title: Thrombolytic efficacy of tissue plasminogen activator-loaded echogenic liposomes in a rabbit thrombus model.
abstract: BACKGROUND
  Ultrasound (US)-enhanced thrombolytic treatment protocols currently in clinical trials for stroke applications involve systemic administration of tissue plasminogen activator (tPA; Alteplase), which carries a risk of adverse bleeding events. The present study aimed to compare the thrombolytic efficacy of a tPA-loaded echogenic liposome (ELIP) formulation with insonification protocols causing rapid fragmentation or acoustically-driven diffusion.
  
  
  METHODS
  Thrombi were induced in the abdominal aortas of male New Zealand white rabbits (2-3kg) using thrombin and a sclerosing agent (sodium ricinoleate) after aortic denudation with a balloon catheter. Thrombolytic and cavitation nucleation agents (200μg of tPA alone, tPA mixed with 50μg of a microbubble contrast agent, or tPA-loaded ELIP) were bolus- injected proximal to the clot through a catheter introduced into the abdominal aorta from the carotid artery. Clots were exposed to transabdominal color Doppler US (6MHz) for 30 minutes at a low mechanical index (MI=0.2) to induce sustained bubble activity (acoustically-driven diffusion), or for 2 minutes at an MI of 0.4 to cause ELIP fragmentation. Degree of recanalization was determined by Doppler flow measurements distal to the clots.
  
  
  RESULTS
  All treatments showed thrombolysis, but tPA-loaded ELIP was the most efficacious regimen. Both US treatment strategies enhanced thrombolytic activity over control conditions.
  
  
  CONCLUSIONS
  The thrombolytic efficacy of tPA-loaded ELIP is comparable to other clinically described effective treatment protocols, while offering the advantages of US monitoring and enhanced thrombolysis from a site-specific delivery agent.
authors: Dept. of Internal Medicine, Division of Cardiology, University of Texas Health Science Center, Houston.
authors: Susan T
authors: ST
authors: Laing
authors: Melanie R
authors: MR
authors: Moody
authors: Hyunggun
authors: H
authors: Kim
authors: Beverly
authors: B
authors: Smulevitz
authors: Shao-Ling
authors: SL
authors: Huang
authors: Christy K
authors: CK
authors: Holland
authors: David D
authors: DD
authors: McPherson
authors: Melvin E
authors: ME
authors: Klegerman
mesh_terms: D000818:Animals; D001011:Aorta / Q000000981:diagnostic imaging* / Q000187:drug effects* / Q000473:pathology; D003287:Contrast Media / Q000627:therapeutic use; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D008081:Liposomes; D008297:Male; D045423:Microbubbles / Q000627:therapeutic use; D011817:Rabbits; D013016:Sound; D013927:Thrombosis / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000627:therapeutic use*; D014464:Ultrasonic Therapy / Q000379:methods; D018617:Ultrasonography, Doppler, Pulsed / Q000379:methods
chemical_list: D003287:Contrast Media; D005343:Fibrinolytic Agents; D008081:Liposomes; D010959:Tissue Plasminogen Activator