Synthesis of theophylline-polyrotaxane conjugates and their drug release via supramolecular dissociation.
Theophylline-polyrotaxane conjugates were synthesized by coupling theophylline with alpha-cyclodextrins (alpha-CDs) in the polyrotaxane. The polyrotaxane is a molecular assembly in which many alpha-CDs are threaded onto a poly(ethylene glycol) (PEG) chain capped with L-phenylalanine (L-Phe). Theophylline-7-acetic acid was activated by coupling with 4-nitrophenol, and then ethylenediamine 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 theophylline-polyrotaxane conjugates. The conjugates formed a specific association under physiological conditions, depending upon interactions between the theophylline molecules and/or the terminal l-Phe moiety in the conjugates. In vitro degradation of the conjugates revealed that theophylline-immobilized alpha-CDs were completely released by hydrolysis of the terminal peptide linkage in the polyrotaxane. This result indicates that the association of the conjugates does not induce the steric hindrance but rather enhances the accessibility of enzymes to the terminal peptide linkages. It is suggested that our designed drug-polyrotaxane conjugates can release the drugs via the dissociation of the supramolecular structure without steric hindrance of enzymatic accessibility to the terminal peptide linkages.
Ooya
T
T
School of Materials Science, Japan Advanced Institute of Science and Technology, 1-1 Asahidai, Tatsunokuchi, Ishikawa 923-1292, Japan.
Yui
N
N
D001993:Bronchodilator Agents / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D002918:Chymotrypsin / Q000737:chemistry; D003505:Cyclodextrins / Q000737:chemistry; D003692:Delayed-Action Preparations / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D004337:Drug Carriers; D005029:Ethylenediamines / Q000737:chemistry; D009596:Nitrophenols / Q000737:chemistry; D010206:Papain / Q000737:chemistry; D010649:Phenylalanine / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D012995:Solubility; D013806:Theophylline / Q000031:analogs & derivatives / Q000737:chemistry*; D047391:alpha-Cyclodextrins
D001993:Bronchodilator Agents; D003505:Cyclodextrins; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D005029:Ethylenediamines; D009596:Nitrophenols; D011108:Polymers; D047391:alpha-Cyclodextrins; D011092:Polyethylene Glycols; D010649:Phenylalanine; C031234:ethylenediamine; D013806:Theophylline; D002918:Chymotrypsin; D010206:Papain; C019140:acefylline; C024836:4-nitrophenol; C032613:alpha-cyclodextrin