Synthesis of theophylline-polyrotaxane conjugates and their drug release via supramolecular dissociation

Theophylline-polyrotaxane conjugates were synthesized by coupling theophyll ine with alpha-cyclodextrins (alpha-CDs) in the polyrotaxane. The polyrotax ane is a molecular assembly in which many a-CDs are threaded onto a poly(et hylene glycol) (PEG) chain capped with L-phenylalanine (L-Phe). Theophyllin e-7-acetic acid was activated by coupling with 4-nitrophenol, and then ethy lenediamine was allowed to react with the active ester in order to obtain N -aminoethyl-theophylline-7-acetoamide. This derivative was coupled with a 4 -nitrophenyl chloroformate-activated polyrotaxane to obtain the theophyllin e-polyrotaxane conjugates. The conjugates formed a specific association und er physiological conditions, depending upon interactions between the theoph ylline molecules and/or the terminal L-Phe moiety in the conjugates. In vit ro degradation of the conjugates revealed that theophylline-immobilized alp ha-CDs were completely released by hydrolysis of the terminal peptide linka ge in the polyrotaxane. This result indicates that the association of the c onjugates does not induce the steric hindrance but rather enhances the acce ssibility of enzymes to the terminal peptide linkages. It is suggested that our designed drug-polyrotaxane conjugates can release the drugs via the di ssociation of the supramolecular structure without steric hindrance of enzy matic accessibility to the terminal peptide linkages. (C) 1999 Elsevier Sci ence B.V. All rights reserved.