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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

(a) Representative in vivo fluorescence images of MGC803-tumour-bearing mouse after iv-injected with FA-AlexaFluor647-labeled pRNA nanoparticle. The tumor areas are indicated with arrows. (b) Representative ex vivo images of tumors and organs. Labels: 1, tumor; 2, heart; 3, liver; 4, spleen; 5, lung; 6, Stomach; 7, kidneys; 8, bladder; 9, muscle. (c) The average fluorescence intensities from the tumor areas of post-injection (3 mice per time point). The error bars represent SEM (n = 3).
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f6: (a) Representative in vivo fluorescence images of MGC803-tumour-bearing mouse after iv-injected with FA-AlexaFluor647-labeled pRNA nanoparticle. The tumor areas are indicated with arrows. (b) Representative ex vivo images of tumors and organs. Labels: 1, tumor; 2, heart; 3, liver; 4, spleen; 5, lung; 6, Stomach; 7, kidneys; 8, bladder; 9, muscle. (c) The average fluorescence intensities from the tumor areas of post-injection (3 mice per time point). The error bars represent SEM (n = 3).

Mentions: It has been reported that unmodified siRNA ribonucleic acid sequences have extremely poor pharmacokinetic properties due to short in vivo half-life and fast kidney clearance caused by their small size (hydrodynamic diameters, HDs; typically <5 nm, which is smaller than the kidney filtration threshold (KFT) of 5.5 nm). Tumor targeting efficiency by RNA nanoparticles was investigated by collecting and analyzing in situ fluorescence images of MGC803 xenografts in nude mice at different post-injection (p.i.) time points (Fig. 6a,c). Tumor area was hardly distinguished in the mouse in the first 30 min p.i. because of the strong fluorescence background in normal tissues. However, as the time increased, the decrease in the fluorescence background of normal tissues and the accumulations at the tumor site caused the tumor area became readily defined 5 h p.i.. Ex vivo images of normal tissues, organs, and tumors taken from the RNA nanoparticles-injected mice showed that the tumors taken at 5 and 24 h p.i. exhibited the strongest signal (Fig. 6b). In terms of tumor accumulation kinetics, RNA nanoparticles reached their highest accumulation within 5 h and remained in the tumor site 96 h p.i., which indicted the high tumor targeting efficiency and tumor retention capability of the constructed RNA nanoparticles.


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)

(a) Representative in vivo fluorescence images of MGC803-tumour-bearing mouse after iv-injected with FA-AlexaFluor647-labeled pRNA nanoparticle. The tumor areas are indicated with arrows. (b) Representative ex vivo images of tumors and organs. Labels: 1, tumor; 2, heart; 3, liver; 4, spleen; 5, lung; 6, Stomach; 7, kidneys; 8, bladder; 9, muscle. (c) The average fluorescence intensities from the tumor areas of post-injection (3 mice per time point). The error bars represent SEM (n = 3).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: (a) Representative in vivo fluorescence images of MGC803-tumour-bearing mouse after iv-injected with FA-AlexaFluor647-labeled pRNA nanoparticle. The tumor areas are indicated with arrows. (b) Representative ex vivo images of tumors and organs. Labels: 1, tumor; 2, heart; 3, liver; 4, spleen; 5, lung; 6, Stomach; 7, kidneys; 8, bladder; 9, muscle. (c) The average fluorescence intensities from the tumor areas of post-injection (3 mice per time point). The error bars represent SEM (n = 3).
Mentions: It has been reported that unmodified siRNA ribonucleic acid sequences have extremely poor pharmacokinetic properties due to short in vivo half-life and fast kidney clearance caused by their small size (hydrodynamic diameters, HDs; typically <5 nm, which is smaller than the kidney filtration threshold (KFT) of 5.5 nm). Tumor targeting efficiency by RNA nanoparticles was investigated by collecting and analyzing in situ fluorescence images of MGC803 xenografts in nude mice at different post-injection (p.i.) time points (Fig. 6a,c). Tumor area was hardly distinguished in the mouse in the first 30 min p.i. because of the strong fluorescence background in normal tissues. However, as the time increased, the decrease in the fluorescence background of normal tissues and the accumulations at the tumor site caused the tumor area became readily defined 5 h p.i.. Ex vivo images of normal tissues, organs, and tumors taken from the RNA nanoparticles-injected mice showed that the tumors taken at 5 and 24 h p.i. exhibited the strongest signal (Fig. 6b). In terms of tumor accumulation kinetics, RNA nanoparticles reached their highest accumulation within 5 h and remained in the tumor site 96 h p.i., which indicted the high tumor targeting efficiency and tumor retention capability of the constructed RNA nanoparticles.

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