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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.


Related in: MedlinePlus

Global structure of the therapeutic RNA nanoparticles with BRCAA1 siRNA.(a) Design of the RNA nanoparticles. Left is the one use in animal trial. Right is the extended one to prepare the AFM images. (b) AFM image of extended 3WJ RNA nanoparticles. The RNA complex in left of a is estimated to be around 10 nm. Due to convolution of the tip size (5~10 nm in diameter) in AFM images, features close to the size of the tip cannot be resolved. To characterize the structure of the RNA constructs, the 3WJ nanoparticles were extended by 39–60 base-pairs (in red color), which is within the persistence length of dsRNA and will not affect the 3WJ folding as described before31, to generate the AFM image as shown.
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f1: Global structure of the therapeutic RNA nanoparticles with BRCAA1 siRNA.(a) Design of the RNA nanoparticles. Left is the one use in animal trial. Right is the extended one to prepare the AFM images. (b) AFM image of extended 3WJ RNA nanoparticles. The RNA complex in left of a is estimated to be around 10 nm. Due to convolution of the tip size (5~10 nm in diameter) in AFM images, features close to the size of the tip cannot be resolved. To characterize the structure of the RNA constructs, the 3WJ nanoparticles were extended by 39–60 base-pairs (in red color), which is within the persistence length of dsRNA and will not affect the 3WJ folding as described before31, to generate the AFM image as shown.

Mentions: The pRNA-3WJ nanoparticles were prepared by mixing the three strands a3WJ, b3WJ, and c3WJ respectively, at equal molar ratio (Fig. 1a). The dynamic light scattering (DLS) experiments showed that the size of the nanoparticle is 5.20 ± 0.83 nm in diameter, and the zeta potential is −16.57 ± 0.75 mv, as shown in (supporting data). The effects of pH on the fluorescent intensity and stability of RNA nanoparticles were also investigated. As shown in (supporting data), in the range of pH 2 to 13, RNA nanoparticles exhibited different fluorescent intensity, in the range of pH 5–9, RNA nanoparticles displayed more than 90% strong fluorescent signals. As shown in (supporting data), prepared RNA nanoparticles displayed the identical position on the gel, similar brightness, no degradation, which highly suggest that prepared RNA nanoparticles are very stable in the range of pH 2 to 13.


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)

Global structure of the therapeutic RNA nanoparticles with BRCAA1 siRNA.(a) Design of the RNA nanoparticles. Left is the one use in animal trial. Right is the extended one to prepare the AFM images. (b) AFM image of extended 3WJ RNA nanoparticles. The RNA complex in left of a is estimated to be around 10 nm. Due to convolution of the tip size (5~10 nm in diameter) in AFM images, features close to the size of the tip cannot be resolved. To characterize the structure of the RNA constructs, the 3WJ nanoparticles were extended by 39–60 base-pairs (in red color), which is within the persistence length of dsRNA and will not affect the 3WJ folding as described before31, to generate the AFM image as shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Global structure of the therapeutic RNA nanoparticles with BRCAA1 siRNA.(a) Design of the RNA nanoparticles. Left is the one use in animal trial. Right is the extended one to prepare the AFM images. (b) AFM image of extended 3WJ RNA nanoparticles. The RNA complex in left of a is estimated to be around 10 nm. Due to convolution of the tip size (5~10 nm in diameter) in AFM images, features close to the size of the tip cannot be resolved. To characterize the structure of the RNA constructs, the 3WJ nanoparticles were extended by 39–60 base-pairs (in red color), which is within the persistence length of dsRNA and will not affect the 3WJ folding as described before31, to generate the AFM image as shown.
Mentions: The pRNA-3WJ nanoparticles were prepared by mixing the three strands a3WJ, b3WJ, and c3WJ respectively, at equal molar ratio (Fig. 1a). The dynamic light scattering (DLS) experiments showed that the size of the nanoparticle is 5.20 ± 0.83 nm in diameter, and the zeta potential is −16.57 ± 0.75 mv, as shown in (supporting data). The effects of pH on the fluorescent intensity and stability of RNA nanoparticles were also investigated. As shown in (supporting data), in the range of pH 2 to 13, RNA nanoparticles exhibited different fluorescent intensity, in the range of pH 5–9, RNA nanoparticles displayed more than 90% strong fluorescent signals. As shown in (supporting data), prepared RNA nanoparticles displayed the identical position on the gel, similar brightness, no degradation, which highly suggest that prepared RNA nanoparticles are very stable in the range of pH 2 to 13.

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