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Brief summary: Speciation analysis for the study of metallodrugs and their biomolecular interactions



Metal-based pharmaceuticals (metallodrugs) have received special attention, because of their biomolecule-analog structure. The central metal ion in metal-based pharmaceuticals is usually the key feature of action and fulfills several tasks:
  • forms the active binding site and influences reactivity,
  • determines the structure of the respective molecule,
  • shows strong structural analogy to naturally occurring metal-based substances ? good pharmacokinetic properties

Metallodrugs can be differentiated into therapeutic and diagnostic agents:
Therapeutic agents:

  • Anti-cancer chemotherapeutica (Pt, Ru, Rh, Ti, Ga, As )
  • Anti-arthritic therapeutica (Au)
  • Anti-diabetes therapeutica (V(V/IV), Cr(III), Mo(VI), W(VI), Zn(II), Cu(II), Mn(III))
  • Anti-viral agents (Au)
  • Anti-bacterial agents (Hg, Ag)
  • Anti-protozoans (Sb, As )
  • Gastrointestinal disorders, stomach ulcer (Bi, Al)
  • Organometallic compounds as photosensitizers for photodynamic therapy

Diagnostic agents:

  • MRI contrast agents (Gd)
  • Radiocontrast agents (Ba, I)
  • Metal-based therapeutic radiopharmaceuticals (Tc )

Chemical analysis is used to:

  • Characterize the agent and its interaction
  • Study its pharmacokinetics and metabolism
  • Investigate its function and site-effects
  • Support pre-clinical and clinical evaluation
  • Optimize and monitor treatment
  • Support chemistry based drug design

NB!: It can be expected that the enhanced information provided by chemical speciation analysis will be valuable for the understanding of the functioning and mechanisms involved, guiding future drug design. 

A well designed sampling strategy is a key to obtaining valuable information.

Fractionation allows to study the distribution of metallodrugs between different compartments, such as:

  • Blood components
  • Low/High molecular components

Time based sampling allows to study the kinetics of the metallodrug with respect to:

  • Excretion via urine and other routes           
  • Hydrolysis and metabolism           
  • Interaction with blood components
  • Distribution within different compartments  

Localized sampling allows to study the distribution with respect to:

  • Distribution between different organs (animal experiments)
  • Distribution between different compartments or regions   

Metal determination can be based on any appropriate technique such as: AAS (ETAAS), ICP-AES, ICP-MS, TXRF.

The obtainable information depends on the applied technique and methodology. Molecular and elemental detection delivers complementary information allowing the identification (ESI-MS) and quantification (ICP-MS) of interactions between metallodrugs  and biomolecules.

Concentration  of the metallodrug in patients blood
scheduled sampling
Pharmacokinetics of the metallodrug in patients blood
time series sampling
Stability/Hydrolysis of the metallodrug
time series sampling
Observation of the interaction of metallodrug with selected blood components
incubation/time series sampling/fractionation
Quantification of metabolites
incubation/time series sampling
Identification of metabolites, identification of binding sites
incubation/time series sampling
Distribution of metallodrugs accross tissues
Element mapping

Related publications reviewing the topic (newest first)

D. Clases, M. Sperling, U. Karst, Analysis of Metal-based Contrast Agents in Medicine and the Environment, Trends Anal. Chem., 104 (2018) 135-147. doi: 10.1016/j.trac.2017.12.011

H.U. Holtkamp, C.G. Hartinger, Advanced metallomics methods in anticancer metallodrug mode of action studies, Trends Anal. Chem., 104 (2018) 110-117. doi: 10.1016/j.trac.2017.09.023

A. Levina, D.C. Crans, P.A. Lay, Speciation of metal drugs, supplements and toxins in media and bodily fluids controls in vitro activities, Coord. Chem. Rev., 352 (2017) 473-498. doi: 10.1016/j.ccr.2017.01.002

José L. Domingo, Mercedes Gómez, Vanadium compounds for the treatment of human diabetes mellitus: A scientific curiosity? A review of thirty years of research, Food Chem. Toxicol., 95 (2016) 137-141. doi: 10.1016/j.fct.2016.07.005

Andrei R. Timerbaev, Role of metallomic strategies in developing ruthenium anticancer drugs, Trends Anal. Chem., 80 (2016) 547–554. doi: 10.1016/j.trac.2016.04.015

Melani Sooriyaarachchi, Thomas T. Morris, Jürgen Gailer, Advanced LC-analysis of human plasma for metallodrug metabolites, Drug Discover. Today, 16 (2015) e24-e30. DOI: 10.1016/j.ddtec.2015.08.001

Yuchuan Wang, Haibo Wang, Hongyan Li and Hongzhe Sun, Metallomic and metalloproteomic strategies in elucidating the molecular mechanisms of metallodrugs, DaltonTrans., 44 (2015) 437-447. doi: 10.1039/c4dt02814g

Katja Dralle Mjos and Chris Orvig, Metallodrugs in Medicinal Inorganic Chemistry, Chem.Rev., 114 (2014) 4540-4563. doi: 10.1021/cr400460s

Sophie Jürgens, Wolfgang A. Herrmann, Fritz E. Kühn, Rhenium and technetium based radiopharmaceuticals: Development and recent advances, J. Organomet. Chem., 751 (2014) 83-89. doi: 10.1016/j.jorganchem.2013.07.042

Charles E. Carraher Jr., Michael R. Roner, Organotin polymers as anticancer and antiviral agents, Journal of Organometallic Chemistry 751 (2014) 67-82. doi: 10.1016/j.jorganchem.2013.05.033

Andrei R. Timerbaev, Recent progress of ICP-MS in the development of metal-based drugs and diagnostic agents, J. Anal. At. Spectrom., 29/6 (2014) 1058-1072. DOI: 10.1039/C3JA50394A

Lena Telgmann, Michael Sperling, Uwe Karst, Determination of gadolinium-based MRI contrast agents in biological and environmental samples: A review, Anal. Chim. Acta, 764 (2013) 1–16. doi: 10.1016/j.aca.2012.12.007

Angela Casini, Jan Reedijk, Interactions of anticancer Pt compounds with proteins: an overlooked topic in medicinal inorganic chemistry?,  Chem. Sci., 3 (2012) 3135-3144. DOI: 10.1039/C2SC20627G 

Angela Casini, Exploring the mechanisms of metal­ based pharmacological agents via an integrated approach, J. Inorg. Biochem., 109 (2012) 97.106. DOI: 10.1016/j.jinorgbio.2011.12.007

Andrei R. Timerbaev, Katarzyna Pawlak, Svetlana S. Aleksenko, Lidia S. Foteeva, Magdalena Matczuk, Maciej Jarosz, Advances of CE-ICP-MS in speciation analysis related to metalloproteomics of anticancer drugs, Talanta, 2012. doi: 10.1016/j.talanta.2012.07.031

Seiji Komeda, Angela Casini, Next-Generation Anticancer Metallodrugs, Curr. Topics Med. Chem., 12/3 (2012) 219-235.

Anna K. Bytzek, Christian G. Hartinger, Capillary electrophoretic methods in the development of metal-based therapeutics and diagnostics: New methodology and applications, Electrophoresis, 33 (2012) 622–634. doi: 10.1002/elps.201100402

Björn Meermann, Michael Sperling, Hyphenated techniques as tools for speciation analysis of metal-based pharmaceuticals: developments and applications, Anal. Bioanal. Chem., 403 (2012) 1501–1522. DOI: 10.1007/s00216-012-5915-9

Dipanjan Pan, Anne H. Schmieder, Samuel A. Wickline, Gregory M. Lanza, Manganese-based MRI contrast agents: past, present, and future, Tetrahedron 67 (2011) 8431-8444. doi: 10.1016/j.tet.2011.07.076

Aviva Levina, Peter A. Lay, Metal-based anti-diabetic drugs: advances and challenges, Dalton Trans., 40 (2011) 11675. DOI: 10.1039/c1dt10380f

Susan J. Berners-Price, Aleksandra Filipovska, Gold compounds as therapeutic agents for human diseases, Metallomics, 2011, 3, 863–873. DOI: 10.1039/c1mt00062d

Bernard Boitrel, Bismuth Complexes of Porphyrins and their Potential in Medical Applications, in: Hongzhe Sun (ed.), Biological Chemistry of Arsenic, Antimony and Bismuth, John Wiley & Sons, 2011, 209-240. DOI: 10.1002/9780470975503.ch9

Ruiguang Ge, Xuesong Sun, Qing-Yu He, Overview of the Metallometabolomic Methodology for Metal-Based Drug Metabolism, Curr. Drug Metab., 12/3 (2011) 287-99.

Marijana Petkovic, Tina Kamceva, FAB, ESI and MALDI Mass Spectrometric methods in the study of metallo-drugs and their biomolecular interactions, Metallomics, 3/6 (2011) 550–565. DOI: 10.1039/c0mt00096e

Seiji Komeda, Unique platinum–DNA interactions may lead to more effective platinum-based antitumor drugs, Metallomics, 3/7 (2011) 650–655. DOI: 10.1039/c1mt00012h

A.R. Timerbaev, K. Pawlak, C. Gabbiani, L. Messori, Recent progress in the application of analytical techniques to anticancer metallodrug proteomics, Trends Anal. Chem., 30/7 (2011) 1120-1138. doi: 10.1016/j.trac.2011.03.007

Jade B. Aitken, Aviva Levina, Peter A. Lay, Studies on the Biotransformations and Biodistributions of Metal-Containing Drugs Using X-Ray Absorption Spectroscopy, Curr. Topics Med. Chem., 11/5 (2011) 553-571. doi: 10.2174/156802611794785217

Eddie L. Chang, Christa Simmers, D. Andrew Knight, Cobalt Complexes as Antiviral and Antibacterial Agents, Pharmaceuticals 2010, 3, 1711-1728; doi:10.3390/ph3061711 

Stefania Nobili, Enrico Mini, Ida Landini, Chiara Gabbiani, Angela Casini, Luigi Messori, Gold Compounds as Anticancer Agents: Chemistry, Cellular Pharmacology, and Preclinical Studies, Med. Res. Rev., 30/3 (2010) 550-580. DOI 10.1002/med.20168

Hiromu Sakurai, Overview and Frontier for the Development of Metallopharmaceutics, J. Health Sci., 56/2 (2010) 129-143. doi: 10.1248/jhs.56.129

Daniel García Sar, María Montes-Bayón, Elisa Blanco-González, Alfredo Sanz-Medel, Quantitative methods for studying DNA interactions with chemotherapeutic cisplatin, Trends Anal. Chem., 29/11 (2010) 1390-1398. doi: 10.1016/j.trac.2010.07.019

Diego Esteban-Fernández, Estefanía Moreno-Gordaliza, Benito Canas, María Antonia Palaciosa, María Milagros Gómez-Gómez, Analytical methodologies for metallomics studies of antitumor Pt-containing drugs, Metallomics, 2/1 (2010) 19–38. DOI: 10.1039/b911438f

Ruiguang Ge, Ivan K. Chu, Hongzhe Sun, Nuclear-based Metallomics in Metal-based Drugs, in:  Chunying Chen, Zhifang Chai, Yuxi Gao (eds.), Nuclear Analytical Techniques for Metallomics and Metalloproteomics, RSC, Cambridge, 2010, 265-298. DOI: 10.1039/9781847559913-00265

Dan Gibson, The mechanism of action of platinum anticancer agents—what do we really know about it?, Dalton Trans., 2009, 10681–10689. DOI: 10.1039/b918871c

Ana M. Pizarro, Peter J. Sadler, Unusual DNA binding modes for metal anticancer complexes, Biochimie, 91 (2009) 1198–1211. doi:10.1016/j.biochi.2009.03.017

Aviva Levina, Anannya Mitra and Peter A. Lay, Recent developments in ruthenium anticancer drugs, Metallomics, 1/6 (2009) 458–470. DOI: 10.1039/b904071d

Xuesong Sun, Cheuk-Nam Tsang, Hongzhe Sun, Identification and characterization of metallodrug binding proteins by (metallo)proteomics, Metallomics, 1/1 (2009) 25–31. DOI: 10.1039/b813121j

Ingo Ott, On the medicinal chemistry of gold complexes as anticancer drugs, Coord. Chem. Rev., 253 (2009) 1670–1681. doi:10.1016/j.ccr.2009.02.019

Constantina Chrysochou, David L. Buckley, Paul Dark, Alistair Cowie, Philip A. Kalra, Gadolinium-Enhanced Magnetic Resonance Imaging for Renovascular Disease and Nephrogenic Systemic Fibrosis: Critical Review of the Literature and UK Experience, J. Magn. Reson. Imaging, 29 (2009) 887–894. DOI 10.1002/jmri.21708

Bente Gammelgaard, Helle Rüsz Hansen, Stefan Stürup, Charlotte Møller, The use of inductively coupled plasma mass spectrometry as a detector in drug metabolism studies, Expert Opin. Drug Metab. Toxicol., 4/9 (2008) 1187-1207. doi: 10.1517/17425255.4.9.1187

R.W.Y. Sun, D.L. Ma, E.L.M. Wong, C.M. Che: Some uses of transition
metal complexes
as anti-cancer and anti-HIV agents,
Dalton Trans.,  2007 (2007) 4884-4892. doi: 10.1039/b705079h

Katherine H. Thompson, Chris Orvig, Vanadium in diabetes: 100 years from Phase 0 to Phase I, J. Inorg. Biochem., 100 (2006) 1925–1935. doi: 10.1016/j.jinorgbio.2006.08.016

Roger Alberto, New Organometallic Technetium Complexes for Radiopharmaceutical Imaging, Top. Curr. Chem., 252 (2005) 1–44. DOI: 10.1007/b101223

Enzo Alessio, Giovanni Mestroni, Alberta Bergamo, Gianni Sava, Ruthenium Antimetastatic Agents, Curr. Top. Med. Chem., 4 (2004) 1525-1535.

Philippe Collery, Bernhard Keppler, Claudie Madoulet, Bernard Desoize, Gallium in cancer treatment, Crit. Rev. Oncol. Hematol., 42/3 (2002) 283–296. doi: 10.1016/S1040-8428(01)00225-6

N. Katsaros, A. Anagnostopoulou, Rhodium and its compounds as potential agents in cancer treatment, Crit. Rev. Oncol. Hematol., 42/3 (2002) 297–308. doi: 10.1016/S1040-8428(01)00222-0

Enrique Meléndez, Titanium complexes in cancer treatment, Crit. Rev. Oncol. Hematol, 42/3 (2002) 309-315. doi: 10.1016/S1040-8428(01)00224-4

Angelos M. Evangelou, Vanadium in cancer treatment, Crit. Rev. Oncol. Hematol., 42 (2002) 249–265. doi: 10.1016/S1040-8428(01)00221-9

Breno Pannia Esposito, Renato Najjar, Interactions of antitumoral platinum-group metallodrugs with albumin, Coord. Chem. Rev., 232 (2002) 137-149. doi: 10.1016/S0010-8545(02)00049-8 

Matthew D. Hall, Trevor W. Hambley, Platinum(IV) antitumour compounds: their bioinorganic chemistry, Coord. Chem. Rev., 232 (2002) 49- 67.  DOI: 10.1016/S0010-8545(02)00026-7

Related EVISA Resources

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Glossary: Metallodrugs
Journal Database: Journals related to Medicinal Chemistry
Journal Database: Journals related to Pharmacology and  Pharmacy
Journal Database: Journals related to Oncology
Journal Database: Journals related to Metallomics
Link Database: Research groups working on metallodrugs
Directory of scientists: Researchers working on metallodrugs

Link page: All about Pharmacy and Pharmaceutical Sciences

Related EVISA News (newest first)

July 2, 2018: Thiomersal in influenza vaccine: more than just an adjuvant
April 10, 2016: New Studies Question Safety of MRI Contrast Agents
August 13, 2015: FDA investigating risk of gadolinium contrast agent brain deposits

March 4, 2015: Detection of Gd-based contrast agent in the skin of a patient eight years after administration
March 4, 2015: Copper molecule shows promise in fighting against cancer
October 29, 2014: Side effects of cisplatin chemotherpy: Platinum speciation matters
September 7, 2014: New study finds relationship between organic mercury exposure from Thimerosal-containing vaccines and neurodevelopmental disorders
Januar 21, 2013: UNEP mercury treaty exempts vaccines for children
October 29, 2012: Identification and quantification of potential metabolites of Gd-based contrast agents

October 18, 2012: The behavior of Gd-based contrast agents during wastewater treatment
June 19, 2012: Vaccine ingredient causes brain damage; some nutrients prevent it
October 28, 2011: WHO worries mercury treaty could affect costs and availability of vaccines
July 22, 2010: Nanoscale Metal-Organic Frameworks (NMOFs): A new way to create better MRI Contrast Agents 

March 25, 2010: Publication on the separation of Gd-based contrast agents awarded
July 15, 2009: New Study Finds: Thimerosal Induces Autism-like Neurotoxicity
May 4, 2009: Gadolinium speciation analysis in search for the cause of nephrogenic systemic fibrosis (NSF)
April 17, 2009: Gadolinium-based MRI contrast agents found intact in the outlet of a waste water treatment plant
December 14, 2008: New study investigates the interaction of thimerosal with proteins 

last time modified: July 13, 2019


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