Carboxyethylester-polyrotaxanes as a new calcium chelating polymer: synthesis, calcium binding and mechanism of trypsin inhibition

A carboxyethylester-polyrotaxane was synthesized as a novel calcium chelating polymer in the field of oral drug delivery and characterized in terms of mechanism of trypsin inhibition. Here, carboxyethylester (CEE) groups are introduced to all the primary hydroxyl groups in alpha-cyclodextrins (alpha-CDs), which are threaded onto a poly(ethylene glycol) chain capped with bulky end-groups (polyrotaxane). The solubility of the CEE-polyrotaxane in physiological conditions increased with pH, indicating ionization-related solubility similar to conventional polyacrylates. The ability of calcium (Ca2+) chelation was found to increase in the order of poly(acrylic acid) (PAA) the CEE-polyrotaxane much greater than CEE-alpha-CD, suggesting that the increased density of carboxyl groups enhances the Ca2+ chelating ability. The activity of trypsin was inhibited by these compounds in the same order of the calcium chelation. However, the inhibitory effect of CEE-polyrotaxane was reduced by adding excess Ca2+ without precipitation that was observed in the presence of PAA. Such the reduced inhibition and precipitation by CEE-alpha-CD was not observed. Therefore, the inhibitory effect of CEE-polyrotaxane is due to Ca2+ chelation from trypsin without non-specific interaction. (C) 2002 Elsevier Science B.V. All rights reserved.