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Synthesis and in vivo anticancer evaluation of poly(organo)phosphazene-based metallodrug conjugates
Dalton Transactions ( IF 4 ) Pub Date : 2017-09-01 00:00:00 , DOI: 10.1039/c7dt01767g
Carmen M. Hackl 1, 2, 3, 4 , Beatrix Schoenhacker-Alte 1, 2, 3, 4, 5 , Matthias H. M. Klose 1, 2, 3, 4 , Helena Henke 4, 6, 7, 8 , Maria S. Legina 1, 2, 3, 4 , Michael A. Jakupec 1, 2, 3, 4, 9 , Walter Berger 4, 5, 10, 11, 12 , Bernhard K. Keppler 1, 2, 3, 4, 9 , Oliver Brüggemann 4, 6, 7, 8 , Ian Teasdale 4, 6, 7, 8 , Petra Heffeter 4, 5, 10, 11, 12 , Wolfgang Kandioller 1, 2, 3, 4, 9
Affiliation  

Within this work we aimed to improve the pharmacodynamics and toxicity profile of organoruthenium and -rhodium complexes which had previously been found to be highly potent in vitro but showed unselective activity in vivo. Different organometallic complexes were attached to a degradable poly(organo)phosphazene macromolecule, prepared via controlled polymerization techniques. The conjugation to hydrophilic polymers was designed to increase the aqueous solubility of the typically poorly soluble metal-based half-sandwich compounds with the aim of a controlled, pH-triggered release of the active metallodrug. The synthesized conjugates and their characteristics have been thoroughly studied by means of 31P NMR and UV-Vis spectroscopy, ICP-MS analyses and SEC coupled to ICP-MS. In order to assess their potential as possible anticancer drug candidates, the complexes, as well as their respective macromolecular prodrug formulations were tested against three different cancer cell lines in cell culture. Subsequently, the anticancer activity and organ distribution of the poly(organo)phosphazene drug conjugates were explored in vivo in mice bearing CT-26 colon carcinoma. Our investigations revealed a beneficial influence of this macromolecular prodrug by a significant reduction of adverse effects compared to the free metallodrugs.

中文翻译:

聚(有机)磷腈基金属药物偶联物的合成及体内抗癌评价

在这项工作中,我们旨在改善有机钌和铑络合物的药效学和毒性谱图,先前发现它们在体外具有很强的作用在体内却表现出非选择性的活性。将不同的有机金属配合物连接到可降解的聚(有机)磷腈大分子上,该分子是通过受控聚合技术制备的。设计成与亲水性聚合物的缀合物以增加通常难溶的基于金属的半夹心化合物的水溶性,目的是控制性地,触发pH值释放活性金属药物。合成的结合物及其特性已通过31种方法进行了深入研究P NMR和UV-Vis光谱,ICP-MS分析以及SEC与ICP-MS耦合。为了评估其潜在的抗癌药物候选物,针对细胞培养物中的三种不同癌细胞系测试了复合物及其各自的大分子前药制剂。随后,在携带CT-26结肠癌的小鼠体内研究了聚(有机)磷腈药物偶联物的抗癌活性和器官分布。我们的研究表明,与游离金属药物相比,这种大分子前药具有显着降低的不良反应的有益影响。
更新日期:2017-09-20
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