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Doxorubicin-Loaded PEG-PCL-PEG Micelle Using Xenograft Model of Nude Mice: Effect of Multiple Administration of Micelle on the Suppression of Human Breast Cancer.

Cuong NV, Jiang JL, Li YL, Chen JR, Jwo SC, Hsieh MF - Cancers (Basel) (2010)

Bottom Line: A dose-finding scheme of the polymeric micelle (placebo) showed a safe dose of PEG-PCL-PEG micelles was 71.4 mg/kg in mice.Importantly, the circulation time of DOX-loaded micelles in the plasma significantly increased compared to that of free DOX in rats.Lastly, the tumor growth of human breast cancer cells in nude mice was suppressed by multiple injections (5 mg/kg, three times daily on day 0, 7 and 14) of DOX-loaded micelles as compared to multiple administrations of free DOX.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Chung Yuan Christian University, 200, Chung Pei Rd., Chung Li, Taiwan. mfhsieh@cycu.edu.tw.

ABSTRACT
The triblock copolymer is composed of two identical hydrophilic segments: Monomethoxy poly(ethylene glycol) (mPEG) and one hydrophobic segment poly(ε‑caprolactone) (PCL); which is synthesized by coupling of mPEG-PCL-OH and mPEG‑COOH in a mild condition using dicyclohexylcarbodiimide and 4-dimethylamino pyridine. The amphiphilic block copolymer can self-assemble into nanoscopic micelles to accommodate doxorubixin (DOX) in the hydrophobic core. The physicochemical properties and in vitro tests, including cytotoxicity of the micelles, have been characterized in our previous study. In this study, DOX was encapsulated into micelles with a drug loading content of 8.5%. Confocal microscopy indicated that DOX was internalized into the cytoplasm via endocystosis. A dose-finding scheme of the polymeric micelle (placebo) showed a safe dose of PEG-PCL-PEG micelles was 71.4 mg/kg in mice. Importantly, the circulation time of DOX-loaded micelles in the plasma significantly increased compared to that of free DOX in rats. A biodistribution study displayed that plasma extravasation of DOX in liver and spleen occurred in the first four hours. Lastly, the tumor growth of human breast cancer cells in nude mice was suppressed by multiple injections (5 mg/kg, three times daily on day 0, 7 and 14) of DOX-loaded micelles as compared to multiple administrations of free DOX.

No MeSH data available.


Related in: MedlinePlus

Cytotoxicity of DOX-loaded micelle against MCF-7 cells. The cells were incubated with DOX-loaded micelle (DOX concentration 10 μg/mL) for 2, 24, 48, 72 and 96 h at 37 °C. Each bar represents the mean of five measurements ± S.D. Bar marked with * (p = 0.89) showed no significant difference between 2 h incubation and control. Bars marked with ** (p < 0.001) showed significant difference between 2 h and 24 h and 48 h incubation. *** p > 0.27 as compared to 48 h incubation.
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f5-cancers-03-00061: Cytotoxicity of DOX-loaded micelle against MCF-7 cells. The cells were incubated with DOX-loaded micelle (DOX concentration 10 μg/mL) for 2, 24, 48, 72 and 96 h at 37 °C. Each bar represents the mean of five measurements ± S.D. Bar marked with * (p = 0.89) showed no significant difference between 2 h incubation and control. Bars marked with ** (p < 0.001) showed significant difference between 2 h and 24 h and 48 h incubation. *** p > 0.27 as compared to 48 h incubation.

Mentions: The in vitro cytotoxic effect of DOX-loaded micelle was studied using a tetrazolium dye (MTT assay) in MCF-7 cells. The cell viability was determined by incubating cells in 10 μg/mL DOX for different periods of time. Figure 5 shows the cell viability of MCF-7 treated with DOX-loaded micelle. The cell viability decreased significantly with increased time of treatment (2–96 h). The reason that DOX-loaded micelle did not show cytotoxicity after a 2-h incubation could be attributed to the lag phase of DOX. Similar results were obtained with 3-h incubation of DOX in other formulations [29,30]. However, significant cytotoxicity was observed at 24 h and 48 h. As shown in Figure 4, the cell viability decreased from 98.7% at 2 h to 43.2% and 13.2% at 24 h and 48 h, respectively, compared to control. Similarly, the cell viability was 7.7% and 6.6% for 72 h and 96 h, respectively. These results indicate that the cell viability did not significantly decrease when the treatment time was prolonged, which could be attributed to the sustained effect of DOX-loaded micelle and/or loss of cells. From the above results, we confirmed that the optimal treatment time for cell viability assay of DOX-loaded micelle was approximately 48 h, and prolonging the treatment time did not lead to more cell death.


Doxorubicin-Loaded PEG-PCL-PEG Micelle Using Xenograft Model of Nude Mice: Effect of Multiple Administration of Micelle on the Suppression of Human Breast Cancer.

Cuong NV, Jiang JL, Li YL, Chen JR, Jwo SC, Hsieh MF - Cancers (Basel) (2010)

Cytotoxicity of DOX-loaded micelle against MCF-7 cells. The cells were incubated with DOX-loaded micelle (DOX concentration 10 μg/mL) for 2, 24, 48, 72 and 96 h at 37 °C. Each bar represents the mean of five measurements ± S.D. Bar marked with * (p = 0.89) showed no significant difference between 2 h incubation and control. Bars marked with ** (p < 0.001) showed significant difference between 2 h and 24 h and 48 h incubation. *** p > 0.27 as compared to 48 h incubation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756349&req=5

f5-cancers-03-00061: Cytotoxicity of DOX-loaded micelle against MCF-7 cells. The cells were incubated with DOX-loaded micelle (DOX concentration 10 μg/mL) for 2, 24, 48, 72 and 96 h at 37 °C. Each bar represents the mean of five measurements ± S.D. Bar marked with * (p = 0.89) showed no significant difference between 2 h incubation and control. Bars marked with ** (p < 0.001) showed significant difference between 2 h and 24 h and 48 h incubation. *** p > 0.27 as compared to 48 h incubation.
Mentions: The in vitro cytotoxic effect of DOX-loaded micelle was studied using a tetrazolium dye (MTT assay) in MCF-7 cells. The cell viability was determined by incubating cells in 10 μg/mL DOX for different periods of time. Figure 5 shows the cell viability of MCF-7 treated with DOX-loaded micelle. The cell viability decreased significantly with increased time of treatment (2–96 h). The reason that DOX-loaded micelle did not show cytotoxicity after a 2-h incubation could be attributed to the lag phase of DOX. Similar results were obtained with 3-h incubation of DOX in other formulations [29,30]. However, significant cytotoxicity was observed at 24 h and 48 h. As shown in Figure 4, the cell viability decreased from 98.7% at 2 h to 43.2% and 13.2% at 24 h and 48 h, respectively, compared to control. Similarly, the cell viability was 7.7% and 6.6% for 72 h and 96 h, respectively. These results indicate that the cell viability did not significantly decrease when the treatment time was prolonged, which could be attributed to the sustained effect of DOX-loaded micelle and/or loss of cells. From the above results, we confirmed that the optimal treatment time for cell viability assay of DOX-loaded micelle was approximately 48 h, and prolonging the treatment time did not lead to more cell death.

Bottom Line: A dose-finding scheme of the polymeric micelle (placebo) showed a safe dose of PEG-PCL-PEG micelles was 71.4 mg/kg in mice.Importantly, the circulation time of DOX-loaded micelles in the plasma significantly increased compared to that of free DOX in rats.Lastly, the tumor growth of human breast cancer cells in nude mice was suppressed by multiple injections (5 mg/kg, three times daily on day 0, 7 and 14) of DOX-loaded micelles as compared to multiple administrations of free DOX.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Chung Yuan Christian University, 200, Chung Pei Rd., Chung Li, Taiwan. mfhsieh@cycu.edu.tw.

ABSTRACT
The triblock copolymer is composed of two identical hydrophilic segments: Monomethoxy poly(ethylene glycol) (mPEG) and one hydrophobic segment poly(ε‑caprolactone) (PCL); which is synthesized by coupling of mPEG-PCL-OH and mPEG‑COOH in a mild condition using dicyclohexylcarbodiimide and 4-dimethylamino pyridine. The amphiphilic block copolymer can self-assemble into nanoscopic micelles to accommodate doxorubixin (DOX) in the hydrophobic core. The physicochemical properties and in vitro tests, including cytotoxicity of the micelles, have been characterized in our previous study. In this study, DOX was encapsulated into micelles with a drug loading content of 8.5%. Confocal microscopy indicated that DOX was internalized into the cytoplasm via endocystosis. A dose-finding scheme of the polymeric micelle (placebo) showed a safe dose of PEG-PCL-PEG micelles was 71.4 mg/kg in mice. Importantly, the circulation time of DOX-loaded micelles in the plasma significantly increased compared to that of free DOX in rats. A biodistribution study displayed that plasma extravasation of DOX in liver and spleen occurred in the first four hours. Lastly, the tumor growth of human breast cancer cells in nude mice was suppressed by multiple injections (5 mg/kg, three times daily on day 0, 7 and 14) of DOX-loaded micelles as compared to multiple administrations of free DOX.

No MeSH data available.


Related in: MedlinePlus