title: A fibrin-specific thrombolytic nanomedicine approach to acute ischemic stroke.
abstract: OBJECTIVE
  To develop a fibrin-specific urokinase nanomedicine thrombolytic agent.
  
  
  METHODS
  In vitro fibrin-clot dissolution studies were utilized to develop and characterize simultaneous coupling and loading of anti-fibrin monoclonal antibody and urokinase onto perfluorocarbon nanoparticle (NP) surface. In vivo pharmacokinetics and fibrin-specific targeting of the nanolytic agent was studied in dogs.
  
  
  RESULTS
  Simultaneous coupling of up to 40 anti-fibrin antibodies and 400 urokinase enzymes per perfluorocarbon NP produced an effective targeted nanolytic agent with no significant surface protein-protein interference. Fibrin clot dissolution was not improved by increasing homing capacity from 10 to 40 antibodies/NP, but increasing enzymatic payload from 100 to 400/NP resulted in maximized lytic effect. Fluorescent microscopy showed that rhodamine-labeled urokinase nanoparticles densely decorated the intraluminal thrombus in canine clots in vivo analogous to the fibrin pattern, while an irrelevant-targeted agent had negligible binding.
  
  
  CONCLUSIONS
  This agent offers a vascularly constrained, simple to administer, low-dose nanomedicine approach that may present an attractive alternative for treating acute stroke victims.
authors.affiliation: Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Jon N
authors.initials: JN
authors.lastname: Marsh
authors.forename: Grace
authors.initials: G
authors.lastname: Hu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Scott
authors.forename: Huiying
authors.initials: H
authors.lastname: Zhang
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Goette
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Gaffney
authors.forename: Shelton D
authors.initials: SD
authors.lastname: Caruthers
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Wickline
authors.forename: Dana
authors.initials: D
authors.lastname: Abendschein
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Lanza
mesh_terms: D000818:Animals; D004285:Dogs; D005337:Fibrin / Q000378:metabolism*; D005466:Fluorocarbons / Q000737:chemistry; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use*; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D005466:Fluorocarbons; D005337:Fibrin; D014568:Urokinase-Type Plasminogen Activator