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

Cui D, Zhang C, Liu B, Shu Y, Du T, Shu D, Wang K, Dai F, Liu Y, Li C, Pan F, Yang Y, Ni J, Li H, Brand-Saberi B, Guo P - Sci Rep (2015)

Bottom Line: 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.Apoptosis of gastric cancer cells was observed.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Nano Biomedicine and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of the Ministry of Education, Department of Instrument Science and Engineering, Bio-X center, National Center for Translational Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China.

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.

No MeSH data available.


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The potential mechanism of RNA nanoparticles for gastric cancer therapy.
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f11: The potential mechanism of RNA nanoparticles for gastric cancer therapy.

Mentions: In this study, the results of in vivo evaluation of therapeutic efficacy also showed that the prepared RNA nanoparticles can actively target in vivo gastric cancer tissues and inhibited tumor growth significantly. However, the concrete molecular mechanism is not well understood. In order to investigate the potential molecular mechanism, we used Western Blot to detect the expression level of BRCAA1, Bcl-2, Rb and Bax in MGC803 cells treated with prepared RNA nanoparticles for 24 h and 48 h. As shown in Fig. 10, RNA nanoparticles can down-regulate or silence the expression of BRCAA1 gene, down-regulate the expression of Bcl-2 gene, adversely up-regulate the expression of Rb and Bax genes in MGC803 cells. Based on these results, we proposed a molecular mechanism of RNA nanoparticle induced MGC803 growth inhibition: the prepared RNA nanoparticles (FA-pRNA-3WJ-BRCAA1 siRNA) actively bind to the folic acid receptor on the surface of MGC803 cells via folic acids conjugated on the RNA nanoparticles, and then induce the endocytosis of RNA nanoparticles into tumor cytoplasm. The double-stranded BRCAA1 siRNA region on the RNA nanoparticle can be recognized by RNA-induced silencing complex (RISC) in the cytoplasm and processed. The released siRNA antisense strand can further recognize target BRCAA1 mRNA, degrade it, and result in silence of BRCAA1 gene in MGC80 3 cells. The down regulate or silencing of the BRCAA1 gene will cause subsequent down-regulation of Bcl-2 gene, and further up-regulation of Rb and Bax gene, which will end up with inducing cell apoptosis and inhibiting the cell growth. The proposed mechanism is summarized in Fig. 11 and the concrete study of the regulation signal pathway is under way.


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

Cui D, Zhang C, Liu B, Shu Y, Du T, Shu D, Wang K, Dai F, Liu Y, Li C, Pan F, Yang Y, Ni J, Li H, Brand-Saberi B, Guo P - Sci Rep (2015)

The potential mechanism of RNA nanoparticles for gastric cancer therapy.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490273&req=5

f11: The potential mechanism of RNA nanoparticles for gastric cancer therapy.
Mentions: In this study, the results of in vivo evaluation of therapeutic efficacy also showed that the prepared RNA nanoparticles can actively target in vivo gastric cancer tissues and inhibited tumor growth significantly. However, the concrete molecular mechanism is not well understood. In order to investigate the potential molecular mechanism, we used Western Blot to detect the expression level of BRCAA1, Bcl-2, Rb and Bax in MGC803 cells treated with prepared RNA nanoparticles for 24 h and 48 h. As shown in Fig. 10, RNA nanoparticles can down-regulate or silence the expression of BRCAA1 gene, down-regulate the expression of Bcl-2 gene, adversely up-regulate the expression of Rb and Bax genes in MGC803 cells. Based on these results, we proposed a molecular mechanism of RNA nanoparticle induced MGC803 growth inhibition: the prepared RNA nanoparticles (FA-pRNA-3WJ-BRCAA1 siRNA) actively bind to the folic acid receptor on the surface of MGC803 cells via folic acids conjugated on the RNA nanoparticles, and then induce the endocytosis of RNA nanoparticles into tumor cytoplasm. The double-stranded BRCAA1 siRNA region on the RNA nanoparticle can be recognized by RNA-induced silencing complex (RISC) in the cytoplasm and processed. The released siRNA antisense strand can further recognize target BRCAA1 mRNA, degrade it, and result in silence of BRCAA1 gene in MGC80 3 cells. The down regulate or silencing of the BRCAA1 gene will cause subsequent down-regulation of Bcl-2 gene, and further up-regulation of Rb and Bax gene, which will end up with inducing cell apoptosis and inhibiting the cell growth. The proposed mechanism is summarized in Fig. 11 and the concrete study of the regulation signal pathway is under way.

Bottom Line: 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.Apoptosis of gastric cancer cells was observed.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Nano Biomedicine and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of the Ministry of Education, Department of Instrument Science and Engineering, Bio-X center, National Center for Translational Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China.

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.

No MeSH data available.


Related in: MedlinePlus