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.
References
1
De WoodDA,
Spores J,
Notske R,
Mouser LT,
Burroughs R,
Golden MS,
Lang HT.
Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. New Engl J Med 1980; 303: 897-902
11
Nguyen PD,
O’Rear EA,
Johnson AE,
Patterson E,
Whitsett TL,
Bhakta R.
Accelerated thrombolysis and reperfusion in a canine model of myocardial infarction by liposomal encapsulation of streptokinase. Circulation Res 1990; 66: 875-878
16
Jackson KW,
Esmon N,
Tang J.
Streptokinase and staphylokinase. Methods in Enzymology. Ed.
Perlman GE,
Lorand L.
Academic Press Inc; New York: 1980. 80. 387-394
22
Doerschuk CM,
Gie RP,
Bally MB,
Cullis PR,
Reinish LW.
Platelet distribution in rabbits following infusion of liposomes. Thromb Haemost 1989; 61: 392-396
25
Hsu MJ,
Juliano RL.
Interactions of liposomes with the reticuloendothelial system. II. Nonspecific and receptor mediated uptake of liposomes by mouse peritoneal macrophages. Biochim Biophys Acta 1982; 720: 411-419
26
Fitzgerald DJ,
Catella F,
Roy L,
Fitzgerald GA.
Marked platelet activation in vivo after intravenous streptokinase in patients with acute myocardial infarction. Circulation 1988; 77: 142-150
