title: Complexation of albendazole with hydroxypropyl-β-cyclodextrin significantly improves its pharmacokinetic profile, cell cytotoxicity and antitumor efficacy in nude mice.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cancer Research Laboratories, Department of Surgery, University of New South Wales, Sydney, Australia.
authors.forename: Anahid
authors.initials: A
authors.lastname: Ehteda
authors.forename: Peter
authors.initials: P
authors.lastname: Galettis
authors.forename: Stephanie Wai Ling
authors.initials: SW
authors.lastname: Chu
authors.forename: Krishna
authors.initials: K
authors.lastname: Pillai
authors.forename: David L
authors.initials: DL
authors.lastname: Morris
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D019342:Acetic Acid / Q000737:chemistry; D015766:Albendazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D045325:HCT116 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D065347:Hypromellose Derivatives; D007274:Injections, Intraperitoneal; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D012996:Solutions / Q000737:chemistry; D013535:Suspensions / Q000737:chemistry; D050257:Tubulin Modulators / Q000737:chemistry / Q000493:pharmacokinetics; D023041:Xenograft Model Antitumor Assays; D047392:beta-Cyclodextrins / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*
chemical_list: D012996:Solutions; D013535:Suspensions; D050257:Tubulin Modulators; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D065347:Hypromellose Derivatives; D008747:Methylcellulose; D015766:Albendazole; D019342:Acetic Acid