Subscribe to RSS
DOI: 10.1055/s-0038-1653802
Thrombolytic Treatment with Tissue-type Plasminogen Activator (t-PA) Containing Liposomes in Rabbits: a Comparison with Free t-PA
Publication History
Received 25 August 1994
Accepted after resubmission 29 November 1994
Publication Date:
26 July 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/199503/lookinside/thumbnails/10-1055-s-0038-1653802-1.jpg)
Summary
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-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.
-
References
- 1 Gaffney PJ. Tissue plasminogen activator for thrombolytic therapy: expectation versus reality. Journal of the Royal Society of Medicine 1992; 85: 692-698
- 2 Collen D. Plasminogen activators and thrombolytic therapy. In: ISI Atlas of Science: Pharmacology. 1988; pp 116-120
- 3 Owen J, Friedman KD, Grossman BA, Wilkins C, Berke AD, Powers ER. Thrombolytic therapy with tissue plasminogen activator or streptokinase induces transient thrombin activity. Blood 1988; 72 (02) 616-620
- 4 Seitz R, Blanke H, Strauer BE, Egbring R. Increased thrombin activity during thrombolysis. Thromb Haemost 1988; 59 (03) 541-542
- 5 Seitz R, Pelzer H, Immel A, Egbring R. Prothrombin activation by thrombolytic agents. Fibrinolysis 1993; 7: 109-115
- 6 Andreotti F, Kluft C, Hackett DR, Davies GJ, Maseri A. Thrombin generation after fast or prolonged regimens of tissue-type plasminogen activator. The Lancet 1993; 342: 937-938
- 7 Gram J, Munkvad S, Leebeek FW G, Kluft C, Jespersen J. Reactive coagulation induced by plasmin in patients treated with recombinant tissue-type plasminogen activator. Coronary Artery Disease 1993; 4: 371-377
- 8 Kluft C, Verheyen JH. Plasminogen activators as pharmaceutical enzymes. In: Topics in pharmaceutical sciences. Breimer DD, Commelin DJ A, Midha KK. eds. Fédération Internationale Pharmaceutique. 1989: 153-176
- 9 Gold HK, Leinbach RC, Garabedian HD, Yasuda T, Johns JA, Grossbard EB, Palacios I, Collen D. Acute coronary reocclusion after thrombolysis with recombinant human tissue-type plasminogen activator: prevention by a maintenance infusion. Circulation 1986; 73 (02) 347-352
- 10 Martin U, Sponer G, Strein K. Evaluation of thrombolytic and systemic effects of the novel recombinant plasminogen activator BM 06.022 compared with alteplase, anistreplase, streptokinase and urokinase in a canine model of coronary artery thrombosis. J Am Coll Cardiol 1992; 19: 433-440
- 11 Crommelin DJ A, Kluft C. Pharmaceutical composition for site-specific release of a clot-dissolving protein. Patent Appl No PCT/NL93/00195, 1993
- 12 Poznansky MJ, Juliano RL. Biological approaches to the controlled delivery of drugs: a critical review. Pharmacol Rev 1984; 36: 277-336
- 13 Heeremans JL M, Kraaijenga JJ, Los P, Kluft C, Crommelin DJ A. Development of a procedure for coupling the homing device glu-plasminogen to liposomes. Biochim Biophys Acta 1992; 1117: 258-264
- 14 Collen D, Stassen JM, Verstraete M. Thrombolysis with human extrinsic tissue-type plasminogen activator in rabbits with experimental jugular vein thrombosis. J Clin Invest 1983; 71: 368-376
- 15 Martin FJ, Papahadjopoulos D. Irreversible coupling of immuno-globulin fragments to preformed vesicles. J Biol Chem 1982; 257 (01) 286-288
- 16 Bangham AD, Standish MM, Watkins JC. Diffusion of univalent ions across the lamellae of swollen phospholipids. J Mol Biol 1965; 13: 238-252
- 17 Hope MJ, Bally MB, Mayer LD, Janoff AS, Cullis PR. Generation of multilamellar and unilamellar phospholipid vesicles. Chem and Phys of Lipids 1986; 40: 89-107
- 18 Chapman CJ, Erdahl WL, Taylor RW, Pfeiffer DR. Factors effecting solute entrapment in phospholipid vesicles prepared by the freeze-thaw extrusion method: a possible general method for improving the efficiency of entrapment. Chemistry and Physics of Lipids 1990; 55: 73-83
- 19 Gibaldi M, Perrier D. Multicompartment models. In: Pharmacokinetics. Marcel Dekker Inc; New York: 1982. pp 45-111
- 20 Korninger C, Stassen JM, Collen D. Turnover of human extrinsic (tissue- type) plasminogen activator in rabbits. Thromb Haemost 1981; 46 (03) 658-661
- 21 Verstraete M, Bounameaux H, Cock F, Van de Werf F, Collen D. Pharma cokinetics and systemic fibrinogenolytic effects of recombinant human tissue-type plasminogen activator (rt-PA) in humans. J Pharm Exp Ther 1985; 235 (02) 506-512
- 22 Fiske CH, Subbarow Y. The colorimetric determination of phosphorus. J Biol Chem 1925; 66: 375-400
- 23 Rijken DC, Wijngaards G, Zaal de Jong M, Welbergen J. Purification and partial characterization of plasminogen activator from human uterine tissue. Biochim Biophys Acta 1979; 580: 140-153
- 24 Emeis JJ, Verheijen JH. Thrombolytic properties in a rabbit jugular vein thrombosis model of a tissue-type plasminogen activator mutant lacking the growth factor- and kringle one- domains. Arzneimittel-Forschung/Drug Research 1992; 42 (01) 358-362
- 25 Mohler MA, Refino CJ, Chen AB, Hotchkiss AJ. D-Phe-Pro-Arg-Chloro-methylketone: its potential use in inhibiting the formation of in vitro artifacts in blood collected during tissue-type plasminogen activator thrombolytic therapy. Thromb Haemost 1986; 56 (02) 160-164
- 26 Mussoni L, Raczka E, Chmielewska J, Donati MB, Latallo ZS. Plasminogen assay in rabbit, rat and mouse plasma using the chromogenic substrate S-2251. Thromb Res 1979; 15: 341-349
- 27 Kluft C. a2-Antiplasmin activity. In: ECAT assay procedures. A manual of laboratory techniques. Jespersen J, Bertina RM, Haverkate F. eds. Dordrecht: 1992. pp 165-171
- 28 Senior J. Fate and behaviour of liposomes in vivo: a review of controlling factors. CRC Crit Rev Therapeut Drug Carrier Syst 1987; 3: 123-193
- 29 Crommelin DJ A, Schreier H. Liposomes. In: Colloidal drug delivery systems. Kreuter J. ed. Marcel Dekker Inc; New York: 1994. pp 73-190
- 30 Blume G, Cevc G, Crommelin DJ, Bakker-Woudenberg IA J M, Kluft C, Storm G. Specific targeting with polyethylene glycolj-modified liposomes: coupling of homing devices to the ends of the polymeric chains combines effective target binding with long circulation times. Biochim Biophys Acta 1993; 1149: 180-184
- 31 Woodle MC, Storm G, Newman MS, Jekot JJ, Collins LR, Martin FJ, Szoka FC. Prolonged systemic delivery of peptide drugs by long-circulating liposomes: illustration with vasopressin in the brattleboro rat. Pharm Res 1992; 9 (02) 260-265