title: An ultrasound-responsive nano delivery system of tissue-type plasminogen activator for thrombolytic therapy.
abstract: This study is undertaken to design a novel nano-sized delivery system of tissue-type plasminogen activator (t-PA) which has a suppressed thrombolytic activity of t-PA, but recovered the activity only when exposed to ultrasound. Various amounts of ethylenediamine were chemically introduced into gelatin (cationized gelatins) to complex with t-PA. To modify the surface of complexes with polyethylene glycol (PEG), PEG was chemically grafted to the anionic gelatin (PEG-gelatin). The simple mixing with the PEG-gelatin enabled the t-PA-cationized gelatin complex to form a nano-sized delivery complex with PEG chains on the surface. The t-PA activity of PEG-modified complexes was significantly suppressed to be 45% of original t-PA. However, when exposed to ultrasound in vitro, the t-PA activity was fully recovered. A cell culture experiment demonstrated no cytotoxicity of PEG-modified complexes. The body distribution study indicated that the half-life of t-PA in the blood circulation was prolonged about 3 times. In a rabbit thrombosis model, the intravenous administration of PEG-modified complexes followed by ultrasound irradiation resulted in complete recanalization, in remarked contrast to the complex administration alone. It is concluded that the PEG-modified complex is a promising t-PA delivery system to enhance the biological activity at the site necessary only by a local ultrasound irradiation.
authors.affiliation: Department of Biomaterials, Field of Tissue Engineering, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawara-cho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Uesugi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kawata
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Jo
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Saito
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tabata
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000737:chemistry*; D005029:Ethylenediamines / Q000737:chemistry; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005780:Gelatin / Q000737:chemistry; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D011817:Rabbits; D013499:Surface Properties; D013927:Thrombosis / Q000188:drug therapy* / Q000628:therapy; D014018:Tissue Distribution; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014464:Ultrasonic Therapy / Q000379:methods*
chemical_list: D004337:Drug Carriers; D005029:Ethylenediamines; D005343:Fibrinolytic Agents; D011092:Polyethylene Glycols; C031234:ethylenediamine; D005780:Gelatin; D010959:Tissue Plasminogen Activator