title: Thrombolytic treatment with tissue-type plasminogen activator (t-PA) containing liposomes in rabbits: a comparison with free t-PA.
abstract: In this study, we aimed at improving the therapeutic index of tissue-type Plasminogen Activator (t-PA) as thrombolytic agent in the treatment of myocardial infarction. Liposome-encapsulated t-PA was tested in a rabbit jugular vein thrombosis model: administration of free t-PA (t-PA) as a bolus injection in the ear vein was compared to a similar administration of liposomal t-PA (t-PA-lip), liposomal t-PA in plasminogen-coated liposomes (Plg-t-PA-lip), a mixture of free t-PA and empty liposomes (t-PA+ empty lip) and a saline-blank (blank) in terms of thrombolytic activity and side effects. Liposomal t-PA (t-PA-lip/Plg-t-PA-lip) showed a significantly better thrombolysis efficiency than equimolar doses of free t-PA (t-PA/ t-PA+ empty lip): about 0.24 mg/kg of liposomal t-PA practically equalled the lysis-activity of a dose of free t-PA of 1.0 mg/kg (t-PA1mg/kg). On the other hand, liposome encapsulation did not affect the systemic activation of alpha 2-antiplasmin and plasminogen by t-PA. We conclude that for this model an improvement in thrombolytic efficacy of t-PA is achieved by liposome encapsulation of t-PA. As t-PA-lip and Plg-t-PA-lip -treatment induced similar results, targeting of liposomal t-PA by coupled glu-Plg remains a topic to be optimized in future studies.
authors.affiliation: Dept. of Pharmaceutics, Utrecht University, The Netherlands.
authors.forename: J L
authors.initials: JL
authors.lastname: Heeremans
authors.forename: R
authors.initials: R
authors.lastname: Prevost
authors.forename: M E
authors.initials: ME
authors.lastname: Bekkers
authors.forename: P
authors.initials: P
authors.lastname: Los
authors.forename: J J
authors.initials: JJ
authors.lastname: Emeis
authors.forename: C
authors.initials: C
authors.lastname: Kluft
authors.forename: D J
authors.initials: DJ
authors.lastname: Crommelin
mesh_terms: D000818:Animals; D004337:Drug Carriers; D004339:Drug Compounding; D004353:Drug Evaluation, Preclinical; D007601:Jugular Veins; D008081:Liposomes; D010958:Plasminogen / Q000008:administration & dosage / Q000032:analysis; D011817:Rabbits; D015912:Thrombolytic Therapy; D013927:Thrombosis / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity
chemical_list: D004337:Drug Carriers; D008081:Liposomes; D010958:Plasminogen; D010959:Tissue Plasminogen Activator