Efficient delivery of small interfering RNAs targeting particular mRNAs into pancreatic cancer cells inhibits invasiveness and metastasis of pancreatic tumors
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Keisuke Taniuchi1,2, Toshio Yawata3, Makiko Tsuboi1, Tetsuya Ueba3 and Toshiji Saibara1,2
1 Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan
2 Department of Endoscopic Diagnostics and Therapeutics, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan
3 Department of Neurosurgery, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan
Keywords: pancreatic cancer; small interfering RNA; nanoparticles; delivery system; invasion
Received: January 21, 2019 Accepted: April 08, 2019 Published: April 23, 2019
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.
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