"10.2165\/00063030-200822050-00004","article-title":"The Impact of PEGylation on Biological Therapies","volume":"22","author":"Veronese","year":"2008","journal-title":"BioDrugs"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Georgieva, M., Gospodinova, Z., Keremidarska-Markova, M., Kamenska, T., Gencheva, G., and Krasteva, N. (2021). PEGylated Nanographene Oxide in Combination with Near-Infrared Laser Irradiation as a Smart Nanocarrier in Colon Cancer Targeted Therapy. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13030424"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"26262","DOI":"10.1021\/acsomega.0c04111","article-title":"PEGylation of Polyethylenimine Lowers Acute Toxicity While Retaining Anti-Biofilm and \u03b2-Lactam Potentiation Properties against Antibiotic-Resistant Pathogens","volume":"5","author":"Lam","year":"2020","journal-title":"ACS Omega"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1021\/jm050901o","article-title":"Pegylated Wortmannin and 17-Hydroxywortmannin Conjugates as Phosphoinositide 3-Kinase Inhibitors Active in Human Tumor Xenograft Models","volume":"49","author":"Zhu","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4167","DOI":"10.1002\/jps.21278","article-title":"The Pharmacology of PEGylation: Balancing PD with PK to Generate Novel Therapeutics","volume":"97","author":"Fishburn","year":"2008","journal-title":"J. Pharm. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5269","DOI":"10.1021\/acs.biomac.0c01330","article-title":"Screening and Matching Amphiphilic Cationic Polymers for Efficient Antibiosis","volume":"21","author":"Zhao","year":"2020","journal-title":"Biomacromolecules"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.jconrel.2016.06.040","article-title":"Anti-PEG Antibodies in the Clinic: Current Issues and beyond PEGylation","volume":"244","author":"Zhang","year":"2016","journal-title":"J. Control. Release"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1007\/s002040050238","article-title":"Effect of Lead on Tube Formation by Cultured Human Vascular Endothelial Cells","volume":"69","author":"Kishimoto","year":"1995","journal-title":"Arch. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Anderegg, G. (1977). Critical Survey of Stability Constants of EDTA Complexes. Critical Survey of Stability Constants of EDTA Complexes, Elsevier.","DOI":"10.1016\/B978-0-08-022009-3.50004-0"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"9997","DOI":"10.1002\/chem.201902068","article-title":"Crystal Structures of DOTMA Chelates from Ce3+ to Yb3+: Evidence for a Continuum of Metal Ion Hydration States","volume":"25","author":"Woods","year":"2019","journal-title":"Chem. Eur. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4605","DOI":"10.1021\/la5002336","article-title":"Metal Ion Coordination, Conditional Stability Constants, and Solution Behavior of Chelating Surfactant Metal Complexes","volume":"30","author":"Svanedal","year":"2014","journal-title":"Langmuir"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Muthaiah, S., Bhatia, A., and Kannan, M. (2020). Stability of Metal Complexes. Stability and Applications of Coordination Compounds, IntechOpen.","DOI":"10.5772\/intechopen.90894"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"15975","DOI":"10.1074\/jbc.M800482200","article-title":"Structure-Based Functional Study Reveals Multiple Roles of Transmembrane Segment IX and Loop VIII\u2013IX in NhaA Na+\/H+ Antiporter of Escherichia Coli at Physiological PH","volume":"283","author":"Tzubery","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1111\/j.1442-200X.2012.03733.x","article-title":"Mizoribine Requires Individual Dosing Due to Variation of Bioavailability","volume":"54","author":"Fuke","year":"2012","journal-title":"Pediatr. Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"213809","DOI":"10.1016\/j.ccr.2021.213809","article-title":"EDTA-Based Adsorbents for the Removal of Metal Ions in Wastewater","volume":"434","author":"Zhang","year":"2021","journal-title":"Coord. Chem. Rev."},{"key":"ref_22","first-page":"009","article-title":"Anticancer Potential of EDTA: A Preliminary In Vitro Study","volume":"2","author":"Feril","year":"2017","journal-title":"Mathews J. Cancer Sci."},{"key":"ref_23","first-page":"105","article-title":"Diethylenetriamine Pentaacetic Acid Derivative of Toremifene and In Vitro Evaluation in Human Breast Cancer Cell Line MCF-7","volume":"26","author":"Kilcar","year":"2011","journal-title":"Cancer Biother. Radiopharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1186\/s13287-022-03013-9","article-title":"Oxidative Stress-Induced Endothelial Cells-Derived Exosomes Accelerate Skin Flap Survival through Lnc NEAT1-Mediated Promotion of Endothelial Progenitor Cell Function","volume":"13","author":"Guo","year":"2022","journal-title":"Stem Cell Res. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"47","DOI":"10.2478\/v10102-012-0009-2","article-title":"Toxicity of Lead: A Review with Recent Updates","volume":"5","author":"Flora","year":"2012","journal-title":"Interdiscip. Toxicol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1038\/bjc.2015.133","article-title":"Stress Hormones Reduce the Efficacy of Paclitaxel in Triple Negative Breast Cancer through Induction of DNA Damage","volume":"112","author":"Reeder","year":"2015","journal-title":"Br. J. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1096\/fba.2019-00021","article-title":"Silver Nanoparticles Selectively Treat Triple-negative Breast Cancer Cells without Affecting Non-malignant Breast Epithelial Cells in Vitro and in Vivo","volume":"1","author":"Swanner","year":"2019","journal-title":"FASEB Bioadv."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Balali-Mood, M., Naseri, K., Tahergorabi, Z., Khazdair, M.R., and Sadeghi, M. (2021). Toxic Mechanisms of Five Heavy Metals: Mercury, Lead, Chromium, Cadmium, and Arsenic. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.643972"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"104690","DOI":"10.1016\/j.yrtph.2020.104690","article-title":"Pulmonary Toxicity of Silver Vapours, Nanoparticles and Fine Dusts: A Review","volume":"115","author":"Hadrup","year":"2020","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s00204-024-03903-2","article-title":"Heavy Metals: Toxicity and Human Health Effects","volume":"99","author":"Jomova","year":"2025","journal-title":"Arch. Toxicol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.3390\/ijerph7072745","article-title":"Chelation in Metal Intoxication","volume":"7","author":"Flora","year":"2010","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"106153","DOI":"10.1016\/j.pestbp.2024.106153","article-title":"New Insights into Zinc Alleviating Renal Toxicity of Arsenic-Exposed Carp (Cyprinus Carpio) through YAP-TFR\/ROS Signaling Pathway","volume":"205","author":"Lu","year":"2024","journal-title":"Pestic. Biochem. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"tfad119","DOI":"10.1093\/toxres\/tfad119","article-title":"Selenium and Zinc Supplementation Mitigates Metals-(Loids) Mixture- Mediated Cardiopulmonary Toxicity via Attenuation of Antioxidant, Anti-Inflammatory and Antiapoptotic Mechanisms in Female Sprague Dawley Rats","volume":"13","author":"Antia","year":"2024","journal-title":"Toxicol. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3305","DOI":"10.1166\/jnn.2014.7995","article-title":"Synthesis, Biodistribution, and Imaging of PEGylated-Acetylated Polyamidoamine Dendrimers","volume":"14","author":"Liu","year":"2014","journal-title":"J. Nanosci. Nanotechnol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3033","DOI":"10.1039\/D2SM01698B","article-title":"Charge Shielding Effects of PEG Bound to NH 2 -Terminated PAMAM Dendrimers\u2014An Experimental Approach","volume":"19","author":"Johnston","year":"2023","journal-title":"Soft Matter"},{"key":"ref_36","first-page":"53","article-title":"Spectrophotometric Determination of Zirconium Using Chrome Azurol S (CAS) as a Complexing Agent in Aqueous Streams of Nuclear Fuel Reprocessing","volume":"1","author":"Ganesh","year":"2015","journal-title":"Int. J. Adv. Chem. (IJAC)"},{"key":"ref_37","unstructured":"Smith, R.M., Martell, A.E., and Motekaitis, R.J. (2001). NIST Critically Selected Stability Constants of Metal Complexes, NIST Standard Reference Database 46."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/44\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T11:33:25Z","timestamp":1766489605000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/44"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,20]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["ijms27010044"],"URL":"https:\/\/doi.org\/10.3390\/ijms27010044","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,20]]}}}