Nano Research

, Volume 9, Issue 8, pp 2327–2337 | Cite as

Relief from vascular occlusion using photothermal ablation of thrombus with a multimodal perspective

  • Nitesh Singh
  • Anand Varma
  • Ashish Verma
  • Babu N. Maurya
  • Debabrata DashEmail author
Research Article


Fibrinolytic therapy for arterial or venous thrombotic disorders involves the systemic administration of thrombolytics such as streptokinase, which is associated with serious bleeding complications. With this study, we provide a proof-of-concept of photothermal thrombus ablation with gold nanorods exposed to near-infrared irradiation, both in vitro using materials generated from purified fibrinogen or plasma and in vivo in murine blood vessels. This is the first report of the application of photothermal therapy as an anti-thrombotic measure. Remarkably, the addition of streptokinase had a multimodal additive effect with regard to acceleration of photothermal lysis of thrombi even at a dose significantly below the therapeutic concentration, thus minimizing the life-threatening side effects and adverse complications. This combinatorial approach exhibits great promise for lysing pathological clots while effectively overcoming the drawbacks of existing therapies.


platelet fibrin near-infrared laser photothermal therapy thrombolysis streptokinase 


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  1. [1]
    Canto, J. G.; Rogers, W. J.; Goldberg, R. J.; Peterson, E. D.; Wenger, N. K.; Vaccarino, V.; Kiefe, C. I.; Frederick, P. D.; Sopko, G.; Zheng, Z.-J. et al. Association of age and sex with myocardial infarction symptom presentation and in-hospital mortality. JAMA 2012, 307, 813–822.Google Scholar
  2. [2]
    Weitz, J. I. Antiplatelet, anticoagulant, and fibrinolytic drugs. In Harrison’s Principles of Internal Medicine. Longo, D. L.; Fauci, A. S.; Kasper, D. L.; Hauser, S. L.; Jameson, J. L.; Loscalzo, J., Eds.; McGraw-Hill: New Delhi, 2011; Vol. 1, pp 1001–1003.Google Scholar
  3. [3]
    Tsai, M. F.; Chang, S. H. G.; Cheng, F. Y.; Shanmugam, V.; Cheng, Y. S.; Su, C. H.; Yeh, C. S. Au nanorod design as light-absorber in the first and second biological near-infrared windows for in vivo photothermal therapy. ACS Nano 2013, 7, 5330–5342.CrossRefGoogle Scholar
  4. [4]
    Mosesson, M. W. Fibrinogen and fibrin structure and functions. J. Thromb. Haemost. 2005, 3, 1894–1904.CrossRefGoogle Scholar
  5. [5]
    Hethershaw, E. L.; Cilia La Corte, A. L.; Duval, C.; Ali, M.; Grant, P. J.; Ariëns, R. A. S.; Philippou, H. The effect of blood coagulation factor XIII on fibrin clot structure and fibrinolysis. J. Thromb. Haemost. 2014, 12, 197–205.CrossRefGoogle Scholar
  6. [6]
    Chernysh, I. N.; Everbach, C. E.; Purohit, P. K.; Weisel, J. W. Molecular mechanisms of the effect of ultrasound on the fibrinolysis of clots. J. Thromb. Haemost. 2015, 13, 601–609.CrossRefGoogle Scholar
  7. [7]
    Walters, M. I. An evaluation of hemoglobin concentrations obtained with frozen altered Drabkin’s reagents. Clin. Chem. 1968, 14, 682–691.Google Scholar
  8. [8]
    Chernysh, I. N.; Nagaswami, C.; Purohit, P. K.; Weisel, J. W. Fibrin clots are equilibrium polymers that can be remodeled without proteolytic digestion. Sci. Rep. 2012, 2, 879.CrossRefGoogle Scholar
  9. [9]
    Gersh, K. C.; Zaitsev, S.; Cines, D. B.; Muzykantov, V.; Weisel, J. W. Flow-dependent channel formation in clots by an erythrocyte-bound fibrinolytic agent. Blood 2011, 117, 4964–4967.CrossRefGoogle Scholar
  10. [10]
    Westrick, R. J.; Winn, M. E.; Eitzman, D. T. Murine models of vascular thrombosis. Arterioscler. Thromb. Vasc. Biol. 2007, 27, 2079–2093.CrossRefGoogle Scholar
  11. [11]
    Liopo, A.; Conjusteau, A.; Tsyboulski, D.; Ermolinsky, B.; Kazansky, A.; Oraevsky, A. Biocompatible gold nanorod conjugates for preclinical biomedical research. J. Nanomed. Nanotechnol. 2012, 6, 274.Google Scholar
  12. [12]
    Falati, S.; Gross, P.; Merrill-Skoloff, G.; Furie, B. C.; Furie, B. Real-time in vivo imaging of platelets, tissue factor and fibrin during arterial thrombus formation in the mouse. Nat. Med. 2002, 8, 1175–1180.CrossRefGoogle Scholar
  13. [13]
    Nagai, N.; Vanlinthout, I.; Collen, D. Comparative effects of tissue plasminogen activator, streptokinase, and staphylokinase on cerebral ischemic infarction and pulmonary clot lysis in hamster models. Circulation 1999, 100, 2541–2546.CrossRefGoogle Scholar
  14. [14]
    Small, W.; Wilson, T. S.; Benett, W. J.; Loge, J. M.; Maitland, D. J. Laser-activated shape memory polymer intravascular thrombectomy device. Opt. Express 2005, 13, 8204–8213.CrossRefGoogle Scholar
  15. [15]
    Kuo, W. T.; Odegaard, J. I.; Louie, J. D.; Sze, D. Y.; Unver, K.; Kothary, N.; Rosenberg, J. K.; Hovesepian, D. M.; Hwang, G. L.; Hofmann, L. V. Photothermal ablation with the excimer laser sheath technique for embedded inferior vena cava filter removal: Initial results from a prospective study. J. Vasc. Interv. Radiol. 2011, 22, 813–823.CrossRefGoogle Scholar
  16. [16]
    Kharlamov, A. N.; Gabinsky, J. L. Plasmonic photothermic and stem cell therapy of atherosclerotic plaque as a novel nanotool for angioplasty and artery remodeling. Rejuvenation Res. 2012, 15, 222–230.CrossRefGoogle Scholar
  17. [17]
    Walker, J. M.; Zaleski, J. M. Non-enzymatic remodeling of fibrin biopolymers via photothermally triggered radicalgenerating nanoparticles. Chem. Mater. 2014, 26, 5120–5130.CrossRefGoogle Scholar
  18. [18]
    Choi, J.; Yang, J.; Jang, E.; Suh, J. S.; Huh, Y. M.; Lee, K.; Haam, S. Gold nanostructures as photothermal therapy agent for cancer. Anti-Cancer Agents Med. Chem. 2011, 11, 953–964.CrossRefGoogle Scholar
  19. [19]
    Green, H. N.; Martyshkin, D. V.; Rodenburg, C. M.; Rosenthal, E. L.; Mirov, S. B. Gold nanorod bioconjugates for active tumor targeting and photothermal therapy. J. Nanotechnol. 2011, 2011, Article ID 631753.Google Scholar
  20. [20]
    Gaffney, P. J.; Whitaker, A. N. Fibrin crosslinks and lysis rates. Thromb. Res. 1979, 14, 85–94.CrossRefGoogle Scholar
  21. [21]
    McDonagh Jr, R. P.; McDonagh, J.; Duckert, F. The influence of fibrin crosslinking on the kinetics of urokinase-induced clot lysis. Br. J. Haematol. 1971, 21, 323–332.CrossRefGoogle Scholar
  22. [22]
    Banerjee, A.; Chisti, Y.; Banerjee, U. C. Streptokinase—A clinically useful thrombolytic agent. Biotechnol. Adv. 2004, 22, 287–307.CrossRefGoogle Scholar
  23. [23]
    Collen, D.; de Cock, F.; Stassen, J. M. Comparative immunogenicity and thrombolytic properties toward arterial and venous thrombi of streptokinase and recombinant staphylokinase in baboons. Circulation 1993, 87, 996–1006.CrossRefGoogle Scholar
  24. [24]
    Betancourt, B. Y.; Marrero-Miragaya, M. A.; Jiménez-López, G.; Valenzuela-Silva, C.; García-Iglesias, E.; Hernández-Bernal, F.; Debesa-García, F.; González-López, T.; Alvarez-Falcón, L.; López-Saura, P. A. et al. Pharmacovigilance program to monitor adverse reactions of recombinant streptokinase in acute myocardial infarction. BMC Clin. Pharmacol. 2005, 5, 5.CrossRefGoogle Scholar
  25. [25]
    Kunitada, S.; FitzGerald, G. A.; Fitzgerald, D. J. Inhibition of clot lysis and decreased binding of tissue-type plasminogen activator as a consequence of clot retraction. Blood 1992, 79, 1420–1427.Google Scholar
  26. [26]
    Katori, N.; Tanaka, K. A.; Szlam, F.; Levy, J. H. The effects of platelet count on clot retraction and tissue plasminogen activator-induced fibrinolysis on thrombelastography. Anesth. Analg. 2005, 100, 1781–1785.CrossRefGoogle Scholar
  27. [27]
    Leung, J. P.; Wu, S.; Chou, K. C.; Signorell, R. Investigation of sub-100 nm gold nanoparticles for laser-induced thermotherapy of cancer. Nanomaterials 2013, 3, 86–106.CrossRefGoogle Scholar
  28. [28]
    Kennedy, L. C.; Bickford, L. R.; Lewinski, N. A.; Coughlin, A. J.; Hu, Y.; Day, E. S.; West, J. L.; Drezek, R. A. A new era for cancer treatment: Gold-nanoparticle-mediated thermal therapies. Small 2011, 7, 169–183.CrossRefGoogle Scholar
  29. [29]
    Dickerson, E. B.; Dreaden, E. C.; Huang, X. H.; El-Sayed, I. H.; Chu, H. H.; Pushpanketh, S.; McDonald, J. F.; El-Sayed, M. A. Gold nanorod assisted near-infrared plasmonic photothermal therapy (PPTT) of squamous cell carcinoma in mice. Cancer Lett. 2008, 269, 57–66.CrossRefGoogle Scholar
  30. [30]
    Rengan, A. K.; Bukhari, A. B.; Pradhan, A.; Malhotra, R.; Banerjee, R.; Srivastava, R.; De, A. In vivo analysis of biodegradable liposome gold nanoparticles as efficient agents for photothermal therapy of cancer. Nano Lett. 2015, 15, 842–848.CrossRefGoogle Scholar
  31. [31]
    Hudson, D. E.; Hudson, D. O.; Wininger, J. M.; Richardson, B. D. Penetration of laser light at 808 and 980 nm in bovine tssue samples. Photomed. Laser Surg. 2013, 31, 163–168.CrossRefGoogle Scholar

Copyright information

© Tsinghua University Press and Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Nitesh Singh
    • 1
  • Anand Varma
    • 1
  • Ashish Verma
    • 2
  • Babu N. Maurya
    • 2
  • Debabrata Dash
    • 1
    Email author
  1. 1.Department of Biochemistry, Institute of Medical SciencesBanaras Hindu UniversityVaranasiIndia
  2. 2.Department of Radiodiagnosis and Imaging, Institute of Medical SciencesBanaras Hindu UniversityVaranasiIndia

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