Côrte-Real Leonor, Brás Ana Rita, Pilon Adhan, Mendes Nuno, Ribeiro Ana Sofia, Martins Tiago D, Farinha José Paulo S, Oliveira M Conceição, Gärtner Fátima, Garcia M Helena, Preto Ana, Valente Andreia
Centro de Química Estrutural, Institute of Molecular Sciences and Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal.
Centre of Molecular and Environmental Biology, Department of Biology, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
Pharmaceutics. 2022 Jun 30;14(7):1388. doi: 10.3390/pharmaceutics14071388.
The need for new therapeutic approaches for triple-negative breast cancer is a clinically relevant problem that needs to be solved. Using a multi-targeting approach to enhance cancer cell uptake, we synthesized a new family of ruthenium(II) organometallic complexes envisaging simultaneous active and passive targeting, using biotin and polylactide (PLA), respectively. All compounds with the general formula, [Ru(η-CpR)(P)(2,2'-bipy-4,4'-PLA-biotin)][CFSO], where R is -H or -CH and P is P(CH), P(CHF) or P(CHOCH), were tested against triple-negative breast cancer cells MDA-MB-231 showing IC values between 2.3-14.6 µM, much better than cisplatin, a classical chemotherapeutic drug, in the same experimental conditions. We selected compound (where R is H and P is P(CH)), for further studies as it was the one showing the best biological effect. In a competitive assay with biotin, we showed that cell uptake via SMVT receptors seems to be the main transport route into the cells for this compound, validating the strategy of including biotin in the design of the compound. The effects of the compound on the hallmarks of cancer show that the compound leads to apoptosis, interferes with proliferation by affecting the formation of cell colonies in a dose-dependent manner and disrupts the cell cytoskeleton. Preliminary in vivo assays in N: NIH(S)II-nu/nu mice show that the concentrations of compound used in this experiment (maximum 4 mg/kg) are safe to use in vivo, although some signs of liver toxicity are already found. In addition, the new compound shows a tendency to control tumor growth, although not significantly. In sum, we showed that compound shows promising anti-cancer effects, bringing a new avenue for triple-negative breast cancer therapy.
三阴性乳腺癌需要新的治疗方法，这是一个亟待解决的临床相关问题。我们采用多靶点方法来增强癌细胞摄取，合成了一类新的钌（II）有机金属配合物，分别利用生物素和聚乳酸（PLA）实现主动和被动靶向。所有通式为[Ru(η-CpR)(P)(2,2'-联吡啶-4,4'-PLA-生物素)][CFSO]的化合物，其中R为-H或-CH，P为P(CH)、P(CHF)或P(CHOCH)，均针对三阴性乳腺癌细胞MDA-MB-231进行了测试，在相同实验条件下，其IC值在2.3至14.6 μM之间，比经典化疗药物顺铂要好得多。我们选择了化合物 （其中R为H且P为P(CH)）进行进一步研究，因为它表现出最佳的生物学效应。在与生物素的竞争性试验中，我们表明通过SMVT受体的细胞摄取似乎是该化合物进入细胞的主要运输途径，这验证了在化合物设计中纳入生物素的策略。该化合物对癌症特征的影响表明，它会导致细胞凋亡，通过以剂量依赖方式影响细胞集落形成来干扰增殖，并破坏细胞细胞骨架。在N:NIH(S)II-nu/nu小鼠中进行的初步体内试验表明，本实验中使用的化合物 浓度（最大4 mg/kg）在体内使用是安全的，尽管已经发现了一些肝毒性迹象。此外，新化合物显示出控制肿瘤生长的趋势，尽管不显著。总之，我们表明化合物 显示出有前景的抗癌效果，为三阴性乳腺癌治疗带来了新途径。
