AIM: To develop a fibrin-specific urokinase nanomedicine thrombolytic agent. MATERIALS & 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. CONCLUSION: This agent offers a vascularly constrained, simple to administer, low-dose nanomedicine approach that may present an attractive alternative for treating acute stroke victims.
AIM: To develop a fibrin-specific urokinase nanomedicine thrombolytic agent. MATERIALS & 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. CONCLUSION: 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: Carlos A Molina; Andrew D Barreto; Georgios Tsivgoulis; Paul Sierzenski; Marc D Malkoff; Marta Rubiera; Nicole Gonzales; Robert Mikulik; Greg Pate; James Ostrem; Walter Singleton; Garen Manvelian; Evan C Unger; James C Grotta; Peter D Schellinger; Andrei V Alexandrov Journal: Ann Neurol Date: 2009-07 Impact factor: 10.422
Authors: Werner Hacke; Markku Kaste; Erich Bluhmki; Miroslav Brozman; Antoni Dávalos; Donata Guidetti; Vincent Larrue; Kennedy R Lees; Zakaria Medeghri; Thomas Machnig; Dietmar Schneider; Rüdiger von Kummer; Nils Wahlgren; Danilo Toni Journal: N Engl J Med Date: 2008-09-25 Impact factor: 91.245
Authors: Vincent N S Thijs; Andre Peeters; Milan Vosko; Franz Aichner; Peter D Schellinger; Dietmar Schneider; Tobias Neumann-Haefelin; Joachim Röther; Antoni Davalos; Nils Wahlgren; Peter Verhamme Journal: Stroke Date: 2009-10-15 Impact factor: 7.914
Authors: George J Shaw; Jason M Meunier; Shao-Ling Huang; Christopher J Lindsell; David D McPherson; Christy K Holland Journal: Thromb Res Date: 2009-02-13 Impact factor: 3.944
Authors: Patrick M Winter; Shelton D Caruthers; Huiying Zhang; Todd A Williams; Samuel A Wickline; Gregory M Lanza Journal: JACC Cardiovasc Imaging Date: 2008-09
Authors: Jason R McCarthy; Irina Y Sazonova; S Sibel Erdem; Tetsuya Hara; Brian D Thompson; Purvish Patel; Ion Botnaru; Charles P Lin; Guy L Reed; Ralph Weissleder; Farouc A Jaffer Journal: Nanomedicine (Lond) Date: 2012-02-21 Impact factor: 5.307