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CaCO₃/CaIP₆ composite nanoparticles effectively deliver AKT1 small interfering RNA to inhibit human breast cancer growth.

Zhou H, Wei J, Dai Q, Wang L, Luo J, Cheang T, Wang S - Int J Nanomedicine (2015)

Bottom Line: ACC/CaIP6 nanoparticles effectively transfected cells with little or no toxicity.AKT1 knockdown by ACC/CaIP6/siAKT1 inhibited cell cycle progression and promoted apoptosis of MCF-7 cells.ACC/CaIP6 nanoparticles are a safe and efficient method of delivering siRNA for gene therapy in breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurological Intensive Care Unit, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.

ABSTRACT

Background: Small interfering RNA (siRNA)-mediated gene therapy is a promising strategy to temporarily inhibit the expression of genes involved in development of breast cancer. The lack of a safe and efficient gene delivery system has become a major hurdle for siRNA-mediated gene therapy in breast cancer. Our previous studies have demonstrated that inorganic amorphous calcium carbonate (ACC) hybrid nanospheres functionalized with CaIP6 (ACC/CaIP6) nanoparticles are an efficient nucleic acid delivery tool. The present study aimed to evaluate the safety and efficiency of ACC/CaIP6 in delivering siRNA targeting AKT1 (siAKT1) for the treatment of breast cancer.

Methods: The cytotoxicity of the ACC/CaIP6 nanoparticles was evaluated using a tetrazolium assay. The transfection efficiency and intracellular distribution of ACC/siAKT1 were analyzed by flow cytometry and confocal laser scanning microscopy, respectively. A series of in vitro and in vivo assays was performed to evaluate the effects of ACC/CaIP6/siAKT1 on growth of breast cancer cells.

Results: ACC/CaIP6 nanoparticles effectively transfected cells with little or no toxicity. AKT1 knockdown by ACC/CaIP6/siAKT1 inhibited cell cycle progression and promoted apoptosis of MCF-7 cells. Intratumoral injection of ACC/CaIP6/siAKT1 significantly suppressed the growth of breast cancer in mice.

Conclusion: ACC/CaIP6 nanoparticles are a safe and efficient method of delivering siRNA for gene therapy in breast cancer.

No MeSH data available.


Related in: MedlinePlus

Tumor growth in vivo after intratumoral injections of ACC/CaIP6/siAKT1 nanoparticles.Notes: (A) Representative tumors before and after injection. (B) ACC/CaIP6/siAKT1 (20 µg siAKT1/injection, 50:1 mass ratio) was locally injected into the tumors (100 mm3 in volume at 12 days). Tumor diameter was measured using calipers and tumor volume was calculated using the following formula: volume = W2 × L/2, where W is the width of the tumor and L is the tumor length. Results are presented as the mean ± standard deviation (n=7 per group; ***P<0.001 versus other groups). (C) Mean tumor weight (± standard deviation) after mice were sacrificed (n=7 per group; **P<0.01 versus other groups).Abbreviations: ACC, amorphous calcium carbonate; ACC/CaIP6, amorphous calcium carbonate hybrid nanospheres functionalized with a Ca(II)-inositol hexakisphosphate compound; siAKT1, small interfering AKT1.
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f6-ijn-10-4255: Tumor growth in vivo after intratumoral injections of ACC/CaIP6/siAKT1 nanoparticles.Notes: (A) Representative tumors before and after injection. (B) ACC/CaIP6/siAKT1 (20 µg siAKT1/injection, 50:1 mass ratio) was locally injected into the tumors (100 mm3 in volume at 12 days). Tumor diameter was measured using calipers and tumor volume was calculated using the following formula: volume = W2 × L/2, where W is the width of the tumor and L is the tumor length. Results are presented as the mean ± standard deviation (n=7 per group; ***P<0.001 versus other groups). (C) Mean tumor weight (± standard deviation) after mice were sacrificed (n=7 per group; **P<0.01 versus other groups).Abbreviations: ACC, amorphous calcium carbonate; ACC/CaIP6, amorphous calcium carbonate hybrid nanospheres functionalized with a Ca(II)-inositol hexakisphosphate compound; siAKT1, small interfering AKT1.

Mentions: We performed intratumoral injections of ACC/CaIP6/siAKT1 complexes in mice in order to determine whether delivering siAKT1 to MCF-7 tumors with ACC/CaIP6 nanoparticles had therapeutic effects. Athymic mice with MCF-7 xenografts received weekly intratumoral injections of ACC/CaIP6/siAKT1 (20 µg siRNA/injection). Unloaded ACC/CaIP6 nanoparticles and siAKT1 alone were used as negative controls. Real-time quantitative polymerase chain reaction analysis confirmed no significant difference in AKT1 expression in liver samples from each group that had received intratumoral injection with ACC/CaIP6/siAKT1 complexes (Figure S2). Injecting ACC/CaIP6/siAKT1 inhibited tumor growth, while injecting unloaded ACC/CaIP6 nanoparticles or siAKT1 alone did not (Figure 6A and B). Tumor volume did not significantly increase after ACC/CaIP6/siAKT1 treatment, compared with the increased tumor volume observed in the other groups (P<0.0001, Figure 6B). These results show that delivering siAKT1 with ACC/CaIP6 nanoparticles inhibited tumor growth. This is also consistent with previous studies on the role of AKT1 in carcinogenesis.28–31 More importantly, we demonstrate the potential of ACC/CaIP6 nanoparticles for delivering gene vectors in a human breast tumor cell line.


CaCO₃/CaIP₆ composite nanoparticles effectively deliver AKT1 small interfering RNA to inhibit human breast cancer growth.

Zhou H, Wei J, Dai Q, Wang L, Luo J, Cheang T, Wang S - Int J Nanomedicine (2015)

Tumor growth in vivo after intratumoral injections of ACC/CaIP6/siAKT1 nanoparticles.Notes: (A) Representative tumors before and after injection. (B) ACC/CaIP6/siAKT1 (20 µg siAKT1/injection, 50:1 mass ratio) was locally injected into the tumors (100 mm3 in volume at 12 days). Tumor diameter was measured using calipers and tumor volume was calculated using the following formula: volume = W2 × L/2, where W is the width of the tumor and L is the tumor length. Results are presented as the mean ± standard deviation (n=7 per group; ***P<0.001 versus other groups). (C) Mean tumor weight (± standard deviation) after mice were sacrificed (n=7 per group; **P<0.01 versus other groups).Abbreviations: ACC, amorphous calcium carbonate; ACC/CaIP6, amorphous calcium carbonate hybrid nanospheres functionalized with a Ca(II)-inositol hexakisphosphate compound; siAKT1, small interfering AKT1.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494612&req=5

f6-ijn-10-4255: Tumor growth in vivo after intratumoral injections of ACC/CaIP6/siAKT1 nanoparticles.Notes: (A) Representative tumors before and after injection. (B) ACC/CaIP6/siAKT1 (20 µg siAKT1/injection, 50:1 mass ratio) was locally injected into the tumors (100 mm3 in volume at 12 days). Tumor diameter was measured using calipers and tumor volume was calculated using the following formula: volume = W2 × L/2, where W is the width of the tumor and L is the tumor length. Results are presented as the mean ± standard deviation (n=7 per group; ***P<0.001 versus other groups). (C) Mean tumor weight (± standard deviation) after mice were sacrificed (n=7 per group; **P<0.01 versus other groups).Abbreviations: ACC, amorphous calcium carbonate; ACC/CaIP6, amorphous calcium carbonate hybrid nanospheres functionalized with a Ca(II)-inositol hexakisphosphate compound; siAKT1, small interfering AKT1.
Mentions: We performed intratumoral injections of ACC/CaIP6/siAKT1 complexes in mice in order to determine whether delivering siAKT1 to MCF-7 tumors with ACC/CaIP6 nanoparticles had therapeutic effects. Athymic mice with MCF-7 xenografts received weekly intratumoral injections of ACC/CaIP6/siAKT1 (20 µg siRNA/injection). Unloaded ACC/CaIP6 nanoparticles and siAKT1 alone were used as negative controls. Real-time quantitative polymerase chain reaction analysis confirmed no significant difference in AKT1 expression in liver samples from each group that had received intratumoral injection with ACC/CaIP6/siAKT1 complexes (Figure S2). Injecting ACC/CaIP6/siAKT1 inhibited tumor growth, while injecting unloaded ACC/CaIP6 nanoparticles or siAKT1 alone did not (Figure 6A and B). Tumor volume did not significantly increase after ACC/CaIP6/siAKT1 treatment, compared with the increased tumor volume observed in the other groups (P<0.0001, Figure 6B). These results show that delivering siAKT1 with ACC/CaIP6 nanoparticles inhibited tumor growth. This is also consistent with previous studies on the role of AKT1 in carcinogenesis.28–31 More importantly, we demonstrate the potential of ACC/CaIP6 nanoparticles for delivering gene vectors in a human breast tumor cell line.

Bottom Line: ACC/CaIP6 nanoparticles effectively transfected cells with little or no toxicity.AKT1 knockdown by ACC/CaIP6/siAKT1 inhibited cell cycle progression and promoted apoptosis of MCF-7 cells.ACC/CaIP6 nanoparticles are a safe and efficient method of delivering siRNA for gene therapy in breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurological Intensive Care Unit, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.

ABSTRACT

Background: Small interfering RNA (siRNA)-mediated gene therapy is a promising strategy to temporarily inhibit the expression of genes involved in development of breast cancer. The lack of a safe and efficient gene delivery system has become a major hurdle for siRNA-mediated gene therapy in breast cancer. Our previous studies have demonstrated that inorganic amorphous calcium carbonate (ACC) hybrid nanospheres functionalized with CaIP6 (ACC/CaIP6) nanoparticles are an efficient nucleic acid delivery tool. The present study aimed to evaluate the safety and efficiency of ACC/CaIP6 in delivering siRNA targeting AKT1 (siAKT1) for the treatment of breast cancer.

Methods: The cytotoxicity of the ACC/CaIP6 nanoparticles was evaluated using a tetrazolium assay. The transfection efficiency and intracellular distribution of ACC/siAKT1 were analyzed by flow cytometry and confocal laser scanning microscopy, respectively. A series of in vitro and in vivo assays was performed to evaluate the effects of ACC/CaIP6/siAKT1 on growth of breast cancer cells.

Results: ACC/CaIP6 nanoparticles effectively transfected cells with little or no toxicity. AKT1 knockdown by ACC/CaIP6/siAKT1 inhibited cell cycle progression and promoted apoptosis of MCF-7 cells. Intratumoral injection of ACC/CaIP6/siAKT1 significantly suppressed the growth of breast cancer in mice.

Conclusion: ACC/CaIP6 nanoparticles are a safe and efficient method of delivering siRNA for gene therapy in breast cancer.

No MeSH data available.


Related in: MedlinePlus