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Metallomic study on the metabolism of RAPTA-C and cisplatin in cell culture medium and its impact on cell accumulation†
Metallomics ( IF 3.4 ) Pub Date : 2018-02-19 00:00:00 , DOI: 10.1039/c8mt00024g
Hannah U. Holtkamp 1, 2, 3, 4 , Sanam Movassaghi 1, 2, 3, 4 , Stuart J. Morrow 1, 2, 3, 4 , Mario Kubanik 1, 2, 3, 4 , Christian G. Hartinger 1, 2, 3, 4
Affiliation  

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 IC50 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.

中文翻译:

RAPTA-C和顺铂在细胞培养基中的代谢及其对细胞积累的影响的金属学研究

金属基抗癌剂的开发可以通过先进的金属学方法来改进,该方法可以快速有效地筛选金属药物中生物介质中代谢物的含量。体外环境中的细胞蓄积并不总是与细胞毒性相关。蛋白质的结合,特别是与白蛋白和转铁蛋白的结合,可能对金属药物的运输,选择性和功效产生重要影响。我们通过CE-ICP-MS分析对比了顺铂和临床前研究的RAPTA-C的时间依赖性细胞蓄积,这涉及细胞在培养基中的摄取和形态。尽管RAPTA-C的IC 50值比顺铂高40倍,但仍比顺铂高40倍值,随着时间的推移积累仅高10倍。一种经过优化的CE-ICP-MS方法,通过覆盖毛细管来防止蛋白质-毛细管表面相互作用,从而实现了卓越的分离度和金属-蛋白质加合物的鉴定。然后将其与[三(乙酰丙酮基)钴(III)]作为内部标准。发现RAPTA-C对细胞外反应的活性比顺铂高,后者可用于合理化观察到的细胞摄取模式。虽然对于顺铂而言,转铁蛋白和白蛋白均被确定为主要的结合伴侣,但发现RAPTA-C几乎只与白蛋白发生反应。此外,这种行为是时间依赖性的,我们的结果还表明,随着时间的流逝,癌细胞会对细胞培养基中金属种类的分布产生影响。
更新日期:2018-02-19
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