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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 matallodrug
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)

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 metal­based 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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Brief summary: GC-ICP-MS
Brief summary: CE-ICP-MS for speciation analysis
Brief summary: ESI-MS: The tool for the identification of species
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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)

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: August 5, 2016


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