Complexation of Albendazole with Hydroxypropyl-β-Cyclodextrin Significantly Improves its Pharmacokinetic Profile, Cell Cytotoxicity and Antitumor Efficacy in Nude Mice
Albendazole (ABZ) is a microtubule depolymerizing agent with a remarkable activity against a variety of tumor cells in vitro and in vivo. However, the lack of water solubility limits its application. Therefore, the aim of this study was to formulate ABZ with acetic acid/2-hydroxypropyl-β-cyclodextri...
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Published in | Anticancer research Vol. 32; no. 9; pp. 3659 - 3666 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
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International Institute of Anticancer Research
01.09.2012
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Abstract | Albendazole (ABZ) is a microtubule depolymerizing agent with a remarkable activity against a variety of tumor cells in vitro and in vivo. However, the lack of water solubility limits its application. Therefore, the aim of this study was to formulate ABZ with acetic acid/2-hydroxypropyl-β-cyclodextrin (HPβCD) with the view of improving its aqueous solubility and therefore, its antitumor efficacy.
ABZ was dissolved in acetic acid and 25% HPβCD (w/v). Mice received a single dose of ABZ/HPβCD or a conventional suspension in hydroxypropyl methyl cellulose (HPMC) over 24 h and the concentration of ABZ and its metabolites in plasma were measured by HPLC. The antitumor efficacy of the two formulations were then evaluated and compared in nude mice bearing HCT-116 colorectal cancer xenografts.
Ionization with acetic acid together with complexation with hydroxylpropyl-β-cyclodextrin (HPβCD) dramatically improved the solubility of ABZ. The area under the curve (AUC) of ABZ and its active metabolite, ABZ sulfoxide (ABZSO) were approximately 2.3- and 7.3-folds higher in mice that received ABZ/HPβCD in comparison with animals that were treated with ABZ/HPMC. Additionally, the peak plasma concentration (C(max)) of ABZSO was nearly 18-times higher in mice that received ABZ/HPβCD. Furthermore, a significant delay in tumor growth that led to longer survival in mice was observed in the ABZ/HPβCD-treated group as compared to the ABZ/HPMC group.
These findings demonstrate that the combination of acetic acid and HPβCD significantly improves the solubility, pharmacokinetic profile and antitumor efficacy of ABZ. This newly-developed formulation of ABZ may be suitable for parenteral administration. |
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AbstractList | BACKGROUNDAlbendazole (ABZ) is a microtubule depolymerizing agent with a remarkable activity against a variety of tumor cells in vitro and in vivo. However, the lack of water solubility limits its application. Therefore, the aim of this study was to formulate ABZ with acetic acid/2-hydroxypropyl-β-cyclodextrin (HPβCD) with the view of improving its aqueous solubility and therefore, its antitumor efficacy.MATERIALS AND METHODSABZ was dissolved in acetic acid and 25% HPβCD (w/v). Mice received a single dose of ABZ/HPβCD or a conventional suspension in hydroxypropyl methyl cellulose (HPMC) over 24 h and the concentration of ABZ and its metabolites in plasma were measured by HPLC. The antitumor efficacy of the two formulations were then evaluated and compared in nude mice bearing HCT-116 colorectal cancer xenografts.RESULTSIonization with acetic acid together with complexation with hydroxylpropyl-β-cyclodextrin (HPβCD) dramatically improved the solubility of ABZ. The area under the curve (AUC) of ABZ and its active metabolite, ABZ sulfoxide (ABZSO) were approximately 2.3- and 7.3-folds higher in mice that received ABZ/HPβCD in comparison with animals that were treated with ABZ/HPMC. Additionally, the peak plasma concentration (C(max)) of ABZSO was nearly 18-times higher in mice that received ABZ/HPβCD. Furthermore, a significant delay in tumor growth that led to longer survival in mice was observed in the ABZ/HPβCD-treated group as compared to the ABZ/HPMC group.CONCLUSIONThese findings demonstrate that the combination of acetic acid and HPβCD significantly improves the solubility, pharmacokinetic profile and antitumor efficacy of ABZ. This newly-developed formulation of ABZ may be suitable for parenteral administration. Albendazole (ABZ) is a microtubule depolymerizing agent with a remarkable activity against a variety of tumor cells in vitro and in vivo. However, the lack of water solubility limits its application. Therefore, the aim of this study was to formulate ABZ with acetic acid/2-hydroxypropyl-β-cyclodextrin (HPβCD) with the view of improving its aqueous solubility and therefore, its antitumor efficacy. ABZ was dissolved in acetic acid and 25% HPβCD (w/v). Mice received a single dose of ABZ/HPβCD or a conventional suspension in hydroxypropyl methyl cellulose (HPMC) over 24 h and the concentration of ABZ and its metabolites in plasma were measured by HPLC. The antitumor efficacy of the two formulations were then evaluated and compared in nude mice bearing HCT-116 colorectal cancer xenografts. Ionization with acetic acid together with complexation with hydroxylpropyl-β-cyclodextrin (HPβCD) dramatically improved the solubility of ABZ. The area under the curve (AUC) of ABZ and its active metabolite, ABZ sulfoxide (ABZSO) were approximately 2.3- and 7.3-folds higher in mice that received ABZ/HPβCD in comparison with animals that were treated with ABZ/HPMC. Additionally, the peak plasma concentration (C(max)) of ABZSO was nearly 18-times higher in mice that received ABZ/HPβCD. Furthermore, a significant delay in tumor growth that led to longer survival in mice was observed in the ABZ/HPβCD-treated group as compared to the ABZ/HPMC group. These findings demonstrate that the combination of acetic acid and HPβCD significantly improves the solubility, pharmacokinetic profile and antitumor efficacy of ABZ. This newly-developed formulation of ABZ may be suitable for parenteral administration. |
Author | PILLAI, Krishna GALETTIS, Peter LING CHU, Stephanie Wai MORRIS, David L EHTEDA, Anahid |
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Keywords | Antineoplastic agent Complexation Oligosaccharide Treatment efficiency Rodentia Cytotoxicity hydroxypropyl-β-cyclodextrin β-Cyclodextrin Cyclodextrin Vertebrata Mammalia Albendazole Cancerology Mouse Benzimidazole derivatives Ionization Animal Acetic acid Pharmacokinetics |
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Snippet | Albendazole (ABZ) is a microtubule depolymerizing agent with a remarkable activity against a variety of tumor cells in vitro and in vivo. However, the lack of... BACKGROUNDAlbendazole (ABZ) is a microtubule depolymerizing agent with a remarkable activity against a variety of tumor cells in vitro and in vivo. However,... |
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SubjectTerms | 2-Hydroxypropyl-beta-cyclodextrin Acetic Acid - chemistry Albendazole - administration & dosage Albendazole - analogs & derivatives Albendazole - chemistry Albendazole - pharmacokinetics Animals beta-Cyclodextrins - administration & dosage beta-Cyclodextrins - chemistry beta-Cyclodextrins - pharmacokinetics Biological and medical sciences Chromatography, High Pressure Liquid Colorectal Neoplasms - drug therapy Colorectal Neoplasms - metabolism Female HCT116 Cells Human Umbilical Vein Endothelial Cells - drug effects Human Umbilical Vein Endothelial Cells - metabolism Humans Hypromellose Derivatives Injections, Intraperitoneal Medical sciences Methylcellulose - analogs & derivatives Methylcellulose - chemistry Mice Mice, Nude Solutions - chemistry Suspensions - chemistry Tubulin Modulators - chemistry Tubulin Modulators - pharmacokinetics Tumors Xenograft Model Antitumor Assays |
Title | Complexation of Albendazole with Hydroxypropyl-β-Cyclodextrin Significantly Improves its Pharmacokinetic Profile, Cell Cytotoxicity and Antitumor Efficacy in Nude Mice |
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