title: Thrombus-targeted nanocarrier attenuates bleeding complications associated with conventional thrombolytic therapy.
abstract: OBJECTIVE
  To test the hypothesis that thrombus-specific tissue plasminogen activator (tPA)-loaded nanocarriers enhance thrombolytic efficacy and attenuate hemorrhagic complications.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  tPA-loaded homing-peptide-grafted-liposomes demonstrate enhanced thrombolytic activity with reduced hemorrhagic risk.
authors.affiliation: Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, 1300 Coulter St., Amarillo, Texas 79106, USA.
authors.forename: Shahriar
authors.initials: S
authors.lastname: Absar
authors.forename: Kamrun
authors.initials: K
authors.lastname: Nahar
authors.forename: Young Min
authors.initials: YM
authors.lastname: Kwon
authors.forename: Fakhrul
authors.initials: F
authors.lastname: Ahsan
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004337:Drug Carriers / Q000008:administration & dosage* / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000378:metabolism; D006207:Half-Life; D006470:Hemorrhage / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage / Q000378:metabolism; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage* / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015912:Thrombolytic Therapy / Q000379:methods*; D013927:Thrombosis / Q000188:drug therapy / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D004337:Drug Carriers; D005343:Fibrinolytic Agents; D008081:Liposomes; D010455:Peptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C027539:fibrinopeptides gamma; D005337:Fibrin; D005340:Fibrinogen; D010959:Tissue Plasminogen Activator