Monocomponent hexa- and dodecaethylene glycol succinyl-tocopherol esters: Self-assembly structures, cellular uptake and sensitivity to enzyme hydrolysis

• Published in: Biochemical pharmacology 2009-12, Vol.78 (12), p.1464-1474
• Main Authors: Folmer, Britta M., Barron, Denis, Hughes, Eric, Miguet, Laurence, Sanchez, Belén, Heudi, Olivier, Rouvet, Martine, Sagalowicz, Laurent, Callier, Philippe, Michel, Martin, Williamson, Gary
• Format: Article
• Language: English
• Subjects: alpha-Tocopherol - analogs & derivatives; alpha-Tocopherol - chemical synthesis; alpha-Tocopherol - pharmacokinetics; Binding Sites; Biological and medical sciences; Biological Availability; Caco-2 cell; Caco-2 Cells - metabolism; Carboxylic Ester Hydrolases - metabolism; Docking model; Esterase; Humans; Hydrolysis; Medical sciences; Pharmacology. Drug treatments; Polyethylene Glycols - chemical synthesis; Polyethylene Glycols - pharmacokinetics; Self-assembly structure; Structure-Activity Relationship; Vitamin E
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2009.07.009

We have chemically synthesized two water-soluble forms of tocopherol succinate linked via an ester bond to hexaethylene glycol and dodecaethylene glycol. The self-assembly structure of the former in water is vesicular, whereas the latter forms elongated micelles. We treated Caco-2 cells with these compounds in these physical forms, in addition to a mixed micelle form. The intact compounds were taken up into the cells, influenced by both the chain length and the physical structure. In addition, the tocopherol derivatives were also metabolized into tocopherol succinate and tocopherol inside the cell. The total hydrolysis and uptake into the cells was two-fold higher from tocopherol hexaethylene glycol succinate in the form of mixed micelles than in vesicular form as assessed by analyzing intracellular tocopherol and tocopherol succinate. The longer polyethylene glycol chain gave a higher intracellular tocopherol succinate/tocopherol ratio. The major intracellular esterase in Caco-2 cells is carboxyl esterase 1 (EC 3.1.1.1), and in silico modelling studies show that the position of docking and hence the site of hydrolysis is influenced by the chain length. The in silico prediction is consistent with the in vitro data, since a longer chain length is predicted to favour hydrolysis of the ester bond between the succinate and polyethylene glycol moieties.