Antitumor Effect of Oleoyl-siRNA against Pancreatic Cancer Using a Portal Vein Infusion Liver-Metastatic Mouse Model

IF 5.4 3区材料科学 Q2 CHEMISTRY, PHYSICAL

ACS Applied Energy Materials Pub Date : 2024-09-16 DOI:10.1021/acs.molpharmaceut.4c00502

Takanori Kubo, Kazuyoshi Yanagihara, Yoshio Nishimura, Yuki Iino, Teruo Komatsu, Rina Tansou, Keichiro Mihara, Toshio Seyama

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Abstract

In this study, we developed an oleoyl-siRNA conjugate in which oleic acid was conjugated at the 5′-end of the sense strand of the siRNA. Furthermore, we examined the effects of RNAi in a mouse model of pancreatic cancer with liver metastasis. The mouse model of pancreatic cancer with liver metastasis was developed by implanting Sui67Luc human pancreatic cancer cells into the portal veins of mice. Sui67Luc cells have high expression of tumor-related genes such as β-catenin, vascular endothelial growth factor, and programmed cell death ligand-1. All genes were knocked down using siRNA, among which siRNA targeting β-catenin exhibited the most suitable RNAi effect. Therefore, we investigated the in vitro RNAi effect of oleoyl-siRNA (Ole-siRNA) targeting the β-catenin gene in Sui67Luc cells and found that it was stronger than that of unmodified siRNA. For in vivo experiments, we investigated the biodistribution, antitumor effect, and change in life expectancy of mice upon systemic administration of Ole-siRNA complexed with Invivofectamine 3.0 (IVF). In terms of biodistribution, the Ole-siRNA/IVF complex likely accumulates in the liver of mice. The antitumor effect of Ole-siRNA in a portal vein infusion liver-metastatic Sui67Luc tumor mouse model was evaluated using an in vivo imaging system. Ole-siRNA had a significant antitumor effect compared with nonmodified siRNA. In addition, mice with metastatic liver Sui67Luc tumors treated with Ole-siRNA showed increased survival. These results suggest that Ole-siRNAs are useful novel RNAi molecules for treating pancreatic cancer and liver metastasis.

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利用门静脉灌注肝转移小鼠模型研究油酰-siRNA 对胰腺癌的抗肿瘤作用

在这项研究中，我们开发了一种油脂酰-siRNA 连接物，其中油酸连接在 siRNA 有义链的 5′端。此外，我们还研究了 RNAi 在肝转移胰腺癌小鼠模型中的效果。胰腺癌肝转移小鼠模型是通过将人胰腺癌细胞 Sui67Luc 植入小鼠门静脉而建立的。Sui67Luc细胞高表达肿瘤相关基因，如β-catenin、血管内皮生长因子和程序性细胞死亡配体-1。我们使用 siRNA 敲除了所有基因，其中靶向 β-catenin 的 siRNA 表现出最合适的 RNAi 效果。因此，我们研究了油酰基 siRNA（Ole-siRNA）在隋67Luc细胞中靶向β-catenin基因的体外 RNAi 效果，发现它比未修饰的 siRNA 更强。在体内实验中，我们研究了小鼠全身给药与 Invivofectamine 3.0（IVF）复合物 Ole-siRNA 后的生物分布、抗肿瘤效果和预期寿命的变化。在生物分布方面，Ole-siRNA/IVF 复合物可能在小鼠肝脏中蓄积。利用体内成像系统评估了 Ole-siRNA 在门静脉输注肝转移性 Sui67Luc 肿瘤小鼠模型中的抗肿瘤效果。与未修饰的 siRNA 相比，Ole-siRNA 具有显著的抗肿瘤效果。此外，接受 Ole-siRNA 治疗的转移性肝脏 Sui67Luc 肿瘤小鼠的存活率也有所提高。这些结果表明，Ole-siRNA 是治疗胰腺癌和肝转移的有用新型 RNAi 分子。

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来源期刊

ACS Applied Energy Materials Materials Science-Materials Chemistry

CiteScore

10.30

自引率

6.20%

发文量

1368

期刊介绍： ACS Applied Energy Materials is an interdisciplinary journal publishing original research covering all aspects of materials, engineering, chemistry, physics and biology relevant to energy conversion and storage. The journal is devoted to reports of new and original experimental and theoretical research of an applied nature that integrate knowledge in the areas of materials, engineering, physics, bioscience, and chemistry into important energy applications.