Regression of Gastric Cancer by Systemic Injection of RNA Nanoparticles Carrying both Ligand and siRNA.

Daxiang Cui,Fangping Dai,Peixuan Guo,Yuming Yang,Chunlei Zhang,Yanlei Liu,Hui Li,Tong Du,Yi Shu,Kan Wang,Dan Shu,Beate Brand-Saberi,Chao Li,Bing Liu,Jian Ni,Fei Pan

doi:10.1038/srep10726

Abstract

Gastric cancer is the second leading cause of cancer-related death worldwide. RNA nanotechnology has recently emerged as an important field due to recent finding of its high thermodynamic stability, favorable and distinctive in vivo attributes. Here we reported the use of the thermostable three-way junction (3WJ) of bacteriophage phi29 motor pRNA to escort folic acid, a fluorescent image marker and BRCAA1 siRNA for targeting, imaging, delivery, gene silencing and regression of gastric cancer in animal models. In vitro assay revealed that the RNA nanoparticles specifically bind to gastric cancer cells, and knock-down the BRCAA1 gene. Apoptosis of gastric cancer cells was observed. Animal trials confirmed that these RNA nanoparticles could be used to image gastric cancer in vivo, while showing little accumulation in crucial organs and tissues. The volume of gastric tumors noticeably decreased during the course of treatment. No damage to important organs by RNA nanoparticles was detectible. All the results indicated that this novel RNA nanotechnology can overcome conventional cancer therapeutic limitations and opens new opportunities for specific delivery of therapeutics to stomach cancer without damaging normal cells and tissues, reduce the toxicity and side effect, improve the therapeutic effect, and exhibit great potential in clinical tumor therapy.

Highlights

Gastric cancer is the second most common cancer in China, and the second leading cause of cancer-related death in the world[1,2]
Our objective is to construct multi-functional, thermodynamically and chemically stable RNA nanoparticles that allow specific binding to stomach cancer specific cell surface antigens or receptors resulting in the internalization of RNA nanoparticles into target cells and delivery of the siRNA, miRNA, and drugs for attaining synergistic effects for the treatment of stomach cancer, we investigated the effects of prepared RNA nanoparticles on the regression of gastric cancer tissues in vivo, and potential molecular mechanism, with the aim of laying foundation for further clinical application in near future
These results show that prepared Folic acid (FA)-packaging RNA (pRNA)-3WJ-BRCAA1 siRNA nanoparticles can induce apoptosis of MGC803 cells

Summary

Introduction

Gastric cancer is the second most common cancer in China, and the second leading cause of cancer-related death in the world[1,2]. Boiling resistant RNA nanoparticles with controllable shapes and defined stoichiometry have recently been reported[36] Various imaging groups, such as fluorophores; targeting ligands, such as receptor binding aptamers; and therapeutic modules, such as siRNA, miRNA or ribozymes can be integrated into the 3WJ scaffold without affecting the folding and functionality of the core motif and incorporated functional moieties[27,30,31,35]. The pRNA nanoparticles are non-toxic, non-immunogenic, and display favorable biodistribution and pharmacokinetic profiles in mice[32] These favorable findings prompted the use of this novel platform for the treatment of stomach cancer, which is one of the challenging tasks in clinical oncology. We confirmed that folic acid receptor exhibited overexpression in gastric cancer MGC803 cells, prepared folic acid-conjugated silica-modified gold nanorods were successfully used for X-ray/CT imaging-guided dual-mode radiation and photothermal therapy of gastric cancer[15]

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