Serum-binding properties of isosteric ruthenium and osmium anticancer agents elucidated by SEC-ICP-MS.

IF 1.7 4区化学 Q3 CHEMISTRY, MULTIDISCIPLINARY

Monatshefte Fur Chemie Pub Date : 2018-01-01 Epub Date: 2018-08-25 DOI:10.1007/s00706-018-2280-1

Matthias H M Klose, Anna Schöberl, Petra Heffeter, Walter Berger, Christian G Hartinger, Gunda Koellensperger, Samuel M Meier-Menches, Bernhard K Keppler

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引用次数: 22

Abstract

Abstract: Size-exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS) was used to study the serum-binding preferences of two metallodrugs with anticancer activities in vivo, namely the organoruthenium compound plecstatin-1 and its isosteric osmium analog. The complexes were administered intraperitoneally into mice bearing a CT-26 tumor. Comparing the total metal content of mouse whole blood and serum underlined that the metallodrugs are mainly located in serum and not in the cellular fraction of the blood samples. In mouse serum, both compounds were not only found to bind extensively to the serum albumin/transferrin fraction but also to immunoglobulins. Free drug was not observed in any of the samples indicating rapid protein binding of the metallodrugs. These findings were validated by spiking human serum with the respective compounds ex vivo. An NCI-60 screen is reported for the osmium analog, which revealed a relative selectivity for cancer cell lines of the ovary and the central nervous system with respect to plecstatin-1. Finally, a COMPARE 170 analysis revealed disruption of DNA synthesis as a possible treatment effect of the osmium-based drug candidate.

Graphical abstract:

Abstract Image

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SEC-ICP-MS阐明了钌和锇抗癌剂的血清结合特性。

摘要：采用尺寸排阻色谱-电感耦合等离子体质谱法（SEC-ICP-MS）研究了两种具有体内抗癌活性的金属药物，即有机钌化合物plecstatin-1及其同位锇类似物的血清结合偏好。将所述复合物腹膜内给予携带CT-26肿瘤的小鼠。比较小鼠全血和血清中的总金属含量，发现金属药物主要存在于血清中，而不存在于血液样品的细胞部分。在小鼠血清中，发现这两种化合物不仅与血清白蛋白/转铁蛋白部分广泛结合，而且与免疫球蛋白广泛结合。在任何样品中都没有观察到游离药物，这表明金属药物的蛋白质快速结合。这些发现通过在人体血清中加入相应的离体化合物得到了验证。报道了锇类似物的NCI-60筛选，其揭示了相对于普乐司他丁-1，卵巢和中枢神经系统的癌症细胞系的相对选择性。最后，COMPARE 170分析显示，DNA合成的破坏可能是锇类候选药物的治疗效果。图形摘要：

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来源期刊

Monatshefte Fur Chemie 化学-化学综合

CiteScore

3.70

自引率

5.60%

发文量

116

审稿时长

3.3 months

期刊介绍： "Monatshefte für Chemie/Chemical Monthly" was originally conceived as an Austrian journal of chemistry. It has evolved into an international journal covering all branches of chemistry. Featuring the most recent advances in research in analytical chemistry, biochemistry, inorganic, medicinal, organic, physical, structural, and theoretical chemistry, Chemical Monthly publishes refereed original papers and a section entitled "Short Communications". Reviews, symposia in print, and issues devoted to special fields will also be considered.