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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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Related in: MedlinePlus

A comparison of the release of DOX encapsulated in liposomes in vitro via different ion gradients: 200 mM NH4EDTA solution and 200 mM (NH4)2SO4 solutions. Drug release profiles were analyzed in conventional PBS buffer (pH 7.4) and a special PBS buffer with ammonium chloride (80 mM), histidine (10 mM), penicillin (100 μg/mL), and streptomycin (100 μg/mL) (pH 7.4).Note: **P<0.01 versus (NH4)2SO4-L in PBS buffer with ammonium chloride.Abbreviations: DOX, doxorubicin; EDTA, ethylenediaminetetraacetic acid; L, doxorubicin-loaded liposomes; PBS, phosphate-buffered saline.
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f3-ijn-9-3611: A comparison of the release of DOX encapsulated in liposomes in vitro via different ion gradients: 200 mM NH4EDTA solution and 200 mM (NH4)2SO4 solutions. Drug release profiles were analyzed in conventional PBS buffer (pH 7.4) and a special PBS buffer with ammonium chloride (80 mM), histidine (10 mM), penicillin (100 μg/mL), and streptomycin (100 μg/mL) (pH 7.4).Note: **P<0.01 versus (NH4)2SO4-L in PBS buffer with ammonium chloride.Abbreviations: DOX, doxorubicin; EDTA, ethylenediaminetetraacetic acid; L, doxorubicin-loaded liposomes; PBS, phosphate-buffered saline.

Mentions: Drug release experiments were performed for the quantitative comparison of the release kinetics of DOX from NH4EDTA-L and (NH4)2SO4-L, and the results are shown in Figure 3. When the release medium was conventional PBS (pH 7.4), the drug release rates from both liposomes over 24 hours were less than 5% with no significant difference between them (P>0.05). When the release medium was a special PBS buffer (pH 7.4) with ammonium chloride (80 mM), the release of encapsulated drug from NH4EDTA-L was much slower than (NH4)2SO4-L, and the total amounts of released DOX were 11.4% and 23.7%, respectively. Furthermore, it was noted that was a small difference between the release profiles of the two DOX liposomes. For the NH4EDTA-L preparation, release occurred at a constant slow and steady rate, while release from the (NH4)2SO4-L preparation followed a biphasic pattern, in which the first phase of drug release was a rapid response that lasted nearly 5 hours, which was followed by a slow and prolonged second phase.


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)

A comparison of the release of DOX encapsulated in liposomes in vitro via different ion gradients: 200 mM NH4EDTA solution and 200 mM (NH4)2SO4 solutions. Drug release profiles were analyzed in conventional PBS buffer (pH 7.4) and a special PBS buffer with ammonium chloride (80 mM), histidine (10 mM), penicillin (100 μg/mL), and streptomycin (100 μg/mL) (pH 7.4).Note: **P<0.01 versus (NH4)2SO4-L in PBS buffer with ammonium chloride.Abbreviations: DOX, doxorubicin; EDTA, ethylenediaminetetraacetic acid; L, doxorubicin-loaded liposomes; PBS, phosphate-buffered saline.
© Copyright Policy
Related In: Results  -  Collection

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

f3-ijn-9-3611: A comparison of the release of DOX encapsulated in liposomes in vitro via different ion gradients: 200 mM NH4EDTA solution and 200 mM (NH4)2SO4 solutions. Drug release profiles were analyzed in conventional PBS buffer (pH 7.4) and a special PBS buffer with ammonium chloride (80 mM), histidine (10 mM), penicillin (100 μg/mL), and streptomycin (100 μg/mL) (pH 7.4).Note: **P<0.01 versus (NH4)2SO4-L in PBS buffer with ammonium chloride.Abbreviations: DOX, doxorubicin; EDTA, ethylenediaminetetraacetic acid; L, doxorubicin-loaded liposomes; PBS, phosphate-buffered saline.
Mentions: Drug release experiments were performed for the quantitative comparison of the release kinetics of DOX from NH4EDTA-L and (NH4)2SO4-L, and the results are shown in Figure 3. When the release medium was conventional PBS (pH 7.4), the drug release rates from both liposomes over 24 hours were less than 5% with no significant difference between them (P>0.05). When the release medium was a special PBS buffer (pH 7.4) with ammonium chloride (80 mM), the release of encapsulated drug from NH4EDTA-L was much slower than (NH4)2SO4-L, and the total amounts of released DOX were 11.4% and 23.7%, respectively. Furthermore, it was noted that was a small difference between the release profiles of the two DOX liposomes. For the NH4EDTA-L preparation, release occurred at a constant slow and steady rate, while release from the (NH4)2SO4-L preparation followed a biphasic pattern, in which the first phase of drug release was a rapid response that lasted nearly 5 hours, which was followed by a slow and prolonged second phase.

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