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Home ›› About Speciation ›› Speciation News

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

(14.08.2012)

Chemical speciation analysis plays an important role for studying the biological activity, metabolism and side-effects of metal-based pharmaceuticals. It is expected that the enhanced information level provided will also help to guide future drug design.

Metallodrugs

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.

Information
Approach
Technique
Concentration of the metallodrug in patients blood
scheduled sampling
TXRF, ETAAS, ICP-AES, ICP-MS
Pharmacokinetics of the metallodrug in patients blood
time series sampling
TXRF, ETAAS, ICP-AES, ICP-MS
Stability/Hydrolysis of the metallodrug
time series sampling
LC-ICP-MS
CE-ICP-MS
Observation of the interaction of metallodrug with selected blood components
incubation/time series sampling/fractionation
LC-ICP-MS
CE-ICP-MS
LC-ESI-MS
CE-ESI-MS
Quantification of metabolites
incubation/time series sampling
LC-ICP-MS
CE-ICP-MS
Identification of metabolites, identification of binding sites
incubation/time series sampling
LC-ESI-MS
CE-ESI-MS
Distribution of metallodrugs accross tissues
Element mapping
LA-ICP-MS
PIXE
µ-XRF, SR-XRF

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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

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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

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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

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

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