Research Center and School of Chemistry and Chemical Engineering, and Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
Research Center and School of Chemistry and Chemical Engineering, and Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
J Inorg Biochem. 2019 Jul;196:110684. doi: 10.1016/j.jinorgbio.2019.03.024. Epub 2019 Mar 30.
Targeted delivery of clinically approved anticancer drug to tumor sites is an effective way to achieve enhanced drug efficacy as well as reduced side effects and toxicity. Here bicalutamide is caged by the Ru(II) center through the nitrile group, and three photoactive Ru(II) complexes were designed and synthesized. Docking study showed that the ruthenium(II) fragments can effectively block the binding of complexes 1-3 with AR (androgen receptor) owing to the large steric structures, thus bicalutamide in complexes 1-3 could not interact with AR-LBD (ligand binding domain). Once irradiation with blue light (465nm), complexes 1-3 can release bicalutamide and anticancer Ru(II) fragments, which possesses dual-action of AR binding and DNA interaction simultaneously. In vitro cytotoxicity study on these complexes further confirmed that complexes 1-3 exhibited considerable cytotoxicity upon irradiation with blue light. Significantly, complex 3 could be activated at 660nm, which greatly increases the scope of complex 3 to treat deeper within tissue. Theoretical calculations showed that the lowest singlet excitation energy of complex 3 is lower than those of complexes 1-2, which explains the experimental results well. Moreover, the MC (metal centered) states of these complexes are more stable than their MLCT (metal to ligand charge transfer) states, indicating that the photoactive processes of these complexes are likely to result in ligand dissociation.
靶向递送至肿瘤部位的临床批准抗癌药物是提高药物疗效、降低副作用和毒性的有效方法。在这里，比卡鲁胺通过腈基被 Ru(II) 中心笼蔽，设计并合成了三种光活性 Ru(II) 配合物。对接研究表明，由于大的空间位阻结构，钌(II) 片段可以有效地阻止配合物 1-3 与 AR（雄激素受体）的结合，因此配合物 1-3 中的比卡鲁胺不能与 AR-LBD（配体结合域）相互作用。一旦用蓝光（465nm）照射，配合物 1-3 可以释放比卡鲁胺和抗癌 Ru(II) 片段，同时具有 AR 结合和 DNA 相互作用的双重作用。对这些配合物的体外细胞毒性研究进一步证实，配合物 1-3 在蓝光照射下表现出相当大的细胞毒性。值得注意的是，配合物 3 可以在 660nm 下被激活，这大大增加了配合物 3 治疗更深组织的范围。理论计算表明，配合物 3 的最低单重激发能低于配合物 1-2，这很好地解释了实验结果。此外，这些配合物的 MC（金属中心）态比它们的 MLCT（金属到配体电荷转移）态更稳定，表明这些配合物的光活性过程可能导致配体解离。
