Summary
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 apparently 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 efficiency,
termed interdigitation-fusion (IF) liposomes, for the encapsulation of streptokinase.
This system was then tested in an in vivo rabbit model of thrombolysis where animals
with established clots were infused with either free streptokinase (40,000 U/kg),
liposomally entrapped streptokinase, free streptokinase + empty liposomes, or the
corresponding 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 liposomes
plus free streptokinase (38.0 ± 2.0%). We believe the effect of liposomes alone is
due to a transient redistribution or margination of circulating platelets.
When tested in rabbits immunized against streptokinase, 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 to free
streptokinase in nonimmunized rabbits. This suggests liposomal streptokinase would
have better thrombolytic activity than streptokinase alone and still provide to those
patients possessing high levels of anti-streptokinase antibodies (5% of the population)
the equivalent degree of therapy expected from free streptokinase.
