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Thrombus-targeted nanocarrier attenuates bleeding complications associated with conventional thrombolytic therapy

To test the hypothesis that thrombus-specific tissue plasminogen activator (tPA)-loaded nanocarriers enhance thrombolytic efficacy and attenuate hemorrhagic complications. A series of pegylated and non-pegylated tPA-loaded liposomes were prepared and their surfaces were decorated with the peptide se... Full description

Journal Title: Pharmaceutical research June 2013, Vol.30(6), pp.1663-76
Main Author: Absar, Shahriar
Other Authors: Nahar, Kamrun , Kwon, Young Min , Ahsan, Fakhrul
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1573-904X ; PMID: 23468049 Version:1 ; DOI: 10.1007/s11095-013-1011-x
Link: http://pubmed.gov/23468049
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recordid: medline23468049
title: Thrombus-targeted nanocarrier attenuates bleeding complications associated with conventional thrombolytic therapy
format: Article
creator:
  • Absar, Shahriar
  • Nahar, Kamrun
  • Kwon, Young Min
  • Ahsan, Fakhrul
subjects:
  • Drug Carriers -- Administration & Dosage
  • Hemorrhage -- Drug Therapy
  • Nanoparticles -- Administration & Dosage
  • Thrombolytic Therapy -- Methods
  • Thrombosis -- Metabolism
  • Tissue Plasminogen Activator -- Pharmacology
ispartof: Pharmaceutical research, June 2013, Vol.30(6), pp.1663-76
description: To test the hypothesis that thrombus-specific tissue plasminogen activator (tPA)-loaded nanocarriers enhance thrombolytic efficacy and attenuate hemorrhagic complications. A series of pegylated and non-pegylated tPA-loaded liposomes were prepared and their surfaces were decorated with the peptide sequence (CQQHHLGGAKQAGDV) of fibrinogen gamma-chain that binds with GPIIb/IIIa expressed on activated platelets. All formulations were characterized for physical properties, stability and in vitro release profile. The thrombolytic activities of tPA-loaded liposomes were tested by visual end-point detection, fibrin agar-plate and human blood clot-lysis assays. The thrombus-specificity of the peptide-modified-liposomes was evaluated by studying the binding of fluorescent peptide-liposomes with activated platelets. The pharmacokinetic profile and thrombolytic efficacy were evaluated in healthy rats and an inferior vena-cava rat model of thrombosis, respectively. Both pegylated and non-pegylated peptide-modified-liposomes showed favorable physical characteristics and colloidal stability. Formulations exhibited an initial burst release (40-50% in 30 min) followed by a continuous release of tPA (80-90% in 24 h) in vitro. Encapsulated tPA retained >90% fibrinolytic activity as compared to that of native tPA. Peptide-grafted-liposomes containing tPA demonstrated an affinity to bind with activated platelets. The half-life of tPA was extended from 7 to 103 and 141 min for non-pegylated and pegylated liposomes, respectively. Compared to native tPA, liposomal-tPA caused a 35% increase in clot-lysis, but produced a 4.3-fold less depletion of circulating fibrinogen. tPA-loaded homing-peptide-grafted-liposomes demonstrate enhanced thrombolytic activity with reduced hemorrhagic risk.
language: eng
source:
identifier: E-ISSN: 1573-904X ; PMID: 23468049 Version:1 ; DOI: 10.1007/s11095-013-1011-x
fulltext: fulltext
issn:
  • 1573904X
  • 1573-904X
url: Link


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titleThrombus-targeted nanocarrier attenuates bleeding complications associated with conventional thrombolytic therapy
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ispartofPharmaceutical research, June 2013, Vol.30(6), pp.1663-76
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subjectDrug Carriers -- Administration & Dosage ; Hemorrhage -- Drug Therapy ; Nanoparticles -- Administration & Dosage ; Thrombolytic Therapy -- Methods ; Thrombosis -- Metabolism ; Tissue Plasminogen Activator -- Pharmacology
descriptionTo test the hypothesis that thrombus-specific tissue plasminogen activator (tPA)-loaded nanocarriers enhance thrombolytic efficacy and attenuate hemorrhagic complications. A series of pegylated and non-pegylated tPA-loaded liposomes were prepared and their surfaces were decorated with the peptide sequence (CQQHHLGGAKQAGDV) of fibrinogen gamma-chain that binds with GPIIb/IIIa expressed on activated platelets. All formulations were characterized for physical properties, stability and in vitro release profile. The thrombolytic activities of tPA-loaded liposomes were tested by visual end-point detection, fibrin agar-plate and human blood clot-lysis assays. The thrombus-specificity of the peptide-modified-liposomes was evaluated by studying the binding of fluorescent peptide-liposomes with activated platelets. The pharmacokinetic profile and thrombolytic efficacy were evaluated in healthy rats and an inferior vena-cava rat model of thrombosis, respectively. Both pegylated and non-pegylated peptide-modified-liposomes showed favorable physical characteristics and colloidal stability. Formulations exhibited an initial burst release (40-50% in 30 min) followed by a continuous release of tPA (80-90% in 24 h) in vitro. Encapsulated tPA retained >90% fibrinolytic activity as compared to that of native tPA. Peptide-grafted-liposomes containing tPA demonstrated an affinity to bind with activated platelets. The half-life of tPA was extended from 7 to 103 and 141 min for non-pegylated and pegylated liposomes, respectively. Compared to native tPA, liposomal-tPA caused a 35% increase in clot-lysis, but produced a 4.3-fold less depletion of circulating fibrinogen. tPA-loaded homing-peptide-grafted-liposomes demonstrate enhanced thrombolytic activity with reduced hemorrhagic risk.
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titleThrombus-targeted nanocarrier attenuates bleeding complications associated with conventional thrombolytic therapy
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2Both pegylated and non-pegylated peptide-modified-liposomes showed favorable physical characteristics and colloidal stability. Formulations exhibited an initial burst release (40-50% in 30 min) followed by a continuous release of tPA (80-90% in 24 h) in vitro. Encapsulated tPA retained >90% fibrinolytic activity as compared to that of native tPA. Peptide-grafted-liposomes containing tPA demonstrated an affinity to bind with activated platelets. The half-life of tPA was extended from 7 to 103 and 141 min for non-pegylated and pegylated liposomes, respectively. Compared to native tPA, liposomal-tPA caused a 35% increase in clot-lysis, but produced a 4.3-fold less depletion of circulating fibrinogen.
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abstractTo test the hypothesis that thrombus-specific tissue plasminogen activator (tPA)-loaded nanocarriers enhance thrombolytic efficacy and attenuate hemorrhagic complications.
doi10.1007/s11095-013-1011-x
pmid23468049
issn07248741
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date2013-06