A contrast agent recognizing activated platelets reveals murine cerebral malaria pathology undetectable by conventional MRI

Mühlen, Constantin von zur; Sibson, Nicola R.; Peter, Karlheinz; Campbell, Sandra J.; Wilainam, Panop; Grau, Georges E.; Bode, Christoph; Choudhury, Robin P.; Anthony, Daniel C.

doi:10.1172/jci33314

Cited by 57 publications

(70 citation statements)

References 36 publications

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“…12,15 In some studies, new MRI contrast agents targeting activated platelets have been successfully prepared and used to detect endovascular thrombi in vivo. 17,22,23 Similarly, in our previous studies, we synthesized novel types of thrombus-targeting particles and confirmed their targeting ability and contrast-enhancing effects in vitro. 24,25 Although further validation of their targeting ability, biodistribution, and toxicity in vivo are required, there have been few studies of MRI contrast agent behavior, particularly in vivo, which limits their potential translation to clinical use.…”

supporting

confidence: 71%

Fe3O4-based PLGA nanoparticles as MR contrast agents for the detection of thrombosis

Liu¹,

Xu²,

Zhou³

et al. 2017

IJN

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Thrombotic disease is a great threat to human health, and early detection is particularly important. Magnetic resonance (MR) molecular imaging provides noninvasive imaging with the potential for early disease diagnosis. In this study, we developed Fe 3 O 4 -based poly(lactic- co -glycolic acid) (PLGA) nanoparticles (NPs) surface-modified with a cyclic Arg-Gly-Asp (cRGD) peptide as an MR contrast agent for the detection of thrombosis. The physical and chemical characteristics, biological toxicity, ability to target thrombi, and biodistribution of the NPs were studied. The Fe 3 O 4 -PLGA-cRGD NPs were constructed successfully, and hematologic and pathologic assays indicated no in vivo toxicity of the NPs. In a rat model of FeCl 3 -induced abdominal aorta thrombosis, the NPs readily and selectively accumulated on the surface of the thrombosis and under vascular endothelial cells ex vivo and in vivo. In the in vivo experiment, the biodistribution of the NPs suggested that the NPs might be internalized by the macrophages of the reticuloendothelial system in the liver and the spleen. The T2 signal decreased at the mural thrombus 10 min after injection and then gradually increased until 50 min. These results suggest that the NPs are suitable for in vivo molecular imaging of thrombosis under high shear stress conditions and represent a very promising MR contrast agent for sensitive and specific detection of thrombosis.

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supporting

confidence: 71%

Fe3O4-based PLGA nanoparticles as MR contrast agents for the detection of thrombosis

Liu¹,

Xu²,

Zhou³

et al. 2017

IJN

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“…15,19,21 For construction of the contrast agent, cobalt-functionalized autofluorescent MPIOs with a diameter of 1μm were conjugated to the histidine tag of the anti-LIBS/control single-chain antibody as described in the manufacturer's protocol (Dynal Biotech, Oslo, Norway) and in previously published studies. [22][23][24] Throughout this article, MPIOs conjugated to the anti-LIBS antibody are referred to as LIBS-MPIOs, and MPIOs conjugated to control antibody are called control-MPIOs. Injection of the LIBS-MPIO and control-MPIO contrast agent (each with 4×10 8 particles in 50 μL saline) was via an 80-cm-long tube and the tail vein catheter with the animal positioned in the MR scanner.…”

Section: Platelet-specific Contrast Agent (Libs-mpios)mentioning

confidence: 99%

“…LIBS-MPIOs have already been used in a number of studies by our group and have allowed the detection of coronary and carotid thrombosis or cerebrovascular inflammation in mice. 16,22 The LIBS antibody also binds to human platelets, also in an activation-specific manner, which is an important step toward the translation of this promising technology to application in humans. 17 The presence of LIBS-MPIOs in ischemic/reperfused heart correlates well with the histological presence of platelets in the heart.…”

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confidence: 99%

Dual-Contrast Molecular Imaging Allows Noninvasive Characterization of Myocardial Ischemia/Reperfusion Injury After Coronary Vessel Occlusion in Mice by Magnetic Resonance Imaging

et al. 2014

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Background-Inflammation and myocardial necrosis play important roles in ischemia/reperfusion injury after coronary artery occlusion and recanalization. The detection of inflammatory activity and the extent of myocardial necrosis itself are of great clinical and prognostic interest. We developed a dual, noninvasive imaging approach using molecular magnetic resonance imaging in an in vivo mouse model of myocardial ischemia and reperfusion. Methods and Results-Ischemia/reperfusion injury was induced in 10-week-old C57BL/6N mice by temporary ligation of the left anterior descending coronary artery. Activated platelets were targeted with a contrast agent consisting of microparticles of iron oxide (MPIOs) conjugated to a single-chain antibody directed against a ligand-induced binding site (LIBS) on activated glycoprotein IIb/IIIa (LIBS-MPIOs). After injection and imaging of LIBS-MPIOs, late gadolinium enhancement was used to depict myocardial necrosis; these imaging experiments were also performed in P2Y 12 −/− mice. All imaging results were correlated to immunohistochemistry findings. Activated platelets were detectable by magnetic resonance imaging via a significant signal effect caused by LIBS-MPIOs in the area of left anterior descending coronary artery occlusion 2 hours after reperfusion. In parallel, late gadolinium enhancement identified the extent of myocardial necrosis. Immunohistochemistry confirmed that LIBS-MPIOs bound significantly to microthrombi in reperfused myocardium. Only background binding was found in P2Y 12 −/− mice. Conclusions-Dual molecular imaging of myocardial ischemia/reperfusion injury allows characterization of platelet-driven inflammation by LIBS-MPIOs and myocardial necrosis by late gadolinium enhancement. This noninvasive imaging strategy is of clinical interest for both diagnostic and prognostic purposes and highlights the potential of molecular magnetic resonance imaging for characterizing ischemia/reperfusion injury. (Circulation. 2014;130:676-687.)

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“…We have developed conformation-specific anti-GP IIb/IIIa single-chain antibodies (scFvs), 9 -11 some of which bind specifically to a LigandInduced Binding Site (LIBS) on activated GP IIb/IIIa, 9 -11 and have previously demonstrated the ability of scFv anti-LIBS to detect activated platelets in magnetic resonance imaging in the context of inflammation and thrombosis. [12][13][14][15] Ultrasound imaging has several advantages over other imaging modalities. It is noninvasive, is inherently real time, is free of radiation-associated risk, has no known side effects, and only rarely causes discomfort in patients.…”

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confidence: 99%

Novel Single-Chain Antibody-Targeted Microbubbles for Molecular Ultrasound Imaging of Thrombosis

et al. 2012

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Background-Molecular imaging is a fast emerging technology allowing noninvasive detection of vascular pathologies.However, imaging modalities offering high resolution currently do not allow real-time imaging. We hypothesized that contrast-enhanced ultrasound with microbubbles (MBs) selectively targeted to activated platelets would offer high-resolution, real-time molecular imaging of evolving and dissolving arterial thrombi. Methods and Results-Lipid-shell based gas-filled MBs were conjugated to either a single-chain antibody specific for activated glycoprotein IIb/IIIa via binding to a Ligand-Induced Binding Site (LIBS-MBs) or a nonspecific single-chain antibody (control MBs). Successful conjugation was assessed in flow cytometry and immunofluorescence double staining. LIBS-MBs but not control MBs strongly adhered to both immobilized activated platelets and microthrombi under flow. Thrombi induced in carotid arteries of C57Bl6 mice in vivo by ferric chloride injury were then assessed with ultrasound before and 20 minutes after MB injection through the use of gray-scale area intensity measurement. Gray-scale units converted to decibels demonstrated a significant increase after LIBS-MB but not after control MB injection (9.55Ϯ1.7 versus 1.46Ϯ1.3 dB; PϽ0.01). Furthermore, after thrombolysis with urokinase, LIBS-MB ultrasound imaging allows monitoring of the reduction of thrombus size (PϽ0.001). Conclusion-We

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A contrast agent recognizing activated platelets reveals murine cerebral malaria pathology undetectable by conventional MRI

Cited by 57 publications

References 36 publications

Fe<sub>3</sub>O<sub>4</sub>-based PLGA nanoparticles as MR contrast agents for the detection of thrombosis

Fe<sub>3</sub>O<sub>4</sub>-based PLGA nanoparticles as MR contrast agents for the detection of thrombosis

Dual-Contrast Molecular Imaging Allows Noninvasive Characterization of Myocardial Ischemia/Reperfusion Injury After Coronary Vessel Occlusion in Mice by Magnetic Resonance Imaging

Novel Single-Chain Antibody-Targeted Microbubbles for Molecular Ultrasound Imaging of Thrombosis

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