STREPTOKINASE ENTRAPMENT IN INTERDIGITATION-FUSION LIPOSOMES IMPROVESTHROMBOLYSIS IN AN EXPERIMENTAL RABBIT MODEL

The successful design of new thrombolytic agents depends on providing these agents with increased clot selectivity. As recently demonstrated (10), entrapment of tissue plasminogen activator into liposomes appar ently provided the selective targeting needed to improve the efficacy of this fibrinolytic agent. To test whether liposomal entrapment would benefit streptokinase, a fibrinolytic agent with a different mode of action and inactivation, we compared liposomal streptokinase with free streptokinase in an experimental rabbit model of thrombolysis. First we adapted a new method to produce liposomes of high entrapment effici ency, termed interdigitation-fusion (IF) liposomes, for the encapsulat ion of streptokinase. This system was then tested in an in vivo rabbit model of thrombolysis where animals with established clots were infus ed with either free streptokinase (40,000 U/kg), liposomally entrapped streptokinase. free streptokinase + empty liposomes, or the correspon ding amount of empty liposomes or saline. Significant differences (p < 0.05) in the percent clot lysis were observed between saline control ( 22.4 +/- 3.3%, mean +/- S.E.), free streptokinase (36.3 +/- 3.4%), and liposomal streptokinase (47.4 +/- 1.4%). Importantly, animals treated with empty liposomes experienced a level of thrombolysis (32.4 +/- 2. 8%) not different to that produced by free streptokinase or empty lipo somes plus free streptokinase (38.0 +/- 2.0%). We believe the effect o f liposomes alone is due to a transient redistribution or margination of circulating platelets. When tested in rabbits immunized against str eptokinase, liposomal (33.8 +/- 1.5%) but not free streptokinase (29.3 +/- 2.1%) showed significant thrombolytic activity compared to saline (22.4 +/- 3.3%) (p <0.05). The thrombolytic activity was comparable t o free streptokinase in nonimmunized rabbits. This suggests liposomal streptokinase would have better thrombolytic activity than streptokina se alone and still provide to those patients possessing high levels of anti-streptokinase antibodies (5% of the population) the equivalent d egree of therapy expected from free streptokinase.