A New Drug Delivery System for Intravenous Coronary Thrombolysis With Thrombus Targeting and Stealth Activity Recoverable by Ultrasound

作者：Kawata Hiroyuki; Uesugi Yoshiko; Soeda Tsunenari; Takemoto Yasuhiro; Sung Ji Hee; Umaki Kiyotaka; Kato Keiji; Ogiwara Kenichi; Nogami Keiji; Ishigami Kenichi; Horii Manabu; Uemura Shiro; Shima Midori; Tabata Yasuhiko; Saito Yoshihiko^*

来源：Journal of the American College of Cardiology, 2012, 60(24): 2550-2557.

DOI：10.1016/j.jacc.2012.08.1008

• acute myocardial infarction
• drug delivery system
• plasminogen activators
• thrombolysis
• ultrasound

Objectives 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.

• 出版日期2012-12-18