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The application of EDTA in drug delivery systems: doxorubicin liposomes loaded via NH4EDTA gradient.

Song Y, Huang Z, Song Y, Tian Q, Liu X, She Z, Jiao J, Lu E, Deng Y - Int J Nanomedicine (2014)

Bottom Line: In vitro studies revealed that liposomes prepared using an NH4EDTA gradient possessed long-term stability and delayed drug release.The in vivo studies also showed the superiority of the new doxorubicin formulation.These results show that use of the NH4EDTA gradient method to load doxorubicin into liposomes could significantly reduce drug toxicity without influencing antitumor activity.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.

ABSTRACT
The applications of ethylenediaminetetraacetic acid (EDTA) have been expanded from the treatment of heavy metal poisoning to chelation therapies for atherosclerosis, heart disease, and cancers, in which EDTA reduces morbidity and mortality by chelating toxic metal ions. In this study, EDTA was used in a drug delivery system by adopting an NH4EDTA gradient method to load doxorubicin into liposomes with the goal of increasing therapeutic effects and decreasing drug-related cytotoxicity. The particle size of the optimum NH4EDTA gradient liposomes was 79.4±1.87 nm, and the entrapment efficiency was 95.54%±0.59%. In vitro studies revealed that liposomes prepared using an NH4EDTA gradient possessed long-term stability and delayed drug release. The in vivo studies also showed the superiority of the new doxorubicin formulation. Compared with an equivalent drug dose (5 mg/kg) prepared by (NH4)2SO4 gradient, NH4EDTA gradient liposomes showed no significant differences in tumor inhibition ratio, but cardiotoxicity and liposome-related immune organ damage were lower, and no drug-related deaths were observed. These results show that use of the NH4EDTA gradient method to load doxorubicin into liposomes could significantly reduce drug toxicity without influencing antitumor activity.

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Photographs of mixtures of DOX with (1) (NH4)2SO4 and (2) NH4EDTA at 25°C and pH 4 (A) before centrifugation, (B) after centrifugation, and (C) diluted with isochoric distilled water.Abbreviations: DOX, doxorubicin; EDTA, ethylenediaminetetraacetic acid.
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f2-ijn-9-3611: Photographs of mixtures of DOX with (1) (NH4)2SO4 and (2) NH4EDTA at 25°C and pH 4 (A) before centrifugation, (B) after centrifugation, and (C) diluted with isochoric distilled water.Abbreviations: DOX, doxorubicin; EDTA, ethylenediaminetetraacetic acid.

Mentions: As shown in Figure 1, the solubility of DOX in (NH4)2SO4 and NH4EDTA solutions at 25°C was dependent on pH. The solubility of DOX in 200 mM (NH4)2SO4 solution was almost invariable from pH 4 to pH 7 (approximately 0.23 mg/mL) and decreased gradually as pH was raised above pH 7. In 200 mM NH4EDTA solution, the solubility of DOX decreased sharply from 1.92 mg/mL (at pH 4) to 0.23 mg/mL (at pH 5), and the variation in solubility was comparable to that of (NH4)2SO4 solution above pH 5. The solubility of DOX in (NH4)2SO4 and NH4EDTA solutions at pH 4 was further examined by dilution with distilled water. As shown in Figure 2, DOX formed a precipitate in (NH4)2SO4 solution after centrifugation, while it was well dispersed in the NH4EDTA solution. However, when diluted with isochoric distilled water, the supernatant of the (NH4)2SO4 solution appeared to be homogeneous, while that of the NH4EDTA solution appeared layered.


The application of EDTA in drug delivery systems: doxorubicin liposomes loaded via NH4EDTA gradient.

Song Y, Huang Z, Song Y, Tian Q, Liu X, She Z, Jiao J, Lu E, Deng Y - Int J Nanomedicine (2014)

Photographs of mixtures of DOX with (1) (NH4)2SO4 and (2) NH4EDTA at 25°C and pH 4 (A) before centrifugation, (B) after centrifugation, and (C) diluted with isochoric distilled water.Abbreviations: DOX, doxorubicin; EDTA, ethylenediaminetetraacetic acid.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4128794&req=5

f2-ijn-9-3611: Photographs of mixtures of DOX with (1) (NH4)2SO4 and (2) NH4EDTA at 25°C and pH 4 (A) before centrifugation, (B) after centrifugation, and (C) diluted with isochoric distilled water.Abbreviations: DOX, doxorubicin; EDTA, ethylenediaminetetraacetic acid.
Mentions: As shown in Figure 1, the solubility of DOX in (NH4)2SO4 and NH4EDTA solutions at 25°C was dependent on pH. The solubility of DOX in 200 mM (NH4)2SO4 solution was almost invariable from pH 4 to pH 7 (approximately 0.23 mg/mL) and decreased gradually as pH was raised above pH 7. In 200 mM NH4EDTA solution, the solubility of DOX decreased sharply from 1.92 mg/mL (at pH 4) to 0.23 mg/mL (at pH 5), and the variation in solubility was comparable to that of (NH4)2SO4 solution above pH 5. The solubility of DOX in (NH4)2SO4 and NH4EDTA solutions at pH 4 was further examined by dilution with distilled water. As shown in Figure 2, DOX formed a precipitate in (NH4)2SO4 solution after centrifugation, while it was well dispersed in the NH4EDTA solution. However, when diluted with isochoric distilled water, the supernatant of the (NH4)2SO4 solution appeared to be homogeneous, while that of the NH4EDTA solution appeared layered.

Bottom Line: In vitro studies revealed that liposomes prepared using an NH4EDTA gradient possessed long-term stability and delayed drug release.The in vivo studies also showed the superiority of the new doxorubicin formulation.These results show that use of the NH4EDTA gradient method to load doxorubicin into liposomes could significantly reduce drug toxicity without influencing antitumor activity.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.

ABSTRACT
The applications of ethylenediaminetetraacetic acid (EDTA) have been expanded from the treatment of heavy metal poisoning to chelation therapies for atherosclerosis, heart disease, and cancers, in which EDTA reduces morbidity and mortality by chelating toxic metal ions. In this study, EDTA was used in a drug delivery system by adopting an NH4EDTA gradient method to load doxorubicin into liposomes with the goal of increasing therapeutic effects and decreasing drug-related cytotoxicity. The particle size of the optimum NH4EDTA gradient liposomes was 79.4±1.87 nm, and the entrapment efficiency was 95.54%±0.59%. In vitro studies revealed that liposomes prepared using an NH4EDTA gradient possessed long-term stability and delayed drug release. The in vivo studies also showed the superiority of the new doxorubicin formulation. Compared with an equivalent drug dose (5 mg/kg) prepared by (NH4)2SO4 gradient, NH4EDTA gradient liposomes showed no significant differences in tumor inhibition ratio, but cardiotoxicity and liposome-related immune organ damage were lower, and no drug-related deaths were observed. These results show that use of the NH4EDTA gradient method to load doxorubicin into liposomes could significantly reduce drug toxicity without influencing antitumor activity.

Show MeSH
Related in: MedlinePlus