title: Characteristics and anti-proliferative activity of azelaic acid and its derivatives entrapped in bilayer vesicles in cancer cell lines.
abstract: The hydrophilicity and lipophilicity of azelaic acid (AA) were modified to diethyl azelate (DA) which was synthesized by Fisher esterification reaction and identified by IR, MS and (1)H NMR and to azelaic acid-beta-cyclodextrin complex (AACD) which was prepared by inclusion complexation and identified by IR, DSC and XRD respectively. AA, DA and AACD were entrapped in liposomes and niosomes comprising of L-alpha-dipalmitoyl phosphatidylcholine (DPPC)/cholesterol at 7:3 molar ratio and Tween61/cholesterol at 1:1 molar ratio, respectively, using a thin-film hydration method with sonication. The size and morphology of these bilayer vesicles were determined by optical and transmission electron microscopy. The particle size was found to be in the range of 90-190 nm. The entrapment efficiency of AA, DA and AACD in all vesicular formulations was more than 80%, as analyzed by HPLC for AA and AACD, and GC for DA. Anti-proliferative activity of AA and its derivatives (DA and AACD) both entrapped and not entrapped in bilayer vesicles, using MTT assay in three cancer cell lines (HeLa, KB and B(16)F(10)) comparing with vincristine, were investigated. AACD showed the highest potency comparing to AA in HeLa, KB and B(16)F(10) of 1.48, 1.6 and 1.5 times, respectively. AA entrapped in liposomes was about 90 times more potent than the free AA, and about 1.5 times less potent than vincristine. When entrapped in bilayer vesicles, DA and AACD were more effective than AA in killing cancer cells. AACD entrapped in liposomes gave the highest anti-proliferation activity in HeLa cell lines with the IC(50) of 2.3 and 327 times more potent than vincristine and AA, respectively. DA in liposomes demonstrated the IC(50) of 0.03 times less potent than vincristine in KB cell lines, while in B(16)F(10) AACD in niosomes showed the IC(50) of 0.05 times less potent than vincristine. This study has suggested that the modification of AA by derivatization and complexation as well as the entrapment in bilayer vesicles can enhance its therapeutic efficacy.
authors.affiliation: Institute for Science and Technology Research and Development, Natural Products Research and Development Center, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand. pmpti005@chiangmai.ac.th
authors.forename: Aranya
authors.initials: A
authors.lastname: Manosroi
authors.forename: Atchara
authors.initials: A
authors.lastname: Panyosak
authors.forename: Yon
authors.initials: Y
authors.lastname: Rojanasakul
authors.forename: Jiradej
authors.initials: J
authors.lastname: Manosroi
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D003460:Crystallization; D018360:Crystallography, X-Ray / Q000379:methods; D003998:Dicarboxylic Acids / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D004357:Drug Synergism; D006367:HeLa Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008081:Liposomes / Q000737:chemistry*; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D012995:Solubility; D013010:Sonication; D013055:Spectrophotometry, Infrared / Q000379:methods; D044366:Transition Temperature; D014750:Vincristine / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D003998:Dicarboxylic Acids; D008081:Liposomes; D014750:Vincristine; C062819:diethyl azelate; C010038:azelaic acid