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Tissue plasminogen activator-based clot busting: Controlled delivery approaches.

El-Sherbiny IM, Elkholi IE, Yacoub MH - Glob Cardiol Sci Pract (2014)

Bottom Line: Although tPA provides powerful thrombolytic activity, it has many shortcomings, including poor pharmacokinetic profiles, impairment of the reestablishment of normal coronary flow, and impairment of hemostasis, leading to life-threatening bleeding consequences.The bleeding consequence is ascribed to the ability of tPA to circulate throughout the body and therefore can lysis all blood clots in the circulation system, even the good ones that prevent the bleeding and promote injury repair.This review provides an overview of the different delivery approaches for tPA including: liposomes, ultrasound-triggered thrombolysis, anti-fibrin antibody-targeted tPA, camouflaged-tPA, tpA-loaded microcarriers, and nano-modulated delivery approaches.

View Article: PubMed Central - PubMed

Affiliation: Zewail City of Science and Technology, Center for Materials Science, University of Science and Technology, 6th October City, 12588 Giza, Egypt.

ABSTRACT
Cardiovascular diseases are the leading cause of death worldwide. Thrombosis, the formation of blood clot (thrombus) in the circulatory system obstructing the blood flow, is one of the main causes behind various ischemic arterial syndromes such as ischemic stroke and myocardial infarction, as well as vein syndromes such as deep vein thrombosis, and consequently, pulmonary emboli. Several thrombolytic agents have been developed for treating thrombosis, the most common being tissue plasminogen activator (tPA), administrated systemically or locally via IV infusion directly proximal to the thrombus, with the aim of restoring and improving the blood flow. TPA triggers the dissolution of thrombi by inducing the conversion of plasminogen to protease plasmin followed by fibrin digestion that eventually leads to clot lysis. Although tPA provides powerful thrombolytic activity, it has many shortcomings, including poor pharmacokinetic profiles, impairment of the reestablishment of normal coronary flow, and impairment of hemostasis, leading to life-threatening bleeding consequences. The bleeding consequence is ascribed to the ability of tPA to circulate throughout the body and therefore can lysis all blood clots in the circulation system, even the good ones that prevent the bleeding and promote injury repair. This review provides an overview of the different delivery approaches for tPA including: liposomes, ultrasound-triggered thrombolysis, anti-fibrin antibody-targeted tPA, camouflaged-tPA, tpA-loaded microcarriers, and nano-modulated delivery approaches.

No MeSH data available.


Related in: MedlinePlus

An illustration of the various camouflaged-tPA delivery approaches. Adopted with modification from Absar et al.92–94
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Related In: Results  -  Collection


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fig4: An illustration of the various camouflaged-tPA delivery approaches. Adopted with modification from Absar et al.92–94

Mentions: In a number of studies,92–94 Absar et al. tried to introduce an efficient delivery system for tPA. Camouflaged-tPA was produced by conjugating tPA with low molecular weight heparin (LMWH) followed by complexion of this conjugate with albumin-protamine.92 The administration of heparin with tPA led to 71% clot lysis, which is more effective than tPA alone (52% clot lysis). However, using heparin with tPA increased the bleeding risk, which led to a two-fold increase in activated partial thromboplastin time (aPTT). In a contrary situation, albumin-camouflaged heparin triggered strategy achieved a similar clot lysis activity (70%) compared to tPA plus heparin administration, but with no prolongation of aPTT after 1 hour of treatment. This indicates that the camouflaged-tPA can be applied for targeted thrombolysis with a reduced risk of hemorrhage.92 Based on the fact that LMWH is a therapeutically active molecule, Absar et al. in another study93, have tested a relatively inert negatively-charged compound to synthesize oligoanion-modified tPA to avoid any potential side effects. The tPA was conjugated to polyglutamate, and separately the human serum albumin (HSA) was conjugated to protamine. The conjugation of tPA with polyglutamate forms a reversible electrostatic complex that could be disrupted by negatively charged heparin via competitive binding. The electrostatic complex formation between polyglutamate and protamine can be reversed by heparin also. It was found that camouflaged-tPA heparin triggered delivery system demonstrated higher activity than the un-camouflaged tPA, where this higher activity may be attributed to the protection of camouflaged tPA from its macromolecular inhibitors. In another modification for the camouflaged-tPA delivery system, Absar and his colleagues94 have conjugated tPA with HSA via a thrombin-cleavable peptide or linker (GFPRGFPAGGC). In addition, the surface of albumin was decorated by the peptide sequence (CQQHHLGGAKQAGDV) of fibrinogen gamma-chain that has the affinity to bind with GPIIb/IIIa receptors, which are expressed on activated platelets. This conjugate showed an activity of 25%, which increased to about 86% of that of native tPA when the conjugate was incubated with thrombin. This approach can introduce an efficient delivery system for tPA working in an on/off triggered manner (Figure 4).


Tissue plasminogen activator-based clot busting: Controlled delivery approaches.

El-Sherbiny IM, Elkholi IE, Yacoub MH - Glob Cardiol Sci Pract (2014)

An illustration of the various camouflaged-tPA delivery approaches. Adopted with modification from Absar et al.92–94
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4352685&req=5

fig4: An illustration of the various camouflaged-tPA delivery approaches. Adopted with modification from Absar et al.92–94
Mentions: In a number of studies,92–94 Absar et al. tried to introduce an efficient delivery system for tPA. Camouflaged-tPA was produced by conjugating tPA with low molecular weight heparin (LMWH) followed by complexion of this conjugate with albumin-protamine.92 The administration of heparin with tPA led to 71% clot lysis, which is more effective than tPA alone (52% clot lysis). However, using heparin with tPA increased the bleeding risk, which led to a two-fold increase in activated partial thromboplastin time (aPTT). In a contrary situation, albumin-camouflaged heparin triggered strategy achieved a similar clot lysis activity (70%) compared to tPA plus heparin administration, but with no prolongation of aPTT after 1 hour of treatment. This indicates that the camouflaged-tPA can be applied for targeted thrombolysis with a reduced risk of hemorrhage.92 Based on the fact that LMWH is a therapeutically active molecule, Absar et al. in another study93, have tested a relatively inert negatively-charged compound to synthesize oligoanion-modified tPA to avoid any potential side effects. The tPA was conjugated to polyglutamate, and separately the human serum albumin (HSA) was conjugated to protamine. The conjugation of tPA with polyglutamate forms a reversible electrostatic complex that could be disrupted by negatively charged heparin via competitive binding. The electrostatic complex formation between polyglutamate and protamine can be reversed by heparin also. It was found that camouflaged-tPA heparin triggered delivery system demonstrated higher activity than the un-camouflaged tPA, where this higher activity may be attributed to the protection of camouflaged tPA from its macromolecular inhibitors. In another modification for the camouflaged-tPA delivery system, Absar and his colleagues94 have conjugated tPA with HSA via a thrombin-cleavable peptide or linker (GFPRGFPAGGC). In addition, the surface of albumin was decorated by the peptide sequence (CQQHHLGGAKQAGDV) of fibrinogen gamma-chain that has the affinity to bind with GPIIb/IIIa receptors, which are expressed on activated platelets. This conjugate showed an activity of 25%, which increased to about 86% of that of native tPA when the conjugate was incubated with thrombin. This approach can introduce an efficient delivery system for tPA working in an on/off triggered manner (Figure 4).

Bottom Line: Although tPA provides powerful thrombolytic activity, it has many shortcomings, including poor pharmacokinetic profiles, impairment of the reestablishment of normal coronary flow, and impairment of hemostasis, leading to life-threatening bleeding consequences.The bleeding consequence is ascribed to the ability of tPA to circulate throughout the body and therefore can lysis all blood clots in the circulation system, even the good ones that prevent the bleeding and promote injury repair.This review provides an overview of the different delivery approaches for tPA including: liposomes, ultrasound-triggered thrombolysis, anti-fibrin antibody-targeted tPA, camouflaged-tPA, tpA-loaded microcarriers, and nano-modulated delivery approaches.

View Article: PubMed Central - PubMed

Affiliation: Zewail City of Science and Technology, Center for Materials Science, University of Science and Technology, 6th October City, 12588 Giza, Egypt.

ABSTRACT
Cardiovascular diseases are the leading cause of death worldwide. Thrombosis, the formation of blood clot (thrombus) in the circulatory system obstructing the blood flow, is one of the main causes behind various ischemic arterial syndromes such as ischemic stroke and myocardial infarction, as well as vein syndromes such as deep vein thrombosis, and consequently, pulmonary emboli. Several thrombolytic agents have been developed for treating thrombosis, the most common being tissue plasminogen activator (tPA), administrated systemically or locally via IV infusion directly proximal to the thrombus, with the aim of restoring and improving the blood flow. TPA triggers the dissolution of thrombi by inducing the conversion of plasminogen to protease plasmin followed by fibrin digestion that eventually leads to clot lysis. Although tPA provides powerful thrombolytic activity, it has many shortcomings, including poor pharmacokinetic profiles, impairment of the reestablishment of normal coronary flow, and impairment of hemostasis, leading to life-threatening bleeding consequences. The bleeding consequence is ascribed to the ability of tPA to circulate throughout the body and therefore can lysis all blood clots in the circulation system, even the good ones that prevent the bleeding and promote injury repair. This review provides an overview of the different delivery approaches for tPA including: liposomes, ultrasound-triggered thrombolysis, anti-fibrin antibody-targeted tPA, camouflaged-tPA, tpA-loaded microcarriers, and nano-modulated delivery approaches.

No MeSH data available.


Related in: MedlinePlus