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Multi-Target Inhibition of Cancer Cell Growth by SiRNA Cocktails and 5-Fluorouracil Using Effective Piperidine-Terminated Phosphorus Dendrimers

机译：SiRNA鸡尾酒和5-氟尿嘧啶使用有效的哌啶封端的磷树枝状大分子对癌细胞生长的多目标抑制。

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Currently, RNAi based approaches for cancer treatment involving short double stranded RNA molecules (siRNA) are under vigorous scrutinization. Due to numerous biological obstacles, siRNA delivery into target cells requires protective escort. On the other hand, combining of siRNA-mediated gene silencing and action of conventional chemotherapeutics can propose additional enhancement of anticancer activity. In the present study, we investigated a siRNA cocktail able to downregulate anti-apoptotic genes (BCL-xL, BCL-2, MCL-1) and the chemotherapeutic agent 5-fluorouracil (5-FU) to evaluate multi-target cytotoxic effect on human cervical carcinoma cells (HeLa cell line). Novel phosphorus containing dendrimers of 3rd and 4th generations (namely AE2G3 and AE2G4) with voluminous piperidine terminal cationic groups were designed and tested as siRNA carriers. Dendrimers of both generations showed remarkable ability to bind pro-apoptotic siRNAs and provided 80a??100% siRNA uptake by HeLa cells in the serum containing medium, while the widespread transfection agent Lipofectamine showed only ~40% uptake. SiRNA cocktail (in low concentrations 50 and 100 nM) delivered by AE2G3 dendrimer caused almost complete elimination of cancer cells. We have discovered considerable increase of 5-FU cytotoxic effect by addition of AE2G3/siRNA cocktail complexes in low doses. Thus, we demonstrated the effectiveness of combined multi-target siRNA anticancer approach and described new highly effective serum stable nanomaterial vehicle for gene-based drugs.
机译：目前，基于RNAi的涉及短双链RNA分子（siRNA）的癌症治疗方法正在严格审查中。由于许多生物学障碍，将siRNA递送至靶细胞需要保护性护送。另一方面，将siRNA介导的基因沉默与常规化学疗法的作用相结合，可以进一步增强抗癌活性。在本研究中，我们研究了一种能够下调抗凋亡基因（BCL-xL，BCL-2，MCL-1）和化学治疗剂5-氟尿嘧啶（5-FU）的siRNA混合物，以评估对它的多靶细胞毒性作用人宫颈癌细胞（HeLa细胞系）。设计并测试了具有大量哌啶末端阳离子基团的第三和第四代新型含磷树枝状大分子（即AE2G3和AE2G4），并作为siRNA载体进行了测试。两代树状聚合物均显示出显着的结合促凋亡siRNA的能力，并在含血清的血清中被HeLa细胞摄取80a ?? 100％的siRNA，而广泛的转染剂Lipofectamine仅摄取了约40％。 AE2G3树枝状大分子传递的SiRNA混合物（低浓度50和100 nM）导致癌细胞几乎完全消除。我们发现通过低剂量添加AE2G3 / siRNA鸡尾酒复合物可以显着提高5-FU细胞毒性作用。因此，我们证明了多靶点siRNA联合抗癌方法的有效性，并描述了基于基因药物的新型高效血清稳定纳米材料载体。

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