Efficient delivery of small interfering RNAs targeting particular mRNAs into pancreatic cancer cells inhibits invasiveness and metastasis of pancreatic tumors
| Autor: | Toshio Yawata, Makiko Tsuboi, Tetsuya Ueba, Keisuke Taniuchi, Toshiji Saibara |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Small interfering RNA Chemistry pancreatic cancer Motility macromolecular substances delivery system invasion medicine.disease small interfering RNA Metastasis 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology In vivo 030220 oncology & carcinogenesis Pancreatic cancer medicine Cancer research Gene silencing nanoparticles Drug carrier PI3K/AKT/mTOR pathway Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.26880 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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