Platelet-targeted fibrinolysis enhances clot lysis and inhibits platelet aggregation.

Bode, Christoph; Meinhardt, Gabriel; Runge, Marschall S.; Freitag, Mathias; Nordt, Thomas K.; Arens, Matthias; Newell, John; Kübler, W.; Haber, Edgar

doi:10.1161/01.cir.84.2.805

Cited by 69 publications

(43 citation statements)

References 31 publications

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“…The SK activity was determined according to the previously reported method (Bode et al, 1991;Couto et al, 2004) with a slight modification. Entrapment efficiency was calculated by the following equation: C/T Â 100 (C: amount of SK incorporated into liposome, T: total amount of SK).…”

Section: Physicochemical Properties Of Liposomesmentioning

confidence: 99%

Development and characterization of highly selective target-sensitive liposomes for the delivery of streptokinase: in vitro/in vivo studies

et al. 2014

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Streptokinase is one of the most commonly used thrombolytic agents for the treatment of thromboembolism. Short half-life of the streptokinase requires administration of higher dose which results in various side effects including systemic haemorrhage due to activation of systemic plasmin. To increase the selectivity of the streptokinase and hence to reduce side effects, various novel carriers have been developed. Among these carriers, liposomes have been emerged as versatile carrier. In the present study, highly selective target-sensitive liposomes were developed and evaluated by in vitro and in vivo studies. Prepared liposomes were found to release streptokinase in vitro following binding with activated platelets. Intravital microscopy studies in thrombosed murine model revealed higher accumulation of liposomes in the thrombus area. In vivo thrombolysis study was performed in the human clot inoculated rat model. Results of the study showed that target-sensitive liposomes dissolved 28.27 ± 1.56% thrombus as compared to 17.18 ± 1.23% of non-liposomal streptokinase. Further, it was also observed that target-sensitive liposomes reduced the clot dissolution time as compared to streptokinase solution. Studies concluded that developed liposomes might be pragmatic carriers for the treatment of thromboembolism.

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Section: Physicochemical Properties Of Liposomesmentioning

confidence: 99%

Development and characterization of highly selective target-sensitive liposomes for the delivery of streptokinase: in vitro/in vivo studies

et al. 2014

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“…Thrombin is preferentially expressed on the shell of nascent thrombi, where platelet turnover is occurring, whereas in preexisting clots, any residual thrombin is sequestered within the core, where it is less accessible to platelets (18). Drugs used in previous attempts to target uPA to platelets have lacked the thrombin activation mechanism, had short circulating half-lives, and failed to avoid systemic fibrinolysis (19).…”

Section: Discussionmentioning

confidence: 99%

A chimeric platelet-targeted urokinase prodrug selectively blocks new thrombus formation

Fuentes

Зайцев

Ahn

et al. 2015

Journal of Clinical Investigation

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“…32 Despite increasing the potency by fusing PAs to monoclonal antibodies or Fab fragments, chemical conjugation has several disadvantages, including the inactivation of enzymatic sites by the harsh chemical conditions for conjugating, which can reduce efficacy. 31,33 In addition, the large size of the antibody fusion constructs hampered tissue penetration.…”

Section: Discussionmentioning

confidence: 99%

Towards Effective and Safe Thrombolysis and Thromboprophylaxis

Wang¹,

Palasubramaniam²,

Gkanatsas³

et al. 2014

Circulation Research

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Rationale: Fibrinolysis is a valuable alternative for the treatment of myocardial infarction when percutaneous coronary intervention is not available in a timely fashion. For acute ischemic stroke, fibrinolysis is the only treatment option with a very narrow therapeutic window. Clinically approved thrombolytics have significant drawbacks, including bleeding complications. Thus their use is highly restricted, leaving many patients untreated. Objective: We developed a novel targeted fibrinolytic drug that is directed against activated platelets. Methods and Results: We fused single-chain urokinase plasminogen activator (scuPA) to a small recombinant antibody (scFv SCE5 ), which targets the activated form of the platelet–integrin glycoprotein IIb/IIIa. Antibody binding and scuPA activity of this recombinant fusion protein were on par with the parent molecules. Prophylactic in vivo administration of scFv SCE5 –scuPA (75 U/g body weight) prevented carotid artery occlusion after ferric chloride injury in a plasminogen-dependent process compared with saline ( P <0.001), and blood flow recovery was similar to high-dose nontargeted urokinase (500 U/g body weight). Tail bleeding time was significantly prolonged with this high dose of nontargeted urokinase, but not with equally effective targeted scFv SCE5 –scuPA at 75 U/g body weight. Real-time in vivo molecular ultrasound imaging demonstrates significant therapeutic reduction of thrombus size after administration of 75 U/g body weight scFv SCE5 –scuPA as compared with the same dose of a mutated, nontargeting scFv–scuPA or vehicle. The ability of scFv SCE5 –scuPA to lyse thrombi was lost in plasminogen-deficient mice, but could be restored by intravenous injection of plasminogen. Conclusions: Targeting of scuPA to activated glycoprotein IIb/IIIa allows effective thrombolysis and the potential novel use as a fibrinolytic agent for thromboprophylaxis without bleeding complications.

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Platelet-targeted fibrinolysis enhances clot lysis and inhibits platelet aggregation.

Abstract: Therefore, the targeting of urokinase to the GP IIb/IIIa platelet receptor both accelerates clot lysis (when platelets are associated with a fibrin clot) and inhibits platelet aggregation.

Cited by 69 publications

References 31 publications

Development and characterization of highly selective target-sensitive liposomes for the delivery of streptokinase: in vitro/in vivo studies

Development and characterization of highly selective target-sensitive liposomes for the delivery of streptokinase: in vitro/in vivo studies

A chimeric platelet-targeted urokinase prodrug selectively blocks new thrombus formation

Towards Effective and Safe Thrombolysis and Thromboprophylaxis

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