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Dual targeting improves capture of ultrasound microbubbles towards activated platelets but yields no additional benefit for imaging of arterial thrombosis.

ABSTRACT: Platelets can be found on the surface of inflamed and ruptured atherosclerotic plaques. Thus, targeting of activated platelets may allow for molecular imaging of vulnerable atherosclerotic lesions. We here investigated microbubbles (MB) functionalized with the selectin ligand sialyl Lewis^a individually (MB_sLea) or dually with sLe^a and an antibody targeting ligand-induced binding sites of the activated GPIIb/IIIa receptor (MB_Dual). Assessed by in vitro flow chamber, targeted MB exhibited increased adhesion to platelets as compared to MB_Control. While MB_sLea rolled slowly on the platelets' surface, MB_Dual enhanced the percentage of firm adhesion. In vivo, MB were investigated by ultrasound in a model of ferric chloride induced non-occlusive carotid artery thrombosis. MB_sLea and MB_Dual revealed a higher ultrasound mean acoustic intensity than MB_Control (p?Dual demonstrated no additional increase in mean signal intensity as compared to MB_sLea. The degree of carotid artery stenosis on histology correlated well with the ultrasound acoustic intensity of targeted MB (p?

SUBMITTER: Gunther F

PROVIDER: S-EPMC5668440 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Dual targeting improves capture of ultrasound microbubbles towards activated platelets but yields no additional benefit for imaging of arterial thrombosis.

Günther F F Heidt T T Kramer M M Khanicheh E E Klibanov A L AL Geibel-Zehender A A Ferrante E A EA Hilgendorf I I Wolf D D Zirlik A A Reinöhl J J Bode C C Peter K K Kaufmann B A BA Mühlen C von Zur CVZ

Scientific reports 20171102 1

Platelets can be found on the surface of inflamed and ruptured atherosclerotic plaques. Thus, targeting of activated platelets may allow for molecular imaging of vulnerable atherosclerotic lesions. We here investigated microbubbles (MB) functionalized with the selectin ligand sialyl Lewisa individually (MBsLea) or dually with sLea and an antibody targeting ligand-induced binding sites of the activated GPIIb/IIIa receptor (MBDual). Assessed by in vitro ...[more]

PMID: 29097799

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Project description:IntroductionAcute peripheral arterial occlusions can be treated with intra-arterial catheter-directed thrombolysis as an alternative to surgical thromboembolectomy. Although less invasive, this treatment is time-consuming and carries a significant risk of haemorrhagic complications. Contrast-enhanced ultrasound using microbubbles could accelerate dissolution of thrombi by thrombolytic medications due to mechanical effects caused by oscillation; this could allow for lower dosages of thrombolytics and faster thrombolysis, thereby reducing the risk of haemorrhagic complications. In this study, the safety and practical applicability of this treatment will be investigated.Methods and analysisA single-arm phase II trial will be performed in 20 patients with acute peripheral arterial occlusions eligible for thrombolytic treatment. Low-dose catheter-directed thrombolysis with urokinase will be used. The investigated treatment will be performed during the first hour of thrombolysis, consisting of intravenous infusion of 4 Luminity phials (6 mL in total, diluted with saline 0.9% to 40 mL total) of microbubbles with the use of local ultrasound at the site of occlusion. Primary end points are the incidence of complications and technical feasibility. Secondary end points are angiographic and clinical success, duration of thrombolytic infusion, treatment-related mortality, amputations, additional interventions and quality of life.Ethics and disseminationEthical approval for this study was obtained in 2015 from the Medical Ethics Committee of the VU University Medical Center, Amsterdam, the Netherlands. A statement of consent for this study was given by the Dutch national competent authority. Data will be presented at national and international conferences and published in a peer-reviewed journal.Trial registration numbersDutch National Trial Registry: NTR4731; European Clinical Trials Database of the European Medicines Agency: 2014-003469-10; Pre-results.

Project description:Platelet-endothelial interactions have been linked to increased inflammatory activation and a prothrombotic state in atherosclerosis. The interaction between von Willebrand factor (vWF)-A1 domain and platelet glycoprotein (GP) Ib/IX plays a significant role in mediating the adhesion of platelets to the injured endothelium. In the present study, contrast-enhanced ultrasound (CEU) molecular imaging with microbubbles bearing the vWF-A1 domain was performed to non-invasively monitor activated platelets on the vascular endothelium in the procession of atherosclerosis. A targeted CEU contrast agent was prepared by attaching the vWF-A1 domain to the shell of microbubbles (MbA1). Rat isotype control antibody was used to produce control (Mbctrl) microbubbles. The binding of MbA1 and Mbctrl to activated platelets was assessed in in vitro flow chamber experiments. Apolipoprotein E (ApoE-/-) deficient mice were studied as a model of atherosclerosis. At 8, 16 and 32 weeks of age, CEU molecular imaging of the proximal aorta with MbA1 and Mbctrl was performed and the imaging signals from microbubbles were quantified. Atherosclerotic lesion severity and platelets on the endothelial surface were assessed by histology and immunohistochemistry. In in vitro flow chamber studies, attachment of MbA1 to activated platelets on culture dishes was significantly greater than that of Mbctrl across a range of shear stresses (P<0.05). The attachment of Mbctrl was sparse and not related to the aggregated platelets. As lesion development progressed in the ApoE-/- mice, molecular imaging of activated platelets demonstrated selective signal enhancement of MbA1 (P<0.05 vs. Mbctrl) at all ages. Selective signal enhancement from MbA1 increased from 8 to 32 weeks of age. Immunohistochemistry for GPIIb revealed the presence of platelets on the endothelial cell surface in each group of ApoE-/- mice and that the degree of platelet deposits was age-dependent. The results of the present study indicated that non-invasive CEU molecular imaging with targeted microbubbles bearing the vWF-A1 domain could not only detect activated platelets on the vascular endothelium but also indicate lesion severity in atherosclerosis.

Dataset Information

Dual targeting improves capture of ultrasound microbubbles towards activated platelets but yields no additional benefit for imaging of arterial thrombosis.

Publications

Dual targeting improves capture of ultrasound microbubbles towards activated platelets but yields no additional benefit for imaging of arterial thrombosis.

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