Thrombolytic Treatment with Tissue-type Plasminogen Activator (t-PA) Containing Liposomes in Rabbits: a Comparison with Free t-PA

Abstract

SummaryIn 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-PAlmg/kg). On the other hand, liposome encapsulation did not affect the systemic activation of alpha2-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.

Accelerating thrombolysis with chitosan-coated plasminogen activators encapsulated in poly-(lactide-co-glycolide) (PLGA) nanoparticles

“…Hence, developing new cost-effective formulations or approaches, such as new PA delivery systems, to reduce the risk of side effects of conventional thrombolytic therapy is a worthy goal. For example, the use of liposomal-or PEG-encapsulating SK or t-PA microparticles has been demonstrated significantly to promote fibrinolysis and reduce blood loss in vivo animal [8,10,11] and in vitro models [12][13][14]. Related studies have elucidated the effect hemodynamic forces exerted by fluid on fibrinolysis such as the pressure-or convectiondriven permeation of fluid into clots [12][13][14].…”

“…The clinical benefits of administering PAs for thrombolytic therapy may be markedly improved by developing new methods to promote clot lysis with reduced side effects [7]. In this regard, a drug delivery strategy, such as encapsulating PAs (SK) into liposomes or polymeric microspheres as drug carriers, to increase the therapeutic efficacy of conventional thrombolytic therapy has been demonstrated in in vitro and in vivo animal models [8][9][10][11].…”

Liposomes in Diagnosis and Treatment of Cardiovascular Disorders

“…34 For treatment of Mi, a liposome-encapsulated thrombolytic agent (t-Pa) was compared with free t-Pa in a rabbit jugular vein thrombosis model. 35 injection of liposomal t-Pa had significantly better thrombolytic efficiency than equimolar doses of free t-Pa. on the other hand, liposome encapsulation of t-Pa did not affect the systemic activation of alpha 2-antiplasmin and plasminogen. For this model, improved thrombolytic efficacy of t-Pa is achieved by liposome encapsulation.…”

Advanced drug delivery systems for antithrombotic agents

“…17 ATAs encapsulated in PEG liposomes showed encouraging results in vitro and, to a more limited extent, in animal models. For example, liposomal PAs provided superior reperfusion vs free PAs in rabbit models of jugular vein 18 and carotid artery 19 thrombosis. Interactions with cells and lipoproteins, as well as the intense PEGylation needed for a strong stealth effect, destabilize liposomes, limiting their lifetime in the bloodstream.…”