title: A new drug delivery system for intravenous coronary thrombolysis with thrombus targeting and stealth activity recoverable by ultrasound.
abstract: OBJECTIVE
  The purpose of this study was to develop a new intelligent drug delivery system for intracoronary thrombolysis with a strong thrombolytic effect without increasing bleeding risk.
  
  
  BACKGROUND
  Rapid recanalization of an occluded coronary artery is essential for better outcomes in acute myocardial infarction. Catheter-based recanalization is widely accepted, but it takes time to transport patients. Although the current fibrinolytic therapy can be started quickly, it cannot achieve a high reperfusion rate. Recently, we generated nanoparticles comprising tissue-type plasminogen activator (tPA), basic gelatin, and zinc ions, which suppress tPA activity by 50% with 100% recovery by ultrasound (US) in vitro.
  
  
  METHODS
  The thrombus-targeting property of nanoparticles was examined by an in vitro binding assay with von Wilbrand factor and with a mouse arterial thrombosis model in vivo. The thrombolytic efficacy of nanoparticles was evaluated with a swine acute myocardial infarction model.
  
  
  RESULTS
  Nanoparticles bound to von Wilbrand factor in vitro and preferentially accumulated at the site of thrombus in a mouse model. In a swine acute myocardial infarction model, plasma tPA activity after intravenous injection of nanoparticles was approximately 25% of tPA alone and was recovered completely by transthoracic US (1.0 MHz, 1.0 W/cm(2)). During US application, plasma tPA activity near the affected coronary artery was recovered and was higher than that near the femoral artery. Although treatment with tPA alone (55,000 IU/kg) recanalized the occluded coronary artery in only 1 of 10 swine, nanoparticles containing the same dose of tPA with US achieved recanalization in 9 of 10 swine within 30 min.
  
  
  CONCLUSIONS
  We developed an intelligent drug delivery system with promising potential for better intravenous coronary thrombolysis.
authors.affiliation: First Department of Internal Medicine, Nara Medical University, Nara, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kawata
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Uesugi
authors.forename: Tsunenari
authors.initials: T
authors.lastname: Soeda
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takemoto
authors.forename: Ji-Hee
authors.initials: JH
authors.lastname: Sung
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Umaki
authors.forename: Keiji
authors.initials: K
authors.lastname: Kato
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ogiwara
authors.forename: Keiji
authors.initials: K
authors.lastname: Nogami
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ishigami
authors.forename: Manabu
authors.initials: M
authors.lastname: Horii
authors.forename: Shiro
authors.initials: S
authors.lastname: Uemura
authors.forename: Midori
authors.initials: M
authors.lastname: Shima
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tabata
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Saito
mesh_terms: D000818:Animals; D054059:Coronary Occlusion / Q000517:prevention & control; D003328:Coronary Thrombosis / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000517:prevention & control; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D004349:Drug Packaging; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D005780:Gelatin / Q000737:chemistry; D007275:Injections, Intravenous; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D053758:Nanoparticles / Q000737:chemistry*; D011859:Radiography; D013016:Sound; D013318:Stroke Volume; D013552:Swine; D015912:Thrombolytic Therapy / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000097:blood; D014463:Ultrasonography; D016277:Ventricular Function, Left; D019345:Zinc Acetate / Q000737:chemistry
chemical_list: D005343:Fibrinolytic Agents; D005780:Gelatin; D010959:Tissue Plasminogen Activator; D019345:Zinc Acetate