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Nano Research 2016, 9(9): 2652-2661 https://doi.org/10.1007/s12274-016-1152-4
Research Article | Issue | Published: 27 June 2016

Magnetically active Fe3O4 nanorods loaded with tissue plasminogen activator for enhanced thrombolysis

Show Author's Information Jiangnan Hu1,2,§,  Weijie Huang3,§,  Shengwei Huang1,2,§,  Qichuan ZhuGe1( ),  Kunlin Jin1,2( ),  Yiping Zhao3( )
Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder ResearchThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhou325000China
Department of Pharmacology and NeuroscienceUniversity of North Texas Health Science CenterFort WorthTexas76107USA
Department of Physics and AstronomyNanoscale Science and Engineering CenterUniversity of GeorgiaAthensGeorgia30602USA

§These authors contributed equally to this work.

Keywords:
drug delivery, iron oxide, magnetic nanorods, enhanced thrombolysis, tissue plasminogen activator
Cite this article:
Hu J, Huang W, Huang S, et al. Magnetically active Fe3O4 nanorods loaded with tissue plasminogen activator for enhanced thrombolysis. Nano Research, 2016, 9(9): 2652-2661. https://doi.org/10.1007/s12274-016-1152-4
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Abstract Full text Electronic supplementary material About this article

Systemic thrombolysis with intravenous tissue plasminogen activator (tPA) remains the only proven treatment that is effective in improving the clinical outcome of patients with acute ischemic stroke. However, thrombolytic therapy has some major limitations such as hemorrhage, neurotoxicity, and the short time window for the treatment. In this study, we designed iron oxide (Fe3O4) nanorods loaded with 6% tPA, which could be released within ~30 min. The Fe3O4 nanorods could be targeted to blood clots under magnetic guidance. In addition, the release of tPA could be significantly increased using an external rotating magnetic field, which subsequently resulted in a great improvement in the thrombolytic efficiency. Systematic and quantitative studies revealed the fundamental physical processes involved in the enhanced thrombolysis, while the in vitro thrombolysis assay showed that the proposed strategy could improve thrombolysis and recanalization rates and reduce the risk of tPA-mediated hemorrhage in vivo. Such a strategy will be very useful for the treatment of ischemic stroke and other deadly thrombotic diseases such as myocardial infarction and pulmonary embolism in clinical settings.


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Electronic supplementary material
About this article

Magnetically active Fe3O4 nanorods loaded with tissue plasminogen activator for enhanced thrombolysis

Show Author's information Jiangnan Hu1,2,§, Weijie Huang3,§, Shengwei Huang1,2,§, Qichuan ZhuGe1( ), Kunlin Jin1,2( ), Yiping Zhao3( )
Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder ResearchThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhou325000China
Department of Pharmacology and NeuroscienceUniversity of North Texas Health Science CenterFort WorthTexas76107USA
Department of Physics and AstronomyNanoscale Science and Engineering CenterUniversity of GeorgiaAthensGeorgia30602USA

§These authors contributed equally to this work.

Abstract

Systemic thrombolysis with intravenous tissue plasminogen activator (tPA) remains the only proven treatment that is effective in improving the clinical outcome of patients with acute ischemic stroke. However, thrombolytic therapy has some major limitations such as hemorrhage, neurotoxicity, and the short time window for the treatment. In this study, we designed iron oxide (Fe3O4) nanorods loaded with 6% tPA, which could be released within ~30 min. The Fe3O4 nanorods could be targeted to blood clots under magnetic guidance. In addition, the release of tPA could be significantly increased using an external rotating magnetic field, which subsequently resulted in a great improvement in the thrombolytic efficiency. Systematic and quantitative studies revealed the fundamental physical processes involved in the enhanced thrombolysis, while the in vitro thrombolysis assay showed that the proposed strategy could improve thrombolysis and recanalization rates and reduce the risk of tPA-mediated hemorrhage in vivo. Such a strategy will be very useful for the treatment of ischemic stroke and other deadly thrombotic diseases such as myocardial infarction and pulmonary embolism in clinical settings.

Keywords: drug delivery, iron oxide, magnetic nanorods, enhanced thrombolysis, tissue plasminogen activator

References(27)

1

Jørgensen, H. S.; Nakayama, H.; Raaschou, H. O.; Olsen, T. S. Stroke. Neurologic and functional recovery the Copenhagen Stroke Study. Phys. Med. Rehabil. Clin. N. Am. 1999, 10, 887-906.
DOI Google Scholar
2

Furie, B.; Furie, B. C. Mechanisms of thrombus formation. N. Engl. J. Med. 2008, 359, 938-949.
DOI Google Scholar
3

Brott, T.; Bogousslavsky, J. Treatment of acute ischemic stroke. N. Engl. J. Med. 2000, 343, 710-722.
DOI Google Scholar
4

Adams, H. P., Jr.; del Zoppo, G.; Alberts, M. J.; Bhatt, D. L.; Brass, L.; Furlan, A.; Grubb, R. L.; Higashida, R. T.; Jauch, E. C.; Kidwell, C. et al. Guidelines for the early management of adults with ischemic stroke. Stroke 2007, 38, 1655-1711.
DOI Google Scholar
5

Clark, W. M.; Wissman, S.; Albers, G. W.; Jhamandas, J. H.; Madden, K. P.; Hamilton, S. Recombinant tissue-type plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS study: A randomized controlled trial. Alteplase thrombolysis for acute noninterventional therapy in ischemic stroke. JAMA 1999, 282, 2019-2026.
DOI Google Scholar
6

Ogawa, A.; Mori, E.; Minematsu, K.; Taki, W.; Takahashi, A.; Nemoto, S.; Miyamoto, S.; Sasaki, M.; Inoue, T. Randomized trial of intraarterial infusion of urokinase within 6 hours of middle cerebral artery stroke: The middle cerebral artery embolism local fibrinolytic intervention trial (MELT) Japan. Stroke 2007, 38, 2633-2639.
DOI Google Scholar
7

Hua, X.; Zhou, L.; Liu, P.; He, Y.; Tan, K. B.; Chen, Q. H.; Gao, Y. J.; Gao, Y. H. In vivo thrombolysis with targeted microbubbles loading tissue plasminogen activator in a rabbit femoral artery thrombus model. J. Thromb. Thrombolysis 2014, 38, 57-64.
DOI Google Scholar
8

Petit, B.; Yan, F.; Tranquart, F.; Allémann, E. Microbubbles and ultrasound-mediated thrombolysis: A review of recent in vitro studies. J. Drug Deliv. Sci. Tec. 2012, 22, 381-392.
DOI Google Scholar
9

Korin, N.; Kanapathipillai, M.; Matthews, B. D.; Crescente, M.; Brill, A.; Mammoto, T.; Ghosh, K.; Jurek, S.; Bencherif, S. A.; Bhatta, D. et al. Shear-activated nanotherapeutics for drug targeting to obstructed blood vessels. Science 2012, 337, 738-742.
DOI Google Scholar
10

McCarthy, J. R.; Weissleder, R. Multifunctional magnetic nanoparticles for targeted imaging and therapy. Adv. Drug Deliv. Rev. 2008, 60, 1241-1251.
DOI Google Scholar
11

Laurent, S.; Forge, D.; Port, M.; Roch, A.; Robic, C.; Elst, L. V.; Muller, R. N. Magnetic iron oxide nanoparticles: Synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications. Chem. Rev. 2008, 108, 2064-2110.
DOI Google Scholar
12

Voros, E.; Cho, M. J.; Ramirez, M.; Palange, A. L.; De Rosa, E.; Key, J.; Garami, Z.; Lumsden, A. B.; Decuzzi, P. TPA immobilization on iron oxide nanocubes and localized magnetic hyperthermia accelerate blood clot lysis. Adv. Funct. Mater. 2015, 25, 1709-1718.
DOI Google Scholar
13

Cheng, R.; Huang, W. J.; Huang, L. J.; Yang, B.; Mao, L. D.; Jin, K. L.; ZhuGe, Q. C.; Zhao, Y. P. Acceleration of tissue plasminogen activator-mediated thrombolysis by magnetically powered nanomotors. ACS Nano 2014, 8, 7746-7754.
DOI Google Scholar
14

Chen, J. P.; Yang, P. C.; Ma, Y. H.; Tu, S. J.; Lu, Y. J. Targeted delivery of tissue plasminogen activator by binding to silica-coated magnetic nanoparticle. Int. J. Nanomed. 2012, 7, 5137-5149.
DOI Google Scholar
15

Xie, Y. M.; Kaminski, M. D.; Torno, M. D.; Finck, M. R.; Liu, X. Q.; Rosengart, A. J. Physicochemical characteristics of magnetic microspheres containing tissue plasminogen activator. J. Magn. Magn. Mater. 2007, 311, 376-378.
DOI Google Scholar
16

Kempe, H.; Kempe, M. The use of magnetite nanoparticles for implant-assisted magnetic drug targeting in thrombolytic therapy. Biomaterials 2010, 31, 9499-9510.
DOI Google Scholar
17

Zhao, Y. P.; Ye, D. X.; Wang, G. C.; Lu, T. M. Novel nano- column and nano-flower arrays by glancing angle deposition. Nano Lett. 2002, 2, 351-354.
DOI Google Scholar
18

Cornell, R. M.; Schwertmann, U. The Iron Oxides: Structure, Properties, Reactions, Occurrences, and Uses; VCH: Weinheim, New York, 1996.
19

Adams, H. P.; del Zoppo, G.; Alberts, M. J.; Bhatt, D. L.; Brass, L.; Furlan, A.; Grubb, R. L.; Higashida, R. T.; Jauch, E. C.; Kidwell, C. et al. Guidelines for the early management of adults with ischemic stroke. Stroke 2007, 38, 1655-1711.
DOI Google Scholar
20

Hacke, W.; Kaste, M.; Bluhmki, E.; Brozman, M.; Dávalos, A.; Guidetti, D.; Larrue, V.; Lees, K. R.; Medeghri, Z.; Machnig, T. et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N. Engl. J. Med. 2008, 359, 1317-1329.
DOI Google Scholar
21

Armstrong, P. W.; Collen, D. Fibrinolysis for acute myocardial infarction: Current status and new horizons for pharmacological reperfusion, Part 2. Circulation 2001, 103, 2987-2992.
DOI Google Scholar
22

Chandler, W. L.; Alessi, M. C.; Aillaud, M. F.; Henderson, P.; Vague, P.; Juhan-Vague, I. Clearance of tissue plasminogen activator (TPA) and TPA/plasminogen activator inhibitor type 1 (PAI-1) complex: Relationship to elevated TPA antigen in patients with high PAI-1 activity levels. Circulation 1997, 96, 761-768.
DOI Google Scholar
23

Cameron, H. A.; McEwen, B. S.; Gould, E. Regulation of adult neurogenesis by excitatory input and NMDA receptor activation in the dentate gyrus. J. Neurosci. 1995, 15, 4687-4692.
DOI Google Scholar
24

Chen, J. P.; Yang, P. C.; Ma, Y. H.; Wu, T. Characterization of chitosan magnetic nanoparticles for in situ delivery of tissue plasminogen activator. Carbohyd. Polym. 2011, 84, 364-372.
DOI Google Scholar
25

Diamond, S. L. Engineering design of optimal strategies for blood clot dissolution. Annu. Rev. Biomed. Eng. 1999, 1, 427-462.
DOI Google Scholar
26

Diamond, S. L.; Anand, S. Inner clot diffusion and permeation during fibrinolysis. Biophys. J. 1993, 65, 2622-2643.
DOI Google Scholar
27

Pleydell, C. P.; David, T.; Smye, S. W.; Berridge, D. C. A mathematical model of post-canalization thrombolysis. Phys. Med. Biol. 2002, 47, 209-224.
DOI Google Scholar
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Publication history
Copyright
Acknowledgements

Publication history

Received: 02 February 2016
Revised: 04 May 2016
Accepted: 16 May 2016
Published: 27 June 2016
Issue date: September 2016

Copyright

© Tsinghua University Press and Springer‐Verlag Berlin Heidelberg 2016

Acknowledgements

Acknowledgements

This work is supported by National Science Foundation under the contract ECCS-1303134, National Institutes of Health under the contract R21 NS084148-01A1, the National Science Foundation of Beijing (No. 7161014), Key Science and Technology Project of Zhejiang Provincial Health Department (No. WKJ2013-2-022) and National Natural Science Foundation of China (No. 81371396).

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