title: pH-Dependent nanostructure based on isoquinoline-cyclodextrin conjugate for thrombosis therapy.
abstract: The modification of 3S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (THIQA) with β-cyclodextrin (β-CD) provides an oral antithrombotic agent, 6-(3'S-isoquinoline-3'-carboxylaminoethylamino)-6-deoxy-β-CD (THIQA-β-CD). In aqueous solution THIQA-β-CD undergoes intermolecular inclusion complexation and forms pH-dependent nanostructures. The morphological feature of THIQA-β-CD is a nanocloud consisting of numerous particles that are 5 nm-6 nm in diameter at pH 3.0. The nanocloud switches to a nanorod ranging from 100 nm to 385 nm in length at pH 7.2, then to nanowires of 50 nm to 530 nm in length at pH 10.1. THIQA-β-CD, which has unusual nanostructures, offers enhanced stability in blood. Inhibition of thrombin-induced platelet aggregation in vitro and demonstrated antithrombotic efficacy in vivo. This investigation demonstrated that the modification of THIQA with β-CD is a promising approach for clinical therapy of thrombus disease. The pH-dependent nanostructures of conjugate provide the desired in vivo antithrombotic activity and in vitro stability in blood.
  
  
  BACKGROUND
  This study a demonstrates that the modification of 3S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (THIQA) with beta-cyclodextrin, which leads to pH dependent nanostructure formation, is a promising approach for clinical therapy of thrombotic disease.
authors.affiliation: College of Pharmaceutical Science, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Wenhao
authors.initials: W
authors.lastname: Li
authors.forename: Yuji
authors.initials: Y
authors.lastname: Wang
authors.forename: Chunna
authors.initials: C
authors.lastname: Liu
authors.forename: Zhuge
authors.initials: Z
authors.lastname: Zhang
authors.forename: Songchun
authors.initials: S
authors.lastname: Su
authors.forename: Shiqi
authors.initials: S
authors.lastname: Peng
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D049329:Nanostructures / Q000737:chemistry / Q000627:therapeutic use*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D013927:Thrombosis / Q000188:drug therapy*; D047392:beta-Cyclodextrins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors; D044005:Tetrahydroisoquinolines; D047392:beta-Cyclodextrins; C078986:1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; C031215:betadex