一种双靶向钌纳米药物，通过 PARP/ATM 通路抑制原发肿瘤生长和肺转移。

A dual-targeting ruthenium nanodrug that inhibits primary tumor growth and lung metastasis via the PARP/ATM pathway.

机构信息

Department of Medicinal Chemistry, College of Pharmaceutical Sciences of Capital Medical University, 10 Xi Tou Tiao, You An Men, Beijing, 100069, People's Republic of China.

Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, Beijing, 100069, People's Republic of China.

出版信息

J Nanobiotechnology. 2021 Apr 23;19(1):115. doi: 10.1186/s12951-021-00799-3.

BACKGROUND

Many studies have found that ruthenium complexes possess unique biochemical characteristics and inhibit tumor growth or metastasis.

RESULTS

Here, we report the novel dual-targeting ruthenium candidate 2b, which has both antitumor and antimetastatic properties and targets tumor sites through the enhanced permeability and retention (EPR) effect and transferrin/transferrin receptor (TF/TFR) interaction. The candidate 2b is composed of ruthenium-complexed carboline acid and four chloride ions. In vitro, 2b triggered DNA cleavage and thus blocked cell cycle progression and induced apoptosis via the PARP/ATM pathway. In vivo, 2b inhibited not only Lewis lung cancer (LLC) tumor growth but also lung metastasis. We detected apoptosis and decreased CD31 expression in tumor tissues, and ruthenium accumulated in the primary tumor tissue of C57BL/6 mice implanted with LLC cells.

CONCLUSIONS

Thus, we conclude that 2b targets tumors, inhibits tumor growth and prevents lung metastasis.

背景

许多研究发现钌配合物具有独特的生化特性，能抑制肿瘤生长或转移。

结果

在这里，我们报告了一种新型的双重靶向钌候选物 2b，它具有抗肿瘤和抗转移特性，通过增强的通透性和保留（EPR）效应以及转铁蛋白/转铁蛋白受体（TF/TFR）相互作用靶向肿瘤部位。候选物 2b 由钌配合的咔啉酸和四个氯离子组成。在体外，2b 引发 DNA 断裂，从而通过 PARP/ATM 途径阻断细胞周期进程并诱导细胞凋亡。在体内，2b 不仅抑制了 Lewis 肺癌（LLC）肿瘤的生长，而且还抑制了肺转移。我们在肿瘤组织中检测到了细胞凋亡和 CD31 表达的减少，并且在植入 LLC 细胞的 C57BL/6 小鼠的原发性肿瘤组织中检测到了钌的积累。