Magnetic Targeting Improves the Therapeutic Efficacy of Microbubble-Mediated Obstructive Thrombus SonothrombolysisFunding This work was supported by grants awarded to Jianping Bin from the National Natural Science Foundation of China (No. 81771857 and No. 81571698) and the Guangzhou Regenerative Medicine and Health Laboratory of Guangdong (2018GZR110105009).
02 February 2019
05 July 2019
02 September 2019 (online)
Background Magnetic targeting may help microbubbles (MBs) reach obstructive thrombi and improve the efficacy of MB-mediated sonothrombolysis, but the role of magnetic targeting in MB-mediated sonothrombolysis remains elusive.
Objectives We investigate the feasibility and efficacy of magnetically targeted MB-mediated sonothrombolysis for the treatment of obstructive thrombi.
Materials and Methods Red and white thromboembolic models were established in vitro and in vivo. The models were randomly assigned to the control, ultrasound plus control MB (US + C-MB), ultrasound plus magnetic MB (US + M-MB), or US + M-MB + recombinant tissue-type plasminogen activator (r-tPA) groups and treated for 30 minutes. The recanalization rate, average blood flow velocity, hindlimb perfusion, and skeletal muscle injury marker levels were recorded.
Results The recanalization rate, average blood flow velocity, and hindlimb perfusion in the red and white thromboembolic models were all significantly higher in the US + M-MB and US + M-MB + r-tPA groups than in the control and US + C-MB groups both in vitro and in vivo. Moreover, the levels of the skeletal muscle injury markers were all significantly lower in the US + M-MB and US + M-MB + r-tPA groups than in the other two groups in vivo for both thromboembolic models. However, the thrombolytic effects of red thrombi performed better than those of white thrombi in the US + M-MB + r-tPA group.
Conclusion M-MB-mediated sonothrombolysis improves the efficacy of thrombolysis both in vitro and in vivo, and reduces tissue damage in clogging model; thus, this method may serve as a promising approach for treating thrombus-occlusive diseases.
X.C. and W.W. performed the experiments and analyzed the data; S.W., J.Z., and N.M.D. wrote the article; G.W., Y.L., and X.S. analyzed the data; S.C., W.L., and Y.L. provided intellectual review of the article; H.L. and J.B. designed and directed the research.
- 1 Wendelboe AM, Raskob GE. Global burden of thrombosis: epidemiologic aspects. Circ Res 2016; 118 (09) 1340-1347
- 2 Kim JT, Fonarow GC, Smith EE. , et al. Treatment with tissue plasminogen activator in the golden hour and the shape of the 4.5-hour time-benefit curve in the National United States Get With The Guidelines-Stroke Population. Circulation 2017; 135 (02) 128-139
- 3 Zerna C, Siepmann T, Barlinn K. , et al. Association of time on outcome after intravenous thrombolysis in the elderly in a telestroke network. J Telemed Telecare 2016; 22 (01) 18-24
- 4 Minnerup J, Wersching H, Teuber A. , et al; REVASK Investigators. Outcome after thrombectomy and intravenous thrombolysis in patients with acute ischemic stroke: a prospective observational study. Stroke 2016; 47 (06) 1584-1592
- 5 Romano JG, Smith EE, Liang L. , et al. Outcomes in mild acute ischemic stroke treated with intravenous thrombolysis: a retrospective analysis of the Get With the Guidelines-Stroke registry. JAMA Neurol 2015; 72 (04) 423-431
- 6 Vedantham S, Goldhaber SZ, Julian JA. , et al; ATTRACT Trial Investigators. Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis. N Engl J Med 2017; 377 (23) 2240-2252
- 7 Maron BA, Goldhaber SZ, Sturzu AC. , et al. Catheter-directed thrombolysis for giant right atrial thrombus. Circ Cardiovasc Imaging 2010; 3 (01) 126-127
- 8 American College of Emergency Physicians; American Academy of Neurology. Clinical policy: use of intravenous tPA for the management of acute ischemic stroke in the emergency department. Ann Emerg Med 2013; 61 (02) 225-243
- 9 Tian Z, Liao G, Li S. , et al. Comparison of multimodal intra-arterial treatment versus intravenous thrombolysis for hypertensive patients with severe large vessel cerebral infarction. J Investig Med 2017; 65 (07) 1033-1040
- 10 Li Y, Yang R, Li Z. , et al. Urokinase vs tissue-type plasminogen activator for thrombolytic evacuation of spontaneous intracerebral hemorrhage in basal ganglia. Front Neurol 2017; 8: 371
- 11 Marder VJ, Landskroner K, Novokhatny V. , et al. Plasmin induces local thrombolysis without causing hemorrhage: a comparison with tissue plasminogen activator in the rabbit. Thromb Haemost 2001; 86 (03) 739-745
- 12 Wang X, Hagemeyer CE, Hohmann JD. , et al. Novel single-chain antibody-targeted microbubbles for molecular ultrasound imaging of thrombosis: validation of a unique noninvasive method for rapid and sensitive detection of thrombi and monitoring of success or failure of thrombolysis in mice. Circulation 2012; 125 (25) 3117-3126
- 13 Alonso A, Della Martina A, Stroick M. , et al. Molecular imaging of human thrombus with novel abciximab immunobubbles and ultrasound. Stroke 2007; 38 (05) 1508-1514
- 14 Wu W, Wang Y, Shen S. , et al. In vivo ultrasound molecular imaging of inflammatory thrombosis in arteries with cyclic Arg-Gly-Asp-modified microbubbles targeted to glycoprotein IIb/IIIa. Invest Radiol 2013; 48 (11) 803-812
- 15 Hu G, Liu C, Liao Y. , et al. Ultrasound molecular imaging of arterial thrombi with novel microbubbles modified by cyclic RGD in vitro and in vivo. Thromb Haemost 2012; 107 (01) 172-183
- 16 Lu Y, Wang J, Huang R. , et al. Microbubble-mediated sonothrombolysis improves outcome after thrombotic microembolism-induced acute ischemic stroke. Stroke 2016; 47 (05) 1344-1353
- 17 de Saint Victor M, Crake C, Coussios CC, Stride E. Properties, characteristics and applications of microbubbles for sonothrombolysis. Expert Opin Drug Deliv 2014; 11 (02) 187-209
- 18 Bader KB, Bouchoux G, Holland CK. Sonothrombolysis. Adv Exp Med Biol 2016; 880: 339-362
- 19 de Saint Victor M, Barnsley LC, Carugo D, Owen J, Coussios CC, Stride E. Sonothrombolysis with magnetically targeted microbubbles. Ultrasound Med Biol 2019; 45 (05) 1151-1163
- 20 Culp WC, Porter TR, Xie F. , et al. Microbubble potentiated ultrasound as a method of declotting thrombosed dialysis grafts: experimental study in dogs. Cardiovasc Intervent Radiol 2001; 24 (06) 407-412
- 21 Gao S, Zhu Q, Guo M. , et al. Ultrasound and intra-clot microbubbles enhanced catheter-directed thrombolysis in vitro and in vivo. Ultrasound Med Biol 2017; 43 (08) 1671-1678
- 22 de Saint Victor M, Carugo D, Barnsley LC, Owen J, Coussios CC, Stride E. Magnetic targeting to enhance microbubble delivery in an occluded microarterial bifurcation. Phys Med Biol 2017; 62 (18) 7451-7470
- 23 Wu J, Leong-Poi H, Bin J. , et al. Efficacy of contrast-enhanced US and magnetic microbubbles targeted to vascular cell adhesion molecule-1 for molecular imaging of atherosclerosis. Radiology 2011; 260 (02) 463-471
- 24 Bi F, Zhang J, Su Y, Tang YC, Liu JN. Chemical conjugation of urokinase to magnetic nanoparticles for targeted thrombolysis. Biomaterials 2009; 30 (28) 5125-5130
- 25 Ma YH, Wu SY, Wu T, Chang YJ, Hua MY, Chen JP. Magnetically targeted thrombolysis with recombinant tissue plasminogen activator bound to polyacrylic acid-coated nanoparticles. Biomaterials 2009; 30 (19) 3343-3351
- 26 Kempe M, Kempe H, Snowball I. , et al. The use of magnetite nanoparticles for implant-assisted magnetic drug targeting in thrombolytic therapy. Biomaterials 2010; 31 (36) 9499-9510
- 27 Ren L, Wang X, Wu H, Shang B, Wang J. Conjugation of nattokinase and lumbrukinase with magnetic nanoparticles for the assay of their thrombolytic activities. J Mol Catal, B Enzym 2010; 62: 190-196
- 28 Fan CH, Cheng YH, Ting CY. , et al. Ultrasound/magnetic targeting with SPIO-DOX-microbubble complex for image-guided drug delivery in brain tumors. Theranostics 2016; 6 (10) 1542-1556
- 29 Verhaagen B, Boutsioukis C, Sleutel C. , et al. Irrigant transport into dental microchannels. Microfluidics and nanofluidics 2014; 16 (06) 1165-1177
- 30 Nederhoed JH, Ebben HP, Slikkerveer J. , et al. Intravenous targeted microbubbles carrying urokinase versus urokinase alone in acute peripheral arterial thrombosis in a porcine model. Ann Vasc Surg 2017; 44: 400-407
- 31 Wang X, Gkanatsas Y, Palasubramaniam J. , et al. Thrombus-targeted theranostic microbubbles: a new technology towards concurrent rapid ultrasound diagnosis and bleeding-free fibrinolytic treatment of thrombosis. Theranostics 2016; 6 (05) 726-738
- 32 Mathias Jr W, Tsutsui JM, Tavares BG. , et al. Diagnostic ultrasound impulses improve microvascular flow in patients with STEMI receiving intravenous microbubbles. J Am Coll Cardiol 2016; 67 (21) 2506-2515
- 33 Dixon AJ, Rickel JMR, Shin BD, Klibanov AL, Hossack JA. In vitro sonothrombolysis enhancement by transiently stable microbubbles produced by a flow-focusing microfluidic device. Ann Biomed Eng 2018; 46 (02) 222-232
- 34 Dames P, Gleich B, Flemmer A. , et al. Targeted delivery of magnetic aerosol droplets to the lung. Nat Nanotechnol 2007; 2 (08) 495-499
- 35 Cheng K, Li TS, Malliaras K, Davis DR, Zhang Y, Marbán E. Magnetic targeting enhances engraftment and functional benefit of iron-labeled cardiosphere-derived cells in myocardial infarction. Circ Res 2010; 106 (10) 1570-1581
- 36 Owen J, Pankhurst Q, Stride E. Magnetic targeting and ultrasound mediated drug delivery: benefits, limitations and combination. Int J Hyperthermia 2012; 28 (04) 362-373
- 37 Li H, Fu C, Miao X. , et al. Multifunctional magnetic co-delivery system coated with polymer mPEG-PLL-FA for nasopharyngeal cancer targeted therapy and MR imaging. J Biomater Appl 2017; 31 (08) 1169-1181
- 38 Stride EP, Coussios CC. Cavitation and contrast: the use of bubbles in ultrasound imaging and therapy. Proc Inst Mech Eng H 2010; 224 (02) 171-191
- 39 Li H, Lu Y, Sun Y. , et al. Diagnostic ultrasound and microbubbles treatment improves outcomes of coronary no-reflow in canine models by sonothrombolysis. Crit Care Med 2018; 46 (09) e912-e920
- 40 Molina CA, Ribo M, Rubiera M. , et al. Microbubble administration accelerates clot lysis during continuous 2-MHz ultrasound monitoring in stroke patients treated with intravenous tissue plasminogen activator. Stroke 2006; 37 (02) 425-429
- 41 Ribo M, Molina CA, Alvarez B, Rubiera M, Alvarez-Sabin J, Matas M. Intra-arterial administration of microbubbles and continuous 2-MHz ultrasound insonation to enhance intra-arterial thrombolysis. J Neuroimaging 2010; 20 (03) 224-227