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

中文翻译：

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通过 SEC-ICP-MS 阐明等排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（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及其等排锇类似物）的血清结合偏好。将复合物腹膜内注射到携带 CT-26 肿瘤的小鼠体内。比较小鼠全血和血清的总金属含量强调金属药物主要存在于血清中而不是存在于血液样本的细胞部分中。在小鼠血清中，这两种化合物不仅与血清白蛋白/转铁蛋白部分广泛结合，而且还与免疫球蛋白广泛结合。在任何样品中均未观察到游离药物，这表明金属药物的蛋白质快速结合。这些发现通过在体外掺入相应化合物的人血清得到验证。据报道，针对锇类似物进行了 NCI-60 筛选，结果显示 plecstatin-1 对卵巢和中枢神经系统癌细胞系具有相对选择性。最后，COMPARE 170 分析揭示了 DNA 合成的破坏是基于锇的候选药物的可能治疗效果。

图形概要