Functionalization of Osmium Arene Anticancer Complexes with (Poly)arginine: Effect on Cellular Uptake, Internalization, and Cytotoxicity

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• 作者：Sabine H. van Rijt ; Hana Kostrhunova ; Viktor Brabec ; Peter J. Sadler
• 刊名：Bioconjugate Chemistry
• 出版年：2011
• 出版时间：February 16, 2011
• 年：2011
• 卷：22
• 期：2
• 页码：218-226
• 全文大小：934K
• 年卷期：v.22,no.2(February 16, 2011)
• ISSN：1520-4812

文摘

Attaching peptides to metallodrugs may result in improved biological properties of the complexes. The potential use of cell penetrating peptides (CPPs) as cell delivery vectors is attractive, since directed cell uptake of (metallo)drugs remains a major challenge in anticancer drug design. In this work, we report the synthesis of peptide conjugates of the organometallic Os^II anticancer complex [(畏⁶-biphenyl)Os(picolinate)Cl] with different arginine (Arg) chain lengths. Complexes conjugated to Arg₅ or Arg₈ at the 5-position of the picoline ring increase Os uptake into A2780 human ovarian cancer cells by ca. 2脳 and 10脳, respectively, whereas a single Arg had no effect. Furthermore, a 15-fold increase in binding of Os to DNA, a potential target for these complexes, was observed for Arg₈ compared to the Arg₁ conjugate. The Arg₅ and Arg₈ conjugates exhibited fast kinetics of binding to calf thymus DNA and an ability to precipitate DNA at very low concentrations. In serum-free medium, the Arg₈ complex was cytotoxic (IC₅₀ 33 渭M) and appears to be a rare example of a bioactive organometallic peptide conjugate. Experiments on CHO cells deficient in DNA repair suggested that unrepaired DNA damage contributes to the cytotoxicity of the Arg₅ and Arg₈ conjugates. These studies demonstrate the potential for use of cell- and nucleus-penetrating peptides in targeting organometallic arene anticancer complexes.