Translational initiatives in thrombolytic therapy

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

References

[1] Smalling RW. Molecular biology of plasminogen activators: what are the clinical implications of drug design? Am J Cardiol 1996; 78(12 12A): 2–7

[2] Nordt TK, Bode C. Thrombolysis: newer thrombolytic agents and their role in clinical medicine. Heart 2003; 89(11): 1358–1362

[3] Van de Werf FJ. The ideal fibrinolytic: can drug design improve clinical results? Eur Heart J 1999; 20(20): 1452–1458

[4] Al-Shwafi KA, de Meester A, Pirenne B, Col JJ. Comparative fibrinolytic activity of front-loaded alteplase and the single-bolus mutants tenecteplase and lanoteplase during treatment of acute myocardial infarction. Am Heart J 2003; 145(2): 217–225

[5] Onundarson PT, Francis CW, Marder VJ. Depletion of plasminogen in vitro or during thrombolytic therapy limits fibrinolytic potential. J Lab Clin Med 1992; 120(1): 120–128

[6] Sakharov DV, Rijken DC. Superficial accumulation of plasminogen during plasma clot lysis. Circulation 1995; 92(7): 1883–1890

[7] Novokhatny V, Taylor K, Zimmerman TP. Thrombolytic potency of acid-stabilized plasmin: superiority over tissue-type plasminogen activator in an in vitro model of catheter-assisted thrombolysis. J Thromb Haemost 2003; 1(5): 1034–1041

[8] El-Menyar AA, Altamimi OM, Gomaa MM, Dabdoob W, Abbas AA, Abdel Rahman MO, Bener A, Albinali HA. Clinical and biochemical predictors affect the choice and the short-term outcomes of different thrombolytic agents in acute myocardial infarction. Coron Artery Dis 2006; 17(5): 431–437

[9] Jänicke F, Schmitt M, Pache L, Ulm K, Harbeck N, Höfler H, Graeff H. Urokinase (uPA) and its inhibitor PAI-1 are strong and independent prognostic factors in node-negative breast cancer. Breast Cancer Res Treat 1993; 24(3): 195–208

[10] Wessels MR. Regulation of virulence factor expression in group A streptococcus. Trends Microbiol 1999; 7(11): 428–430

[11] White HD, Van de Werf FJ. Thrombolysis for acute myocardial infarction. Circulation 1998; 97(16): 1632–1646

[12] Malke H, Ferretti JJ. Streptokinase: cloning, expression, and excretion by Escherichia coli. Proc Natl Acad Sci USA 1984; 81(11): 3557–3561

[13] Castellino FJ. Recent advances in the chemistry of the fibrinolytic system. Chem Rev 1981; 81(5): 431–446

[14] Jennings K. Antibodies to streptokinase. BMJ 1996; 312(7028): 393–394

[15] Lee HS. How safe is the readministration of streptokinase? Drug Saf 1995; 13(2): 76–80

[16] Wu XC, Ye R, Duan Y, Wong SL. Engineering of plasmin-resistant forms of streptokinase and their production in Bacillus subtilis: streptokinase with longer functional half-life. Appl Environ Microbiol 1998; 64(3): 824–829

[17] Banerjee A, Chisti Y, Banerjee UC. Streptokinase—a clinically useful thrombolytic agent. Biotechnol Adv 2004; 22(4): 287–307

[18] Smith RA, Dupe RJ, English PD, Green J. Fibrinolysis with acyl-enzymes: a new approach to thrombolytic therapy. Nature 1981; 290(5806): 505–508

[19] Shi GY, Chang BI, Su SW, Young KC, Wu DH, Chang LC, Tsai YS, Wu HL. Preparation of a novel streptokinase mutant with improved stability. Thromb Haemost 1998; 79(5): 992–997

[20] Pratap J, Rajamohan G, Dikshit KL. Characteristics of glycosylated streptokinase secreted from Pichia pastoris: enhanced resistance of SK to proteolysis by glycosylation. Appl Microbiol Biotechnol 2000; 53(4): 469–475

[21] Koide A, Suzuki S, Kobayashi S. Preparation of polyethylene glycol-modified streptokinase with disappearance of binding ability towards anti-serum and retention of activity. FEBS Lett 1982; 143(1): 73–76

[22] Rajagopalan S, Gonias SL, Pizzo SV. A nonantigenic covalent streptokinase-polyethylene glycol complex with plasminogen activator function. J Clin Invest 1985; 75(2): 413–419

[23] Torrèns I, Ojalvo AG, Seralena A, Hayes O, de la Fuente J. A mutant streptokinase lacking the C-terminal 42 amino acids is less immunogenic. Immunol Lett 2000; 70(3): 213–218PMID:10656677

[24] MacFarlane RG, Pilling J. Fibrinolytic activity of normal urine. Nature 1947; 159(4049): 779

[25] Williams JRB. The fibrinolytic activity of urine. Br J Exper Pathol 1951; 32:530–537

[26] Collen D, Lijnen HR. Thrombolytic agents. Thromb Haemost 2005; 93(4): 627–630

[27] Bernik MB. Increased plasminogen activator (urokinase) in tissue culture after fibrin deposition. J Clin Invest 1973; 52(4): 823–834

[28] Nolan C, Hall LS, Barlow GH, Tribby II. Plasminogen activator from human embryonic kidney cell cultures. Evidence for a proactivator. Biochim Biophys Acta 1977; 496(2): 384–400

[29] Collen D. On the regulation and control of fibrinolysis. Edward Kowalski Memorial Lecture. Thromb Haemost 1980; 43(2): 77–89

[30] Crippa MP. Urokinase-type plasminogen activator. Int J Biochem Cell Biol 2007; 39(4): 690–694

[31] Rijken DC. Structure/function relationships of t-PA. In: Kluft C. Tissue-type Plasminogen Activator (t-PA): Physiological and Clincial Aspects. Boca Raton, FL: CRC Press, Inc., 1988:101–122

[32] Testa JE, Quigley JP. The role of urokinase-type plasminogen activator in aggressive tumor cell behavior. Cancer Metastasis Rev 1990; 9(4): 353–367

[33] Franco P, Vocca I, Carriero MV, Alfano D, Cito L, Longanesi-Cattani I, Grieco P, Ossowski L, Stoppelli MP. Activation of urokinase receptor by a novel interaction between the connecting peptide region of urokinase and αv β5 integrin. J Cell Sci 2006; 119(Pt 16): 3424–3434PMID:16882693

[34] Irigoyen JP, Muñoz-Cánoves P, Montero L, Koziczak M, Nagamine Y. The plasminogen activator system: biology and regulation. Cell Mol Life Sci 1999; 56(1-2): 104–132

[35] Sidenius N, Blasi F. The urokinase plasminogen activator system in cancer: recent advances and implication for prognosis and therapy. Cancer Metastasis Rev 2003; 22(2-3): 205–222

[36] Alfano D, Iaccarino I, Stoppelli MP. Urokinase signaling through its receptor protects against anoikis by increasing BCL-xL expression levels. J Biol Chem 2006; 281(26): 17758–17767

[37] Collen D, Lijnen HR. Tissue-type plasminogen activator: a historical perspective and personal account. J Thromb Haemost 2004; 2(4): 541–546

[38] Bachmann F, Kruithof IE. Tissue plasminogen activator: chemical and physiological aspects. Semin Thromb Hemost 1984; 10(1): 6–17

[39] Verheijen JH, Caspers MP, Chang GT, de Munk GA, Pouwels PH, Enger-Valk BE. Involvement of finger domain and kringle 2 domain of tissue-type plasminogen activator in fibrin binding and stimulation of activity by fibrin. EMBO J 1986; 5(13): 3525–3530

[40] Hoylaerts M, Rijken DC, Lijnen HR, Collen D. Kinetics of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin. J Biol Chem 1982; 257(6): 2912–2919

[41] Rånby M. Studies on the kinetics of plasminogen activation by tissue plasminogen activator. Biochim Biophys Acta 1982; 704(3): 461–469

[42] Bringmann P, Gruber D, Liese A, Toschi L, Krätzchmar J, Schleuning WD, Donner P. Structural features mediating fibrin selectivity of vampire bat plasminogen activators. J Biol Chem 1995; 270(43): 25596–25603

[43] Nesheim M, Fredenburgh JC, Larsen GR. The dissociation constants and stoichiometries of the interactions of Lys-plasminogen and chloromethyl ketone derivatives of tissue plasminogen activator and the variant delta FEIX with intact fibrin. J Biol Chem 1990; 265(35): 21541–21548

[44] Angles-Cano E. A spectrophotometric solid-phase fibrin-tissue plasminogen activator activity assay (SOFIA-tPA) for high-fibrin-affinity tissue plasminogen activators. Anal Biochem 1986; 153(2): 201–210

[45] Tsurupa G, Medved L. Fibrinogen alpha C domains contain cryptic plasminogen and tPA binding sites. Ann N Y Acad Sci 2001; 936(1): 328–330

[46] Klegerman ME, Zou Y, McPherson DD. Fibrin targeting of echogenic liposomes with inactivated tissue plasminogen activator. J Liposome Res 2008; 18(2): 95–112

[47] Tiukinhoy-Laing SD, Buchanan K, Parikh D, Huang S, MacDonald RC, McPherson DD, Klegerman ME. Fibrin targeting of tissue plasminogen activator-loaded echogenic liposomes. J Drug Target 2007; 15(2): 109–114

[48] Schielen WJ, Adams HP, van Leuven K, Voskuilen M, Tesser GI, Nieuwenhuizen W. The sequence γ-(312-324) is a fibrin-specific epitope. Blood 1991; 77(10): 2169–2173

[49] Schielen WJ, Adams HP, Voskuilen M, Tesser GI, Nieuwenhuizen W. The sequence A α-(154-159) of fibrinogen is capable of accelerating the t-PA catalysed activation of plasminogen. Blood Coagul Fibrinolysis 1991; 2(3): 465–470

[50] Schielen WJ, Voskuilen M, Tesser GI, Nieuwenhuizen W. The sequence A α-(148-160) in fibrin, but not in fibrinogen, is accessible to monoclonal antibodies. Proc Natl Acad Sci USA 1989; 86(22): 8951–8954

[51] Nieuwenhuizen W. Fibrin-mediated plasminogen activation. Ann N Y Acad Sci 2001; 936(1): 237–246

[52] Yakovlev S, Makogonenko E, Kurochkina N, Nieuwenhuizen W, Ingham K, Medved L. Conversion of fibrinogen to fibrin: mechanism of exposure of tPA- and plasminogen-binding sites. Biochemistry 2000; 39(51): 15730–15741

[53] Grailhe P, Nieuwenhuizen W, Anglés-Cano E. Study of tissue-type plasminogen activator binding sites on fibrin using distinct fragments of fibrinogen. Eur J Biochem 1994; 219(3): 961–967

[54] Yonekawa O, Voskuilen M, Nieuwenhuizen W. Localization in the fibrinogen gamma-chain of a new site that is involved in the acceleration of the tissue-type plasminogen activator-catalysed activation of plasminogen. Biochem J 1992; 283(Pt 1): 187–191

[55] Hurtado M, Lozano JJ, Castellanos E, López-Fernández LA, Harshman K, Martínez-A C, Ortiz AR, Thomson TM, Paciucci R. Activation of the epidermal growth factor signalling pathway by tissue plasminogen activator in pancreas cancer cells. Gut 2007; 56(9): 1266–1274

[56] Pennica D, Holmes WE, Kohr WJ, Harkins RN, Vehar GA, Ward CA, Bennett WF, Yelverton E, Seeburg PH, Heyneker HL, Goeddel DV, Collen D. Cloning and expression of human tissue-type plasminogen activator cDNA in E. coli. Nature 1983; 301(5897): 214–221

[57] Wallén P, Pohl G, Bergsdorf N, Rånby M, Ny T, Jörnvall H. Purification and characterization of a melanoma cell plasminogen activator. Eur J Biochem 1983; 132(3): 681–686

[58] Strassburger W, Wollmer A, Pitts JE, Glover ID, Tickle IJ, Blundell TL, Steffens GJ, Günzler WA, Otting F, Flohé L. Adaptation of plasminogen activator sequences to known protease structures. FEBS Lett 1983; 157(2): 219–223

[59] Kaneko M, Sakata Y, Matsuda M, Mimuro J. Interactions between the finger and kringle-2 domains of tissue-type plasminogen activator and plasminogen activator inhibitor-1. J Biochem 1992; 111(2): 244–248

[60] Ibarra CA, Blouse GE, Christian TD, Shore JD. The contribution of the exosite residues of plasminogen activator inhibitor-1 to proteinase inhibition. J Biol Chem 2004; 279(5): 3643–3650

[61] Madison EL, Goldsmith EJ, Gerard RD, Gething MJ, Sambrook JF. Serpin-resistant mutants of human tissue-type plasminogen activator. Nature 1989; 339(6227): 721–724

[62] Rijken DC, Emeis JJ, Gerwig GJ. On the composition and function of the carbohydrate moiety of tissue-type plasminogen activator from human melanoma cells. Thromb Haemost 1985; 54(4): 788–791

[63] Pohl G, Källström M, Bergsdorf N, Wallén P, Jörnvall H. Tissue plasminogen activator: peptide analyses confirm an indirectly derived amino acid sequence, identify the active site serine residue, establish glycosylation sites, and localize variant differences. Biochemistry 1984; 23(16): 3701–3707

[64] Emeis JJ, van den Hoogen CM, Jense D. Hepatic clearance of tissue-type plasminogen activator in rats. Thromb Haemost 1985; 54(3): 661–664

[65] Fuchs HE, Berger H Jr, Pizzo SV. Catabolism of human tissue plasminogen activator in mice. Blood 1985; 65(3): 539–544

[66] Little SP, Bang NU, Harms CS, Marks CA, Mattler LE. Functional properties of carbohydrate-depleted tissue plasminogen activator. Biochemistry 1984; 23(25): 6191–6195

[67] Rånby M, Bergsdorf N, Pohl G, Wallén P. Isolation of two variants of native one-chain tissue plasminogen activator. FEBS Lett 1982; 146(2): 289–292

[68] Zamarron C, Lijnen HR, Collen D. Kinetics of the activation of plasminogen by natural and recombinant tissue-type plasminogen activator. J Biol Chem 1984; 259(4): 2080–2083

[69] Collen D, Stassen JM, Marafino BJ Jr, Builder S, De Cock F, Ogez J, Tajiri D, Pennica D, Bennett WF, Salwa J, . Biological properties of human tissue-type plasminogen activator obtained by expression of recombinant DNA in mammalian cells. J Pharmacol Exp Ther 1984; 231(1): 146–152

[70] TIMI Study Group. The thrombolysis in myocardial infarction (TIMI) trial. Phase I findings. N Engl J Med 1985; 312(14): 932–936

[71] The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329(10): 673–682PMID:8204123

[72] The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 1993; 329(22): 1615–1622

[73] Cannon CP. Advances in the medical management of acute coronary syndromes. J Thromb Thrombolysis 1999; 7(2): 171–189

[74] Katzan IL, Hammer MD, Hixson ED, Furlan AJ, Abou-Chebl A, Nadzam DM; Cleveland Clinic Health System Stroke Quality Improvement Team. Utilization of intravenous tissue plasminogen activator for acute ischemic stroke. Arch Neurol 2004; 61(3): 346–350PMID:15023810

[75] Smith WS. Technology Insight: recanalization with drugs and devices during acute ischemic stroke. Nat Clin Pract Neurol 2007; 3(1): 45–53

[76] The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333(24): 1581–1587PMID:7477192

[77] Barber PA, Zhang J, Demchuk AM, Hill MD, Buchan AM. Why are stroke patients excluded from TPA therapy? An analysis of patient eligibility. Neurology 2001; 56(8): 1015–1020

[78] Kleindorfer D, Kissela B, Schneider A, Woo D, Khoury J, Miller R, Alwell K, Gebel J, Szaflarski J, Pancioli A, Jauch E, Moomaw C, Shukla R, Broderick JP; Neuroscience Institute. Eligibility for recombinant tissue plasminogen activator in acute ischemic stroke: a population-based study. Stroke 2004; 35(2): e27–e29PMID:14739423

[79] Kwan J, Hand P, Sandercock P. A systematic review of barriers to delivery of thrombolysis for acute stroke. Age Ageing 2004; 33(2): 116–121

[80] Brown DL, Barsan WG, Lisabeth LD, Gallery ME, Morgenstern LB. Survey of emergency physicians about recombinant tissue plasminogen activator for acute ischemic stroke. Ann Emerg Med 2005; 46(1): 56–60

[81] Liang BA, Lew R, Zivin JA. Review of tissue plasminogen activator, ischemic stroke, and potential legal issues. Arch Neurol 2008; 65(11): 1429–1433

[82] Graham GD. Tissue plasminogen activator for acute ischemic stroke in clinical practice: a meta-analysis of safety data. Stroke 2003; 34(12): 2847–2850

[83] Berkowitz SD, Granger CB, Pieper KS, Lee KL, Gore JM, Simoons M, Armstrong PW, Topol EJ, Califf RM; The Global Utilization of Streptokinase and Tissue Plasminogen activator for Occluded coronary arteries (GUSTO) I Investigators. Incidence and predictors of bleeding after contemporary thrombolytic therapy for myocardial infarction. Circulation 1997; 95(11): 2508–2516PMID:9184581

[84] Califf RM, Topol EJ, George BS, Boswick JM, Abbottsmith C, Sigmon KN, Candela R, Masek R, Kereiakes D, O’Neill WW, Stack RS, Stump D. Hemorrhagic complications associated with the use of intravenous tissue plasminogen activator in treatment of acute myocardial infarction. Am J Med 1988; 85(3): 353–359

[85] Yadav YR, Mukerji G, Shenoy R, Basoor A, Jain G, Nelson A. Endoscopic management of hypertensive intraventricular haemorrhage with obstructive hydrocephalus. BMC Neurol 2007; 7(1): 1

[86] Wu H, Zhang Z, Hu X, Zhao R, Song Y, Ban X, Qi J, Wang J. Dynamic changes of inflammatory markers in brain after hemorrhagic stroke in humans: a postmortem study. Brain Res 2010; 1342: 111–117

[87] IMS Study Investigators. Combined intravenous and intra-arterial recanalization for acute ischemic stroke: the Interventional Management of Stroke Study. Stroke 2004; 35(4): 904–911

[88] Alexandrov AV, Molina CA, Grotta JC, Garami Z, Ford SR, Alvarez-Sabin J, Montaner J, Saqqur M, Demchuk AM, Moyé LA, Hill MD, Wojner AW; CLOTBUST Investigators. Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med 2004; 351(21): 2170–2178PMID:15548777

[89] Donnan GA, Davis SM, Parsons MW, Ma H, Dewey HM, Howells DW. How to make better use of thrombolytic therapy in acute ischemic stroke. Nat Rev Neurol 2011; 7(7): 400–409

[90] Martin U, Kohnert U, Stern A, Popp F, Fischer S. Comparison of the recombinant Escherichia coli-produced protease domain of tissue-type plasminogen activator with alteplase, reteplase and streptokinase in a canine model of coronary artery thrombolysis. Thromb Haemost 1996; 76(6): 1096–1101

[91] Kohnert U, Hellerbrand K, Martin U, Stern A, Popp F, Fischer S. The recombinant Escherichia coli-derived protease-domain of tissue-type plasminogen activator is a potent and fibrin specific fibrinolytic agent. Fibrinolysis 1996; 10(2): 93–102

[92] Dundar Y, Hill R, Dickson R, Walley T. Comparative efficacy of thrombolytics in acute myocardial infarction: a systematic review. QJM 2003; 96(2): 103–113

[93] Llevadot J, Giugliano RP, Antman EM. Bolus fibrinolytic therapy in acute myocardial infarction. JAMA 2001; 286(4): 442–449

[94] Shaw GJ, Meunier JM, Lindsell CJ, Holland CK. Tissue plasminogen activator concentration dependence of 120 kHz ultrasound-enhanced thrombolysis. Ultrasound Med Biol 2008; 34(11): 1783–1792

[95] Behnke D, Gerlach D. Cloning and expression in Escherichia coli, Bacillus subtilis, and Streptococcus sanguis of a gene for staphylokinase—a bacterial plasminogen activator. Mol Gen Genet 1987; 210(3): 528–534

[96] Collen D, Zhao ZA, Holvoet P, Marynen P. Primary structure and gene structure of staphylokinase. Fibrinolysis 1992; 6(4): 226–231

[97] Laroche Y, Heymans S, Capaert S, De Cock F, Demarsin E, Collen D. Recombinant staphylokinase variants with reduced antigenicity due to elimination of B-lymphocyte epitopes. Blood 2000; 96(4): 1425–1432

[98] Armstrong PW, Burton JR, Palisaitis D, Thompson CR, Van de Werf F, Rose B, Collen D, Teo KK. Collaborative angiographic patency trial of recombinant staphylokinase (CAPTORS). Am Heart J 2000; 139(5): 820–823

[99] Ntimenou V, Mourtas S, Christodoulakis EV, Tsilimbaris M, Antimisiaris SG. Stability of protein-encapsulating DRV liposomes after freeze-drying: A study with BSA and t-PA. J Liposome Res 2006; 16(4): 403–416

[100] Soeda S, Kakiki M, Shimeno H, Nagamatsu A. Some properties of tissue-type plasminogen activator reconstituted onto phospholipid and/or glycolipid vesicles. Biochem Biophys Res Commun 1987; 146(1): 94–100

[101] Heeremans JL, Gerritsen HR, Meusen SP, Mijnheer FW, Gangaram Panday RS, Prevost R, Kluft C, Crommelin DJ. The preparation of tissue-type Plasminogen Activator (t-PA) containing liposomes: entrapment efficiency and ultracentrifugation damage. J Drug Target 1995; 3(4): 301–310

[102] Heeremans JL, Prevost R, Bekkers ME, Los P, Emeis JJ, Kluft C, Crommelin DJ. Thrombolytic treatment with tissue-type plasminogen activator (t-PA) containing liposomes in rabbits: a comparison with free t-PA. Thromb Haemost 1995; 73(3): 488–494

[103] Kim JY, Kim JK, Park JS, Byun Y, Kim CK. The use of PEGylated liposomes to prolong circulation lifetimes of tissue plasminogen activator. Biomaterials 2009; 30(29): 5751–5756

[104] Han SB, Baek SH, Park JS, Yang HK, Kim JY, Kim CK, Hwang JM. Effect of subconjunctivally injected liposome-encapsulated tissue plasminogen activator on the absorption rate of subconjunctival hemorrhages in rabbits. Cornea 2011; 30(12): 1455–1460

[105] Absar S, Choi S, Ahsan F, Cobos E, Yang VC, Kwon YM. Preparation and characterization of anionic oligopeptide-modified tissue plasminogen activator for triggered delivery: an approach for localized thrombolysis. Thromb Res 2013; 131(3): e91–e99

[106] Absar S, Choi S, Yang VC, Kwon YM. Heparin-triggered release of camouflaged tissue plasminogen activator for targeted thrombolysis. J Control Release 2012; 157(1): 46–54

[107] Holt B, Gupta AS. Streptokinase loading in liposomes for vascular targeted nanomedicine applications: encapsulation efficiency and effects of processing. J Biomater Appl 2012; 26(5): 509–527

[108] Kim IS, Choi HG, Choi HS, Kim BK, Kim CK. Prolonged systemic delivery of streptokinase using liposome. Arch Pharm Res 1998; 21(3): 248–252

[109] Erdoğan S, Ozer AY, Volkan B, Caner B, Bilgili H. Thrombus localization by using streptokinase containing vesicular systems. Drug Deliv 2006; 13(4): 303–309

[110] Perkins WR, Vaughan DE, Plavin SR, Daley WL, Rauch J, Lee L, Janoff AS. Streptokinase entrapment in interdigitation-fusion liposomes improves thrombolysis in an experimental rabbit model. Thromb Haemost 1997; 77(6): 1174–1178

[111] Nguyen PD, O’Rear EA, Johnson AE, Patterson E, Whitsett TL, Bhakta R. Accelerated thrombolysis and reperfusion in a canine model of myocardial infarction by liposomal encapsulation of streptokinase. Circ Res 1990; 66(3): 875–878

[112] Wang X, Inapagolla R, Kannan S, Lieh-Lai M, Kannan RM. Synthesis, characterization, and in vitro activity of dendrimer-streptokinase conjugates. Bioconjug Chem 2007; 18(3): 791–799

[113] Leach JK, Patterson E, O’Rear EA. Distributed intraclot thrombolysis: mechanism of accelerated thrombolysis with encapsulated plasminogen activators. J Thromb Haemost 2004; 2(9): 1548–1555

[114] Erdoğan S, Ozer AY, Bilgili H. In vivo behaviour of vesicular urokinase. Int J Pharm 2005; 295(1-2): 1–6

[115] Datta S, Coussios CC, Ammi AY, Mast TD, de Courten-Myers GM, Holland CK. Ultrasound-enhanced thrombolysis using Definity as a cavitation nucleation agent. Ultrasound Med Biol 2008; 34(9): 1421–1433

[116] Alexandrov AV, Mikulik R, Ribo M, Sharma VK, Lao AY, Tsivgoulis G, Sugg RM, Barreto A, Sierzenski P, Malkoff MD, Grotta JC. A pilot randomized clinical safety study of sonothrombolysis augmentation with ultrasound-activated perflutren-lipid microspheres for acute ischemic stroke. Stroke 2008; 39(5): 1464–1469

[117] Molina CA, Ribo M, Rubiera M, Montaner J, Santamarina E, Delgado-Mederos R, Arenillas JF, Huertas R, Purroy F, Delgado P, Alvarez-Sabín J. Microbubble administration accelerates clot lysis during continuous 2-MHz ultrasound monitoring in stroke patients treated with intravenous tissue plasminogen activator. Stroke 2006; 37(2): 425–429

[118] Daffertshofer M, Gass A, Ringleb P, Sitzer M, Sliwka U, Els T, Sedlaczek O, Koroshetz WJ, Hennerici MG. Transcranial low-frequency ultrasound-mediated thrombolysis in brain ischemia: increased risk of hemorrhage with combined ultrasound and tissue plasminogen activator: results of a phase II clinical trial. Stroke 2005; 36(7): 1441–1446

[119] Ren ST, Zhang H, Wang YW, Jing BB, Li YX, Liao YR, Kang XN, Zang WJ, Wang B. The preparation of a new self-made microbubble-loading urokinase and its thrombolysis combined with low-frequency ultrasound in vitro. Ultrasound Med Biol 2011; 37(11): 1828–1837

[120] Francis CW. Ultrasound-enhanced thrombolysis. Echocardiography 2001; 18(3): 239–246

[121] Uesugi Y, Kawata H, Jo J, Saito Y, Tabata Y. An ultrasound-responsive nano delivery system of tissue-type plasminogen activator for thrombolytic therapy. J Control Release 2010; 147(2): 269–277

[122] Kawata H, Uesugi Y, Soeda T, Takemoto Y, Sung JH, Umaki K, Kato K, Ogiwara K, Nogami K, Ishigami K, Horii M, Uemura S, Shima M, Tabata Y, Saito Y. A new drug delivery system for intravenous coronary thrombolysis with thrombus targeting and stealth activity recoverable by ultrasound. J Am Coll Cardiol 2012; 60(24): 2550–2557

[123] Gupta AS, Huang G, Lestini BJ, Sagnella S, Kottke-Marchant K, Marchant RE. RGD-modified liposomes targeted to activated platelets as a potential vascular drug delivery system. Thromb Haemost 2005; 93(1): 106–114

[124] Huang G, Zhou Z, Srinivasan R, Penn MS, Kottke-Marchant K, Marchant RE, Gupta AS. Affinity manipulation of surface-conjugated RGD peptide to modulate binding of liposomes to activated platelets. Biomaterials 2008; 29(11): 1676–1685

[125] Vaidya B, Nayak MK, Dash D, Agrawal GP, Vyas SP. Development and characterization of site specific target sensitive liposomes for the delivery of thrombolytic agents. Int J Pharm 2011; 403(1-2): 254–261

[126] Wang SS, Chou NK, Chung TW. The t-PA-encapsulated PLGA nanoparticles shelled with CS or CS-GRGD alter both permeation through and dissolving patterns of blood clots compared with t-PA solution: an in vitro thrombolysis study. J Biomed Mater Res A 2009; 91(3): 753–761

[127] Mu Y, Li L, Ayoufu G. Experimental study of the preparation of targeted microbubble contrast agents carrying urokinase and RGDS. Ultrasonics 2009; 49(8): 676–681

[128] Hua X, Liu P, Gao YH, Tan KB, Zhou LN, Liu Z, Li X, Zhou SW, Gao YJ. Construction of thrombus-targeted microbubbles carrying tissue plasminogen activator and their in vitro thrombolysis efficacy: a primary research. J Thromb Thrombolysis 2010; 30(1): 29–35

[129] Hua X, Zhou L, Liu P, He Y, Tan K, Chen Q, Gao Y, Gao Y.In vivo thrombolysis with targeted microbubbles loading tissue plasminogen activator in a rabbit femoral artery thrombus model. J Thromb Thrombolysis 2014; 38(1): 57–64

[130] Absar S, Nahar K, Kwon YM, Ahsan F. Thrombus-targeted nanocarrier attenuates bleeding complications associated with conventional thrombolytic therapy. Pharm Res 2013; 30(6): 1663–1676

[131] Absar S, Kwon YM, Ahsan F. Bio-responsive delivery of tissue plasminogen activator for localized thrombolysis. J Control Release 2014; 177: 42–50

[132] Jun CD, Shimaoka M, Carman CV, Takagi J, Springer TA. Dimerization and the effectiveness of ICAM-1 in mediating LFA-1-dependent adhesion. Proc Natl Acad Sci USA 2001; 98(12): 6830–6835

[133] Decuzzi P, Ferrari M. The adhesive strength of non-spherical particles mediated by specific interactions. Biomaterials 2006; 27(30): 5307–5314

[134] Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 2013; 13(3): 159–175

[135] Swirski FK, Nahrendorf M. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science 2013; 339(6116): 161–166

[136] Demos SM, Dagar S, Klegerman M, Nagaraj A, McPherson DD, Onyuksel H. In vitro targeting of acoustically reflective immunoliposomes to fibrin under various flow conditions. J Drug Target 1998; 5(6): 507–518

[137] Klegerman ME, Huang S, Parikh D, Martinez J, Demos SM, Onyuksel HA, McPherson DD. Lipid contribution to the affinity of antigen association with specific antibodies conjugated to liposomes. Biochim Biophys Acta 2007; 1768(7): 1703–1716

[138] Zimarino M, D’Andreamatteo M, Waksman R, Epstein SE, De Caterina R. The dynamics of the coronary collateral circulation. Nat Rev Cardiol 2014; 11(4): 191–197

[139] Bode C, Meinhardt G, Runge MS, Freitag M, Nordt T, Arens M, Newell JB, Kübler W, Haber E. Platelet-targeted fibrinolysis enhances clot lysis and inhibits platelet aggregation. Circulation 1991; 84(2): 805–813

[140] Xie F, Lof J, Matsunaga T, Zutshi R, Porter TR. Diagnostic ultrasound combined with glycoprotein IIb/IIIa-targeted microbubbles improves microvascular recovery after acute coronary thrombotic occlusions. Circulation 2009; 119(10): 1378–1385

[141] Korin N, Kanapathipillai M, Matthews BD, Crescente M, Brill A, Mammoto T, Ghosh K, Jurek S, Bencherif SA, Bhatta D, Coskun AU, Feldman CL, Wagner DD, Ingber DE. Shear-activated nanotherapeutics for drug targeting to obstructed blood vessels. Science 2012; 337(6095): 738–742

[142] Kempe M, Kempe H, Snowball I, Wallén R, Arza CR, Götberg M, Olsson T. The use of magnetite nanoparticles for implant-assisted magnetic drug targeting in thrombolytic therapy. Biomaterials 2010; 31(36): 9499–9510

[143] Chen JP, Yang PC, Ma YH, Tu SJ, Lu YJ. Targeted delivery of tissue plasminogen activator by binding to silica-coated magnetic nanoparticle. Int J Nanomed 2012; 7:5137–5149

[144] Yang HW, Hua MY, Lin KJ, Wey SP, Tsai RY, Wu SY, Lu YC, Liu HL, Wu T, Ma YH. Bioconjugation of recombinant tissue plasminogen activator to magnetic nanocarriers for targeted thrombolysis. Int J Nanomed 2012; 7:5159–5173

[145] Torno MD, Kaminski MD, Xie Y, Meyers RE, Mertz CJ, Liu X, O’Brien WD Jr, Rosengart AJ. Improvement of in vitro thrombolysis employing magnetically-guided microspheres. Thromb Res 2008; 121(6): 799–811

[146] Wang M, Zhang J, Yuan Z, Yang W, Wu Q, Gu H. Targeted thrombolysis by using of magnetic mesoporous silica nanoparticles. J Biomed Nanotechnol 2012; 8(4): 624–632

[147] Vaidya B, Agrawal GP, Vyas SP. Functionalized carriers for the improved delivery of plasminogen activators. Int J Pharm 2012; 424(1-2): 1–11

[148] Dewerchin M, Lijnen HR, Stassen JM, De Cock F, Quertermous T, Ginsberg MH, Plow EF, Collen D. Effect of chemical conjugation of recombinant single-chain urokinase-type plasminogen activator with monoclonal antiplatelet antibodies on platelet aggregation and on plasma clot lysis in vitro and in vivo. Blood 1991; 78(4): 1005–1018

[149] Asahi M, Rammohan R, Sumii T, Wang X, Pauw RJ, Weissig V, Torchilin VP, Lo EH. Antiactin-targeted immunoliposomes ameliorate tissue plasminogen activator-induced hemorrhage after focal embolic stroke. J Cereb Blood Flow Metab 2003; 23(8): 895–899

[150] Underwood MJ, Pringle S, de Bono DP. Reduction of thrombus formation in vivo using a thrombolytic agent targeted at damaged endothelial cells. Br J Surg 1992; 79(9): 915–917

[151] Maksimenko AV, Petrov AD, Tischenko EG, Smirnov MD. Experimentally targeted thrombolytic therapy. Application of modified thrombin conjugated with urokinase. Ann N Y Acad Sci 1995; 750(496–501

[152] Murciano JC, Higazi AA, Cines DB, Muzykantov VR. Soluble urokinase receptor conjugated to carrier red blood cells binds latent pro-urokinase and alters its functional profile. J Control Release 2009; 139(3): 190–196

[153] Lian Q, Szarka SJ, Ng KK, Wong SL. Engineering of a staphylokinase-based fibrinolytic agent with antithrombotic activity and targeting capability toward thrombin-rich fibrin and plasma clots. J Biol Chem 2003; 278(29): 26677–26686

[154] Muzykantov VR, Barnathan ES, Atochina EN, Kuo A, Danilov SM, Fisher AB. Targeting of antibody-conjugated plasminogen activators to the pulmonary vasculature. J Pharmacol Exp Ther 1996; 279(2): 1026–1034

[155] Murciano JC, Muro S, Koniaris L, Christofidou-Solomidou M, Harshaw DW, Albelda SM, Granger DN, Cines DB, Muzykantov VR. ICAM-directed vascular immunotargeting of antithrombotic agents to the endothelial luminal surface. Blood 2003; 101(10): 3977–3984

[156] Hagemeyer CE, Tomic I, Jaminet P, Weirich U, Bassler N, Schwarz M, Runge MS, Bode C, Peter K. Fibrin-targeted direct factor Xa inhibition: construction and characterization of a recombinant factor Xa inhibitor composed of an anti-fibrin single-chain antibody and tick anticoagulant peptide. Thromb Haemost 2004; 92(1): 47–53

[157] Line BR, Weber PB, Lukasiewicz R, Dansereau RN. Reduction of background activity through radiolabeling of antifibrin Fab' with ^99mTc-dextran. J Nucl Med 2000; 41(7): 1264–1270

[158] Marsh JN, Senpan A, Hu G, Scott MJ, Gaffney PJ, Wickline SA, Lanza GM. Fibrin-targeted perfluorocarbon nanoparticles for targeted thrombolysis. Nanomedicine (Lond) 2007; 2(4): 533–543

[159] Yurko Y, Maximov V, Andreozzi E, Thompson GL, Vertegel AA. Design of biomedical nanodevices for dissolution of blood clots. Mater Sci Eng C 2009; 29(3): 737–741

[160] Piras AM, Chiellini F, Fiumi C, Bartoli C, Chiellini E, Fiorentino B, Farina C. A new biocompatible nanoparticle delivery system for the release of fibrinolytic drugs. Int J Pharm 2008; 357(1-2): 260–271

[161] Torchilin VP, Maksimenko AV, Tischenko EG, Ignashenkova GV, Ermolin GA. Immobilized thrombolytic enzymes possessing increased affinity toward substrate. Ann N Y Acad Sci 1984; 434:289–291

[162] Runge MS, Bode C, Matsueda GR, Haber E. Antibody-enhanced thrombolysis: targeting of tissue plasminogen activator in vivo. Proc Natl Acad Sci USA 1987; 84(21): 7659–7662

[163] Runge MS, Bode C, Matsueda GR, Haber E. Conjugation to an antifibrin monoclonal antibody enhances the fibrinolytic potency of tissue plasminogen activator in vitro. Biochemistry 1988; 27(4): 1153–1157

[164] Bode C, Matsueda GR, Hui KY, Haber E. Antibody-directed urokinase: a specific fibrinolytic agent. Science 1985; 229(4715): 765–767

[165] Bode C, Runge MS, Newell JB, Matsueda GR, Haber E. Characterization of an antibody-urokinase conjugate. A plasminogen activator targeted to fibrin. J Biol Chem 1987; 262(22): 10819–10823

[166] Dewerchin M, Lijnen HR, Van Hoef B, De Cock F, Collen D. Biochemical properties of conjugates of urokinase-type plasminogen activator with a monoclonal antibody specific for cross-linked fibrin. Eur J Biochem 1989; 185(1): 141–149

[167] Collen D, Dewerchin M, Rapold HJ, Lijnen HR, Stassen JM. Thrombolytic and pharmacokinetic properties of a conjugate of recombinant single-chain urokinase-type plasminogen activator with a monoclonal antibody specific for cross-linked fibrin in a baboon venous thrombosis model. Circulation 1990; 82(5): 1744–1753

[168] Collen D, Dewerchin M, Stassen JM, Kieckens L, Lijnen HR. Thrombolytic and pharmacokinetic properties of conjugates of urokinase-type plasminogen activator with a monoclonal antibody specific for crosslinked fibrin. Fibrinolysis 1989; 3(4): 197–202

[169] Liang JF, Li YT, Song H, Park YJ, Naik SS, Yang VC. ATTEMPTS: a heparin/protamine-based delivery system for enzyme drugs. J Control Release 2002; 78(1-3): 67–79

[170] Yang VC, Naik SS, Song H, Dombkowski AA, Crippen G, Liang JF. Construction and characterization of a t-PA mutant for use in ATTEMPTS: a drug delivery system for achieving targeted thrombolysis. J Control Release 2005; 110(1): 164–176

[171] Bode C, Runge MS, Schönermark S, Eberle T, Newell JB, Kübler W, Haber E. Conjugation to antifibrin Fab' enhances fibrinolytic potency of single-chain urokinase plasminogen activator. Circulation 1990; 81(6): 1974–1980

[172] Bode C, Runge MS, Newell JB, Matsueda GR, Haber E. Thrombolysis by a fibrin-specific antibody Fab'-urokinase conjugate. J Mol Cell Cardiol 1987; 19(4): 335–341

[173] Dewerchin M, Lijnen HR, Collen D. Characterisation of a chemical conjugate between a low molecular weight form of recombinant single chain urokinase-type plasminogen activator (comprising leu-144 through leu-411) and F(ab')₂-fragments of a fibrin D-dimer-specific monoclonal antibody. Fibrinolysis 1990; 4(1): 11–18

[174] Lijnen HR, Dewerchin M, De Cock F, Collen D. Effect of fibrin-targeting on clot lysis with urokinase-type plasminogen activator. Thromb Res 1990; 57(3): 333–342

[175] Runge MS, Harker LA, Bode C, Ruef J, Kelly AB, Marzec UM, Allen E, Caban R, Shaw SY, Haber E, Hanson SR. Enhanced thrombolytic and antithrombotic potency of a fibrin-targeted plasminogen activator in baboons. Circulation 1996; 94(6): 1412–1422

[176] Holvoet P, Laroche Y, Lijnen HR, Van Cauwenberge R, Demarsin E, Brouwers E, Matthyssens G, Collen D. Characterization of a chimeric plasminogen activator consisting of a single-chain Fv fragment derived from a fibrin fragment D-dimer-specific antibody and a truncated single-chain urokinase. J Biol Chem 1991; 266(29): 19717–19724

[177] Shaw GJ, Meunier JM, Huang SL, Lindsell CJ, McPherson DD, Holland CK. Ultrasound-enhanced thrombolysis with tPA-loaded echogenic liposomes. Thromb Res 2009; 124(3): 306–310

[178] Tiukinhoy-Laing SD, Huang S, Klegerman M, Holland CK, McPherson DD. Ultrasound-facilitated thrombolysis using tissue-plasminogen activator-loaded echogenic liposomes. Thromb Res 2007; 119(6): 777–784

[179] Laing ST, Moody M, Smulevitz B, Kim H, Kee P, Huang S, Holland CK, McPherson DD. Ultrasound-enhanced thrombolytic effect of tissue plasminogen activator-loaded echogenic liposomes in an in vivo rabbit aorta thrombus model—brief report. Arterioscler Thromb Vasc Biol 2011; 31(6): 1357–1359

[180] AIMS Trial Study Group. Effect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo-controlled clinical trial. Lancet 1988; 331(8585): 545–549 PMID:2894490

[181] Robbins KC, Tanaka Y. Covalent molecular weight approximately 92 000 hybrid plasminogen activator derived from human plasmin amino-terminal and urokinase carboxyl-terminal domains. Biochemistry 1986; 25(12): 3603–3611

[182] Robbins KC, Boreisha IG. A covalent molecular weight approximately 92,000 hybrid plasminogen activator derived from human plasmin fibrin-binding and tissue plasminogen activator catalytic domains. Biochemistry 1987; 26(15): 4661–4667

[183] Maksimenko AV, Torchilin VP. Water-soluble urokinase derivatives with increased affinity to the fibrin clot. Thromb Res 1985; 38(3): 289–295

[184] Maksimenko AV, Samarenko MB, Petrov AD, Tischenko EG, Ruda M, Torchilin VP. Fibrinogen-immobilized urokinase demonstrates increased thrombolytic activity in animal experiments. Ann N Y Acad Sci 1990; 613:479–482

[185] Klegerman M, Parikh D, Tiukinhoy-Laing S, McPherson D. Ability of human tissue plasminogen activator to act as a targeting agent in tPA-loaded echogenic liposomes. AAPS J 2006; 8(S2):Abstr. T2111

[186] Moody M, Laing ST, Huang S, Kim H, Smulevitz B, Zou Y, McPherson DD, Klegerman ME. Doppler ultrasound enhances the thrombolytic activity of tissue-plasminogen activator-loaded echogenic liposomes. Circulation 2007; 116: II-646

[187] Smith DA, Vaidya SS, Kopechek JA, Huang SL, Klegerman ME, McPherson DD, Holland CK. Ultrasound-triggered release of recombinant tissue-type plasminogen activator from echogenic liposomes. Ultrasound Med Biol 2010; 36(1): 145–157

[188] Laing ST, Moody MR, Kim H, Smulevitz B, Huang SL, Holland CK, McPherson DD, Klegerman ME. Thrombolytic efficacy of tissue plasminogen activator-loaded echogenic liposomes in a rabbit thrombus model. Thromb Res 2012; 130(4): 629–635

[189] Heeremans JL, Kraaijenga JJ, Los P, Kluft C, Crommelin DJ. Development of a procedure for coupling the homing device glu-plasminogen to liposomes. Biochim Biophys Acta 1992; 1117(3): 258–264

[190] Gidlöf AC, Ocaya P, Krivospitskaya O, Sirsjö A. Vitamin A: a drug for prevention of restenosis/reocclusion after percutaneous coronary intervention? Clin Sci (Lond) 2008; 114(1): 19–25

[191] Glagov S. Intimal hyperplasia, vascular modeling, and the restenosis problem. Circulation 1994; 89(6): 2888–2891

[192] Labinaz M, Pels K, Hoffert C, Aggarwal S, O’Brien ER. Time course and importance of neoadventitial formation in arterial remodeling following balloon angioplasty of porcine coronary arteries. Cardiovasc Res 1999; 41(1): 255–266

[193] Molero L, López-Farré A, Mateos-Cáceres PJ, Fernández-Sánchez R, Luisa Maestro M, Silva J, Rodríguez E, Macaya C. Effect of clopidogrel on the expression of inflammatory markers in rabbit ischemic coronary artery. Br J Pharmacol 2005; 146(3): 419–424

[194] Pickering JG, Weir L, Jekanowski J, Kearney MA, Isner JM. Proliferative activity in peripheral and coronary atherosclerotic plaque among patients undergoing percutaneous revascularization. J Clin Invest 1993; 91(4): 1469–1480

[195] Vandelli L, Marietta M, Gambini M, Cavazzuti M, Trenti T, Cenci MA, Casoni F, Bigliardi G, Pentore R, Nichelli P, Zini A. Fibrinogen decrease after intravenous thrombolysis in ischemic stroke patients is a risk factor for intracerebral hemorrhage. J Stroke Cerebrovasc Dis 2015; 24(2): 394–400

RIGHTS & PERMISSIONS

Higher Education Press and Springer-Verlag Berlin Heidelberg