Enhancement of therapeutic effect in breast cancer with a steroid-conjugated ruthenium complex
Enhancement of therapeutic effect in breast cancer with a steroid-conjugated ruthenium complex
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类固醇缀合钌络合物增强乳腺癌治疗效果
DOI：
10.1039/c8nj04159h
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发表时间：
2019-02-28
影响因子：
3.3
通讯作者：
Lin, Jianguo
中科院分区：
文献类型：
--
作者：
Lv, Gaochao;Qiu, Ling;Lin, Jianguo
一种新的杂化金属前药Te-S-S-NHC-Ru（Te-S-S-NHC：17-[1，3-双（4-叔丁基苄基）-4-甲基-2，3-二氢-1H-咪唑-双（2-碳酸二乙酯）二硫化物-1H-1，2，3-三唑-1-基]-19-睾酮），以17-乙炔基睾酮为载体，通过靶向基团-药物偶联策略，具有二硫键的杂环卡宾络合物（NHC-Ru）。它可以作为GSH诱导的治疗系统，对各种生物化合物的潜在干扰具有高选择性。研究了新钌配合物的体内外抗癌活性。对孕酮受体阳性MCF-7（PR+）和孕酮受体阴性MBA-MD-231（PR-）人乳腺癌细胞系的MTT测定显示，PR靶向剂的细胞毒性在PR（+）细胞中显著高于PR（-）细胞，这是由于选择性细胞摄取引起的。此外，体内抗肿瘤活性研究表明，Te-S-S-NHC-Ru诱导的肿瘤体积更小，荷瘤小鼠的生存时间更长。因此，Te-S-S-NHC-Ru可能是一种很有前途的基于铼的抗癌剂，用于有效治疗肿瘤。
A new hybrid metallic prodrug Te-S-S-NHC-Ru (Te-S-S-NHC: 17--[1,3-bis(4-(tert-butyl)benzyl)-4-methyl-2,3-dihydro-1H-imidazole-bis(2-diethylcarbonate)disulfide-1H-1,2,3-triazol-1-yl]-19-testosterone) was designed and synthesized by a targeting group-drug conjugate strategy with 17-ethynyl testosterone as the carrier vector to conjugate to our previously reported ruthenium N-heterocyclic carbene complex (NHC-Ru) with a disulfide linkage. It could be applied as a GSH-induced therapeutics system with high selectivity over potential interference by various biological compounds. The anticancer activity of the new ruthenium complex was investigated in vitro and in vivo. MTT assay against progesterone receptor positive MCF-7 (PR+) and progesterone receptor negative MBA-MD-231 (PR-) human breast cancer cell lines revealed that the cytotoxicity of the PR-targeted agent was significantly higher in PR(+) than in PR(-) cells caused by the selective cellular uptake. Moreover, in vivo antitumor activity studies indicated that Te-S-S-NHC-Ru induced a smaller tumor volume and a longer survival time of tumor-bearing mice after treatment. Thus Te-S-S-NHC-Ru may be a promising ruthenium-based anti-cancer agent for the effective treatment of tumors.