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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2017, Vol. 11 Issue (1) : 1-19    https://doi.org/10.1007/s11684-017-0497-8
REVIEW
Translational initiatives in thrombolytic therapy
Melvin E. Klegerman()
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77054, USA
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Abstract

Once thrombi have formed as part of the pathology defining myocardial infarction, ischemic stroke, peripheral arterial disease, deep venous thrombosis or other embolic disorders, the only clinically meaningful thrombolytic agents available for reversing the thrombogenic process are various plasminogen activators. These agents are enzymes that reverse fibrin polymerization underlying the coagulation process by converting endogenous plasminogen to plasmin, which cleaves the fibrin network to form increasingly smaller protein fragments, a process known as fibrinolysis. For the most part, the major clinically used thrombolytics, tissue plasminogen activator, urokinase and streptokinase, as well as the experimentally investigated agent staphylokinase, are the products of recombinant DNA technology, which permits molecular optimization of clinical efficacy. In all cases of molecular optimization and targeting, however, the primary challenge of thrombolytic therapy remains hemorrhagic side effects, which are especially devastating when they occur intracerebrally. Currently, the best strategy to ameliorate this adverse effect is nanoparticulate encapsulation or complexation, and many strategies of this sort are being actively pursued. This review summarizes the variety of targeted and untargeted thrombolytic formulations that have been investigated in preclinical studies.

Keywords thrombolytics      nanomedicine      plasminogen activators     
Corresponding Author(s): Melvin E. Klegerman   
Just Accepted Date: 09 December 2016   Online First Date: 23 January 2017    Issue Date: 20 March 2017
 Cite this article:   
Melvin E. Klegerman. Translational initiatives in thrombolytic therapy[J]. Front. Med., 2017, 11(1): 1-19.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-017-0497-8
https://academic.hep.com.cn/fmd/EN/Y2017/V11/I1/1
Fig.1  Putative high-affinity fibrin binding site in the tPA finger domain, based on the thermodynamics of tPA(P) binding to fibrin pads. Box and arrow indicate the 4 residues necessary for the binding characteristics. Reprinted with permission from Ref. 46.
Targeting ligand Thrombolytic Formulation Application Comment
Polyclonal Ab (PAb) a-chymotrypsin Dextran carrier Demonstration of clot lysis in vitro comparable to free enzyme [161]
Monoclonal Ab (MAb)
59D8
tPA Direct conjugation 10× thrombolysis vs. tPA in vitro; 2.8?9.6× thrombolysis vs. tPA in vivo [162,163] Disulfide linkage
MAb 64C5 uPA Direct conjugation 100?250× thrombolysis vs. uPA in vitro [164,165] Disulfide linkage
MAb 15C5 uPA Direct conjugation 2.2?6.4× thrombolysis vs. uPA in vitro [166]; 3?8× thrombolysis vs. uPA in vivo [167,168] Disulfide linkage
Monoclonal anti-human fibrinogen (MAfgn) tPA Ab and tPA conjugated to polystyrene latex NP Targeting and enzyme activity in vitro. Activity one-third vs. tPA [159]
MAb 1H10 (biotinylated) sPA Biotinylated perfluorocarbon NP Targeting and clot volume reduction demonstrated by acoustic microscopy in vitro [158] Avidin linkage of bMAb and bNP
Heparin-conjugated MAb Cationic peptide-conjugated tPA Electrostatic complex Enzyme activity ~ tPA in vitro; prodrug function confirmed [169,170]
MAb Fab uPA VAM41-PEG-Fab NP Retention of uPA enzyme activity after NP loading; in vitro stability [160]
MAb 59D8 Fab' uPA Direct conjugation 230?250× activity vs. uPA in vitro [165,171]; 29× thrombolytic potency vs. scuPA in vivo [171] Disulfide linkage
MAb 64C5 Fab' uPA Direct conjugation 95× activity, 2?4× thrombolysis vs. uPA in vitro [172] Disulfide linkage
MAb 15C5 F(ab')2 LMW rscuPA Direct conjugation 2?5× thrombolysis vs. LMW rscuPA in vitro [173,174] Disulfide linkage
MAb 59D8 scFv rscuPA Fusion protein 6× thrombolysis vs. scuPA or tPA in vivo [175] Heavy chain domains
MAb 59D8 scFv Factor Xa inhibitory peptide Fusion protein Potentiation of TAP anticoagulation in vitro [156] Tick anticoagulant peptide (TAP)
MAb 15C5 Fv LMW rscuPA Fusion protein 13×fibrinolysis vs. scuPA in vitro [176] Variable region Fv
“Intrinsic” tPA tPA tPA-loaded echogenic liposomes (TELIP) 1.25× vs. tPA in vitro with ultrasound (US) [177,178]; 1.7× US effect in vivo [179] Ultrasound-enhanced thrombolysis
Probable intrinsic tPA tPA tPA-loaded liposomes 4× vs. tPA in vivo [102] Rabbit jugular vein thrombosis model
Plasminogen sPA Direct conjugation 50% reduction in mortality vs. placebo following acute MI in AIMS clinical trial [180] Acylated plasminogen-streptokinase activator complex (APSAC)
Plasminogen uPA Direct conjugation 2× thrombolysis vs. uPA in vitro [181] Disulfide linkage between pgn A-chain and uPA B-chain
Plasminogen tPA Direct conjugation 1× fibrinolysis vs. tPA in vitro [182] Disulfide linkage between pgn A-chain and tPA B-chain
Fibrinogen uPA Direct conjugation 2.5× overall fibrinolytic efficacy vs. uPA in vitro [183]; 67% complete recanalization vs. 0% for uPA in vivo [184] Fgn is incorporated into the forming clot
Tab.1  Fibrin-targeted thrombolytic formulations
Fig.2  Epicardial sonogram of an induced left ventricular thrombus in a dog before and after left atrial administration of TELIP. Unpublished results.
Fig.3  Negative staining transmission electron micrograph of intact TELIP, 1 mg lipid/ml PBS; 150 000× magnification. Unpublished results.
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