Metallomic study on the metabolism of RAPTA-C and cisplatin in cell culture medium and its impact on cell accumulation

Abstract

Metal-based anticancer agent development can be improved with advanced metallomics methods that allow for quick and efficient screening of metallodrugs for their metabolites in biological media. Cellular accumulation in in vitro settings is not always correlated with cytotoxicity; and protein binding, particularly with albumin and transferrin, can have an important influence on metallodrug transportation, selectivity, and efficacy. We contrast the time-dependent cellular accumulation of both cisplatin and the pre-clinically investigated RAPTA-C in terms of cell uptake and speciation in culture medium via CE-ICP-MS analysis. Despite RAPTA-C being administered at 40-fold higher dose than cisplatin, owing to its much higher IC value, the accumulation over time was only 10-fold higher. An optimised CE-ICP-MS method, through the coating of the capillary to prevent protein-capillary surface interactions, resulted in superior resolution and metal-protein adduct identification. It was then used for extracellular speciation in conjunction with [tris(acetylacetonato)cobalt(iii)] as an internal standard. RAPTA-C was found to be more inert to extracellular reactions than cisplatin which could be used to rationalise the observed cellular uptake patterns. While for cisplatin both transferrin and albumin were identified as the main binding partners, RAPTA-C was found to react nearly exclusively with albumin. Moreover, this behaviour was time-dependent and our results also demonstrate that cancer cells have an influence on metal species distribution in the cell culture medium over time.

Recent advances in capillary electrophoresis‐mass spectrometry: Instrumentation, methodology and applications

“…Metallodrug complexes play a major role as pharmaceuticals, especially for cancer treatment. In this context, CE‐ICP‐MS has proved its worth as analytical technique for the characterization of the biodistribution of these drugs, including their binding properties to various biomolecules . For example, Holtkamp et al.…”

“…For example, Holtkamp et al. characterized metabolites of RAPTA‐C and cisplatin in cell culture medium . Interestingly, the amounts of observed protein adducts were affected by the type of cell culture medium.…”

Recent Considerations in the Application of RAPTA‐C for Cancer Treatment and Perspectives for Its Combination with Immunotherapies

“…[6,7] With a view to overcome drug resistance, cisplatin derivatives, for example, oxaliplatin (platinum-ethanedioate-(1R,2R)-1,2-cyclohexanediamine), [8] carboplatin (cis-(1,1-cyclobutane-dicarboxylato) diammineplatinum(II)), [9] or lipoplatin a Food and Drug Administration (FDA)approved liposomal nanoparticle, [10][11][12][13][14][15] were developed and are in clinical use. [28,29] Notably, ruthenium-based compounds have gained attention as some ruthenium compounds have been found to overcome established platinum-resistance pathways, [17][18][19][20][21] and operate via alternative mechanisms to platinum drugs. [28,29] Notably, ruthenium-based compounds have gained attention as some ruthenium compounds have been found to overcome established platinum-resistance pathways, [17][18][19][20][21] and operate via alternative mechanisms to platinum drugs.…”

“…[25,[27][28][29] Furthermore, RAPTA-C in combination with the targeted agent www.advancedsciencenews.com www.advtherap.com erlotinib reduced tumor growth and presented a desirable safety profile. [25,[27][28][29] Furthermore, RAPTA-C in combination with the targeted agent www.advancedsciencenews.com www.advtherap.com erlotinib reduced tumor growth and presented a desirable safety profile.…”

“…With a view to overcome drug resistance, cisplatin derivatives, for example, oxaliplatin (platinum‐ethanedioate‐(1R,2R)‐1,2‐cyclohexanediamine), carboplatin (cis‐(1,1‐cyclobutane‐dicarboxylato) diammineplatinum(II)), or lipoplatin a Food and Drug Administration (FDA)‐approved liposomal nanoparticle, were developed and are in clinical use. The continuous occurrence of side effects limits the efficacy of these derivatives, while alternative approaches focus on the development of new compounds based on platinum(IV) or on other metals that also have relevant pharmacological properties . Notably, ruthenium‐based compounds have gained attention as some ruthenium compounds have been found to overcome established platinum‐resistance pathways, and operate via alternative mechanisms to platinum drugs …”