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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

The size distribution (A) and TEM image (B) of DOX-loaded DOX-hyd-PEG-ALN micelle. The size distribution (C) and TEM image (D) of DOX loaded DOX-hyd-PEG micelle. The pH responsive characteristics of DOX loaded DOX-hyd-PEG-ALN micelle monitored by DLS and TEM in pH 7.4 medium for 4 h (E,G) and in pH 5.0 medium for 4 h (F,H). n = 3. Stability of DOX loaded DOX-hyd-PEG-ALN micelle in the presence of 20% fetal bovine serum (FBS) in PBS at room temperature (I). n = 3.
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f5: The size distribution (A) and TEM image (B) of DOX-loaded DOX-hyd-PEG-ALN micelle. The size distribution (C) and TEM image (D) of DOX loaded DOX-hyd-PEG micelle. The pH responsive characteristics of DOX loaded DOX-hyd-PEG-ALN micelle monitored by DLS and TEM in pH 7.4 medium for 4 h (E,G) and in pH 5.0 medium for 4 h (F,H). n = 3. Stability of DOX loaded DOX-hyd-PEG-ALN micelle in the presence of 20% fetal bovine serum (FBS) in PBS at room temperature (I). n = 3.

Mentions: The particle size and size distribution of the DOX loaded DOX-hyd-PEG-ALN micelle and DOX loaded DOX-hyd-PEG micelle are showed in Table 1, Fig. 5A,C. The average size of the DOX loaded DOX-hyd-PEG-ALN micelle and DOX loaded DOX-hyd-PEG micelle was approximately 114 nm and 278 nm, respectively. The size of DOX loaded DOX-hyd-PEG-ALN micelle was smaller than that of DOX loaded DOX-hyd-PEG micelle. This was probably because that ALN changed the physiochemical properties of surface of DOX loaded DOX-hyd-PEG-ALN micelle (for example the absolute value of zeta potential of DOX loaded DOX-hyd-PEG-ALN micelle was greater than that of DOX loaded DOX-hyd-PEG micelle), which reduced the aggregation of the micelle38. The result was consistent with what was reported in the literature. For example, it was reported that the size of cholic acid modified nanoparticles CA-PLA-TPGS (112.9 ± 3.1 nm) was smaller than PLA-TPGS nanoparticles (125.7 ± 3.5 nm)39. Beside, the size of DOX-loaded M-PLGA-b-TPGS NPs (110.9 nm) was much smaller than DOX-loaded PLGA NPs (143.7  nm)40. The size of the DOX loaded DOX-hyd-PEG-ALN micelle was in the suitable size range for accumulating in tumor tissue by EPR effects41. In addition, PDI is a very important index of size distribution4243. Zahra Hami et al. prepared DOX loaded DOX-Hyd-PLA-PEG-FOL micelle with DOX and PLA as hydrophobic core. The size and PDI of DOX-Hyd-PLA-PEG-FOL micelle were 182 nm and 0.28 ± 0.04, respectively44. A redox-responsive star-shaped PECLss-FA micelle was prepared. The size and PDI of star-shaped PECLss-FA micelle were 200 nm and 0.279, respectively29. Besides, Craparo EF et al. prepared beclomethasone dipropionate loaded PHEA-PEG2000-DSPE micelles. The size and PDI of this micelle were 200 nm and 0.4, respectively45. Recently, FA-PECL-SS-CPT was synthesized by using disulfide as a linker between poly(ethylene glycol)-b-poly(ε-caprolactone) (PECL) and camptothecin (CPT). With PCL and CPT as hydrophobic core and PEG as hydrophilic corona, FA-PECL-SS-CPT assembled itself into micelle. The size and PDI of FA-PECL-SS-CPT micelle were 155 nm and 0.512, respectively46. The size and PDI of DOX loaded DOX-hyd-PEG-ALN micelle was 114 nm and 0.142 ± 0.08, respectively. Thus, compared with above reported micelles, the size distribution of DOX loaded DOX-hyd-PEG-ALN micelle was relatively narrow. The TEM result showed that DOX loaded DOX-hyd-PEG-ALN micelle was generally spherical in shape (Fig. 5B).


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)

The size distribution (A) and TEM image (B) of DOX-loaded DOX-hyd-PEG-ALN micelle. The size distribution (C) and TEM image (D) of DOX loaded DOX-hyd-PEG micelle. The pH responsive characteristics of DOX loaded DOX-hyd-PEG-ALN micelle monitored by DLS and TEM in pH 7.4 medium for 4 h (E,G) and in pH 5.0 medium for 4 h (F,H). n = 3. Stability of DOX loaded DOX-hyd-PEG-ALN micelle in the presence of 20% fetal bovine serum (FBS) in PBS at room temperature (I). n = 3.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: The size distribution (A) and TEM image (B) of DOX-loaded DOX-hyd-PEG-ALN micelle. The size distribution (C) and TEM image (D) of DOX loaded DOX-hyd-PEG micelle. The pH responsive characteristics of DOX loaded DOX-hyd-PEG-ALN micelle monitored by DLS and TEM in pH 7.4 medium for 4 h (E,G) and in pH 5.0 medium for 4 h (F,H). n = 3. Stability of DOX loaded DOX-hyd-PEG-ALN micelle in the presence of 20% fetal bovine serum (FBS) in PBS at room temperature (I). n = 3.
Mentions: The particle size and size distribution of the DOX loaded DOX-hyd-PEG-ALN micelle and DOX loaded DOX-hyd-PEG micelle are showed in Table 1, Fig. 5A,C. The average size of the DOX loaded DOX-hyd-PEG-ALN micelle and DOX loaded DOX-hyd-PEG micelle was approximately 114 nm and 278 nm, respectively. The size of DOX loaded DOX-hyd-PEG-ALN micelle was smaller than that of DOX loaded DOX-hyd-PEG micelle. This was probably because that ALN changed the physiochemical properties of surface of DOX loaded DOX-hyd-PEG-ALN micelle (for example the absolute value of zeta potential of DOX loaded DOX-hyd-PEG-ALN micelle was greater than that of DOX loaded DOX-hyd-PEG micelle), which reduced the aggregation of the micelle38. The result was consistent with what was reported in the literature. For example, it was reported that the size of cholic acid modified nanoparticles CA-PLA-TPGS (112.9 ± 3.1 nm) was smaller than PLA-TPGS nanoparticles (125.7 ± 3.5 nm)39. Beside, the size of DOX-loaded M-PLGA-b-TPGS NPs (110.9 nm) was much smaller than DOX-loaded PLGA NPs (143.7  nm)40. The size of the DOX loaded DOX-hyd-PEG-ALN micelle was in the suitable size range for accumulating in tumor tissue by EPR effects41. In addition, PDI is a very important index of size distribution4243. Zahra Hami et al. prepared DOX loaded DOX-Hyd-PLA-PEG-FOL micelle with DOX and PLA as hydrophobic core. The size and PDI of DOX-Hyd-PLA-PEG-FOL micelle were 182 nm and 0.28 ± 0.04, respectively44. A redox-responsive star-shaped PECLss-FA micelle was prepared. The size and PDI of star-shaped PECLss-FA micelle were 200 nm and 0.279, respectively29. Besides, Craparo EF et al. prepared beclomethasone dipropionate loaded PHEA-PEG2000-DSPE micelles. The size and PDI of this micelle were 200 nm and 0.4, respectively45. Recently, FA-PECL-SS-CPT was synthesized by using disulfide as a linker between poly(ethylene glycol)-b-poly(ε-caprolactone) (PECL) and camptothecin (CPT). With PCL and CPT as hydrophobic core and PEG as hydrophilic corona, FA-PECL-SS-CPT assembled itself into micelle. The size and PDI of FA-PECL-SS-CPT micelle were 155 nm and 0.512, respectively46. The size and PDI of DOX loaded DOX-hyd-PEG-ALN micelle was 114 nm and 0.142 ± 0.08, respectively. Thus, compared with above reported micelles, the size distribution of DOX loaded DOX-hyd-PEG-ALN micelle was relatively narrow. The TEM result showed that DOX loaded DOX-hyd-PEG-ALN micelle was generally spherical in shape (Fig. 5B).

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