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Doxorubicin-poly (ethylene glycol)-alendronate self-assembled micelles for targeted therapy of bone metastatic cancer.

Ye WL, Zhao YP, Li HQ, Na R, Li F, Mei QB, Zhao MG, Zhou SY - Sci Rep (2015)

Bottom Line: In pH 5.0 phosphate buffer solution (PBS), the micelle released DOX significantly faster than in pH 7.4 PBS.Finally, DOX loaded DOX-hyd-PEG-ALN micelle effectively delayed the tumor growth, decreased the bone loss and reduced the cardiac toxicity in tumor-bearing nude mice as compared with free DOX.In conclusion, DOX loaded DOX-hyd-PEG-ALN micelle had potential in treating bone metastatic tumor.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China.

ABSTRACT
In order to increase the therapeutic effect of doxorubicin (DOX) on bone metastases, a multifunctional micelle was developed by combining pH-sensitive characteristics with bone active targeting capacity. The DOX loaded micelle was self-assembled by using doxorubicin-poly (ethylene glycol)-alendronate (DOX-hyd-PEG-ALN) as an amphiphilic material. The size and drug loading of DOX loaded DOX-hyd-PEG-ALN micelle was 114 nm and 24.3%. In pH 5.0 phosphate buffer solution (PBS), the micelle released DOX significantly faster than in pH 7.4 PBS. In addition, with the increase of incubation time, more red DOX fluorescence was observed in tumor cells and trafficked from cytoplasm to nucleus. The IC50 of DOX loaded DOX-hyd-PEG-ALN micelle on A549 cells was obviously lower than that of free DOX in 48 h. Furthermore, the in vivo image experimental results indicated that a larger amount of DOX was accumulated in the bone metastatic tumor tissue after DOX loaded DOX-hyd-PEG-ALN micelle was intravenously administered, which was confirmed by histological analysis. Finally, DOX loaded DOX-hyd-PEG-ALN micelle effectively delayed the tumor growth, decreased the bone loss and reduced the cardiac toxicity in tumor-bearing nude mice as compared with free DOX. In conclusion, DOX loaded DOX-hyd-PEG-ALN micelle had potential in treating bone metastatic tumor.

No MeSH data available.


Related in: MedlinePlus

Tissue distribution of DOX detected by living image system (A) and distribution of DOX in the tumor tissue section detected by CLSM (C) at 24 h after free DOX (5 mg/kg) and DOX loaded DOX-hyd-PEG-ALN micelles (equivalent dose of DOX: 5 mg/kg) was intravenously administered to tumor-bearing nude mice. Quantitative analysis of in-Vivo Images (B, *P < 0.05 vs DOX in the same organ tissue) and CLSM images (D, *P < 0.05 vs DOX). Data are presented as the average ± standard deviation.
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f11: Tissue distribution of DOX detected by living image system (A) and distribution of DOX in the tumor tissue section detected by CLSM (C) at 24 h after free DOX (5 mg/kg) and DOX loaded DOX-hyd-PEG-ALN micelles (equivalent dose of DOX: 5 mg/kg) was intravenously administered to tumor-bearing nude mice. Quantitative analysis of in-Vivo Images (B, *P < 0.05 vs DOX in the same organ tissue) and CLSM images (D, *P < 0.05 vs DOX). Data are presented as the average ± standard deviation.

Mentions: To further verify the active targeting capability of the DOX loaded DOX-hyd-PEG-ALN micelle, the distribution of DOX in different organs was observed and quantitatively analyzed by using the living image system. As showed in Fig. 11A,B, after free DOX was administered to tumor-bearing nude mice, red DOX fluorescence was distributed in heart, liver, lung and kidney tissue. There is a significant amount of red DOX fluorescence in leg bone tumor tissues after free DOX was intravenously administered. But in leg bone tumor tissues from DOX loaded DOX-hyd-PEG-ALN micelle treated tumor-bearing nude mice, the red DOX fluorescence intensity was approximately 2-fold higher than from free DOX treated tumor-bearing nude mice. After DOX loaded DOX-hyd-PEG-ALN micelle was intravenously administered, the red DOX fluorescence intensity was significantly reduced in heart and kidney as compared with free DOX treatment. The low concentration in tumor and high content in normal tissue led to the high systematic toxicity and low therapeutic index of free DOX. After DOX loaded DOX-hyd-PEG-ALN micelle was administered to tumor-bearing nude mice, a large amount of DOX was distributed in leg bone tumor tissue due to the EPR effect and the targeted moiety of the ALN. The high accumulation of DOX in leg bone tumor site could enhance its antitumor activity and decrease the systematic toxicity in vivo. Meanwhile, the red DOX fluorescence was also found in high blood perfused organs such as liver and lung after DOX loaded DOX-hyd-PEG-ALN micelle was intravenously administered. This was due to much blood passing through these organs and non specific uptake by MPS in these organs.


Doxorubicin-poly (ethylene glycol)-alendronate self-assembled micelles for targeted therapy of bone metastatic cancer.

Ye WL, Zhao YP, Li HQ, Na R, Li F, Mei QB, Zhao MG, Zhou SY - Sci Rep (2015)

Tissue distribution of DOX detected by living image system (A) and distribution of DOX in the tumor tissue section detected by CLSM (C) at 24 h after free DOX (5 mg/kg) and DOX loaded DOX-hyd-PEG-ALN micelles (equivalent dose of DOX: 5 mg/kg) was intravenously administered to tumor-bearing nude mice. Quantitative analysis of in-Vivo Images (B, *P < 0.05 vs DOX in the same organ tissue) and CLSM images (D, *P < 0.05 vs DOX). Data are presented as the average ± standard deviation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588583&req=5

f11: Tissue distribution of DOX detected by living image system (A) and distribution of DOX in the tumor tissue section detected by CLSM (C) at 24 h after free DOX (5 mg/kg) and DOX loaded DOX-hyd-PEG-ALN micelles (equivalent dose of DOX: 5 mg/kg) was intravenously administered to tumor-bearing nude mice. Quantitative analysis of in-Vivo Images (B, *P < 0.05 vs DOX in the same organ tissue) and CLSM images (D, *P < 0.05 vs DOX). Data are presented as the average ± standard deviation.
Mentions: To further verify the active targeting capability of the DOX loaded DOX-hyd-PEG-ALN micelle, the distribution of DOX in different organs was observed and quantitatively analyzed by using the living image system. As showed in Fig. 11A,B, after free DOX was administered to tumor-bearing nude mice, red DOX fluorescence was distributed in heart, liver, lung and kidney tissue. There is a significant amount of red DOX fluorescence in leg bone tumor tissues after free DOX was intravenously administered. But in leg bone tumor tissues from DOX loaded DOX-hyd-PEG-ALN micelle treated tumor-bearing nude mice, the red DOX fluorescence intensity was approximately 2-fold higher than from free DOX treated tumor-bearing nude mice. After DOX loaded DOX-hyd-PEG-ALN micelle was intravenously administered, the red DOX fluorescence intensity was significantly reduced in heart and kidney as compared with free DOX treatment. The low concentration in tumor and high content in normal tissue led to the high systematic toxicity and low therapeutic index of free DOX. After DOX loaded DOX-hyd-PEG-ALN micelle was administered to tumor-bearing nude mice, a large amount of DOX was distributed in leg bone tumor tissue due to the EPR effect and the targeted moiety of the ALN. The high accumulation of DOX in leg bone tumor site could enhance its antitumor activity and decrease the systematic toxicity in vivo. Meanwhile, the red DOX fluorescence was also found in high blood perfused organs such as liver and lung after DOX loaded DOX-hyd-PEG-ALN micelle was intravenously administered. This was due to much blood passing through these organs and non specific uptake by MPS in these organs.

Bottom Line: In pH 5.0 phosphate buffer solution (PBS), the micelle released DOX significantly faster than in pH 7.4 PBS.Finally, DOX loaded DOX-hyd-PEG-ALN micelle effectively delayed the tumor growth, decreased the bone loss and reduced the cardiac toxicity in tumor-bearing nude mice as compared with free DOX.In conclusion, DOX loaded DOX-hyd-PEG-ALN micelle had potential in treating bone metastatic tumor.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China.

ABSTRACT
In order to increase the therapeutic effect of doxorubicin (DOX) on bone metastases, a multifunctional micelle was developed by combining pH-sensitive characteristics with bone active targeting capacity. The DOX loaded micelle was self-assembled by using doxorubicin-poly (ethylene glycol)-alendronate (DOX-hyd-PEG-ALN) as an amphiphilic material. The size and drug loading of DOX loaded DOX-hyd-PEG-ALN micelle was 114 nm and 24.3%. In pH 5.0 phosphate buffer solution (PBS), the micelle released DOX significantly faster than in pH 7.4 PBS. In addition, with the increase of incubation time, more red DOX fluorescence was observed in tumor cells and trafficked from cytoplasm to nucleus. The IC50 of DOX loaded DOX-hyd-PEG-ALN micelle on A549 cells was obviously lower than that of free DOX in 48 h. Furthermore, the in vivo image experimental results indicated that a larger amount of DOX was accumulated in the bone metastatic tumor tissue after DOX loaded DOX-hyd-PEG-ALN micelle was intravenously administered, which was confirmed by histological analysis. Finally, DOX loaded DOX-hyd-PEG-ALN micelle effectively delayed the tumor growth, decreased the bone loss and reduced the cardiac toxicity in tumor-bearing nude mice as compared with free DOX. In conclusion, DOX loaded DOX-hyd-PEG-ALN micelle had potential in treating bone metastatic tumor.

No MeSH data available.


Related in: MedlinePlus