title: Engineering of plasminogen activators for targeting to thrombus and heightening thrombolytic efficacy.
abstract: Thrombotic occlusion of the coronary artery, which triggers acute myocardial infarction, is one of the major causes of death in the USA. Currently, arterial occlusions are treated with intravenous plasminogen activators (PAs), which dissolve the clot by activating plasminogen. However, PAs indiscriminately generate plasmin, which depletes critical clotting factors (fibrinogen, factor V, and factor VIII), precipitates a lytic state in the blood, and produces bleeding complications in a large patient population. PAs have been extensively investigated to achieve thrombus specificity, to attenuate the bleeding risk, and to widen their clinical applications. In this review, we discuss various strategies that have been pursued since the beginning of thrombolytic therapy. We review the biotechnological approaches that have been used to develop mutant and chimeric PAs for thrombus selectivity, including the use of specific antibodies for targeting thrombi. We discuss particulate carrier-based systems and triggered-release concepts. We propose new hypotheses and strategies to spur future studies in this research arena. Overall, we describe the approaches and accomplishments in the development of patient-friendly and workable delivery systems for thrombolytic drugs.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Absar
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
authors.forename: N
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
authors.forename: K
authors.initials: K
authors.lastname: Nahar
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
authors.forename: F
authors.initials: F
authors.lastname: Ahsan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D001792:Blood Platelets / Q000187:drug effects / Q000276:immunology; D005337:Fibrin / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000378:metabolism / Q000627:therapeutic use*; D006493:Heparin / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D010960:Plasminogen Activators / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D011479:Protamines / Q000494:pharmacology / Q000627:therapeutic use; D015202:Protein Engineering / Q000379:methods*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000627:therapeutic use; D015912:Thrombolytic Therapy; D013927:Thrombosis / Q000188:drug therapy*
chemical_list: D000911:Antibodies, Monoclonal; D005343:Fibrinolytic Agents; D011479:Protamines; D011993:Recombinant Fusion Proteins; D005337:Fibrin; D006493:Heparin; D010960:Plasminogen Activators
keywords: bleeding; fibrinolytic agents; molecular targeted therapy; thrombolytic therapy; tissue plasminogen activator