Efficient delivery of small interfering RNAs targeting particular mRNAs into pancreatic cancer cells inhibits invasiveness and metastasis of pancreatic tumors
Efficient delivery of small interfering RNAs targeting particular mRNAs into pancreatic cancer cells inhibits invasiveness and metastasis of pancreatic tumors
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DOI：
10.18632/oncotarget.26880
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发表时间：
2019-04
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影响因子：
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通讯作者：
Keisuke Taniuchi;T. Yawata;M. Tsuboi;T. Ueba;T. Saibara
中科院分区：
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作者：
Keisuke Taniuchi;T. Yawata;M. Tsuboi;T. Ueba;T. Saibara
我们报告了针对ARHGEF 4、CCDC 88 A、LAMTOR 2、mTOR、NUP 85和WASF 2的小干扰RNA（siRNA）和叶酸（FA）修饰的聚乙二醇（PEG）-壳寡糖乳酸盐（COL）纳米颗粒在原位异种移植模型中用于靶向、成像、递送、基因沉默以及抑制侵袭和转移的用途。体外试验表明，与永生化的正常胰腺上皮细胞相比，这些siRNA-FA-PEG-COL纳米颗粒特异性地插入胰腺癌细胞中，并敲低胰腺癌细胞中相应靶标的表达。加入靶向siRNA-FA-PEG-COL纳米粒后，细胞运动和侵袭能力明显受到抑制。体内小鼠实验证实，当静脉内递送时，这些siRNA-FA-PEG-COL纳米颗粒被掺入小鼠胰腺肿瘤中的人胰腺癌细胞中。在正常胰腺和重要器官中观察到少量蓄积。所有靶向siRNA-FA-PEG-COL纳米颗粒均显著抑制腹膜后侵袭。与其他纳米颗粒相比，针对LAMTOR 2、mTOR和NUP 85的siRNA-FA-PEG-COL纳米颗粒强烈抑制腹膜后侵袭并显著抑制腹膜播散，改善了小鼠的预后。我们的研究结果表明，针对这六个靶点的siRNA-FA-PEG-COL纳米颗粒可能具有作为可生物降解药物载体的巨大潜力。特别地，针对LAMTOR 2、mTOR和NUP 85的siRNA纳米颗粒可能具有显著的临床前景。
We report the use of small interfering RNAs (siRNAs) against ARHGEF4, CCDC88A, LAMTOR2, mTOR, NUP85, and WASF2 and folic acid (FA)-modified polyethylene glycol (PEG)-chitosan oligosaccharide lactate (COL) nanoparticles for targeting, imaging, delivery, gene silencing, and inhibition of invasiveness and metastasis in an orthotopic xenograft model. In vitro assays revealed that these siRNA-FA-PEG-COL nanoparticles were specifically inserted into pancreatic cancer cells compared to immortalized normal pancreatic epithelial cells and knocked down expression of the corresponding targets in pancreatic cancer cells. Cell motility and invasion were significantly inhibited by adding target siRNA-FA-PEG-COL nanoparticles into the culture medium. In vivo mouse experiments confirmed that when intravenously delivered, these siRNA-FA-PEG-COL nanoparticles became incorporated into human pancreatic cancer cells in mouse pancreatic tumors. Little accumulation was seen in the normal pancreas and vital organs. All target siRNA-FA-PEG-COL nanoparticles significantly inhibited retroperitoneal invasion. The siRNA-FA-PEG-COL nanoparticles against LAMTOR2, mTOR, and NUP85, which strongly inhibited retroperitoneal invasion and significantly inhibited peritoneal dissemination compared to the other nanoparticles, improved prognosis of the mice. Our results imply that siRNA-FA-PEG-COL nanoparticles against these six targets could have great potential as biodegradable drug carriers. In particular, siRNA nanoparticles against LAMTOR2, mTOR, and NUP85 may hold significant clinical promise.