Title:Application of a Novel Metallomics Tool to Probe the Fate of Metal-Based Anticancer Drugs in Blood Plasma: Potential, Challenges and Prospects
Volume: 21
Issue: 1
Author(s): Sophia Sarpong-Kumankomah and Jürgen Gailer*
Affiliation:
- Department of Chemistry, Faculty of Science, University of Calgary, Calgary,Canada
Keywords:
Metal-based drugs, Combination therapy, Bimetallic complexes, Biotransformation, Safety, Side-effects, Metallomics,
Drug development.
Abstract: Although metallodrugs are used to treat a variety of human disorders and exhibit a remarkable
diversity of therapeutic properties, they constitute only a tiny minority of all medicinal drugs that
are currently on the market. This undesirable situation must be partially attributed to our general lack of
understanding the fate of metallodrugs in the extremely ligand-rich environment of the bloodstream. The
challenge of gaining insight into these bioinorganic processes can be overcome by the application of
‘metallomics tools’, which involve the analysis of biological fluids (e.g., blood plasma) with a separation
method in conjunction with multi-element specific detectors. To this end, we have developed a metallomics
tool that is based on size-exclusion chromatography (SEC) hyphenated to an inductively coupled
plasma atomic emission spectrometer (ICP-AES). After the successful application of SEC-ICPAES
to analyze plasma for endogenous copper, iron and zinc-metalloproteins, it was subsequently applied
to probe the metabolism of a variety of metal-based anticancer drugs in plasma. The versatility of
this metallomics tool is exemplified by the fact that it has provided insight into the metabolism of individual
Pt-based drugs, the modulation of the metabolism of cisplatin by sulfur-containing compounds,
the metabolism of two metal-based drugs that contain different metals as well as a bimetallic anticancer
drug, which contained two different metals. After adding pharmacologically relevant doses of metallodrugs
to plasma, the temporal analysis of aliquots by SEC-ICP-AES allows to observe metal-protein
adducts, metallodrug-derived degradation products and the parent metallodrug(s). This unique capability
allows to obtain comprehensive insight into the fate of metal-based drugs in plasma and can be extended
to in vivo studies. Thus, the application of this metallomics tool to probe the fate of novel metalcomplexes
that exert the desired biological activity in plasma has the potential to advance more of these
to animal/preclinical studies to fully explore the potential that metallodrugs inherently offer.
