Evaluation of [99mTc]Radiolabeled Macrophage Mannose Receptor-Specific Nanobodies for Targeting of Atherosclerotic Lesions in Mice | springermedizin.de

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Molecular Imaging and Biology

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01.04.2018 | Research Article

Evaluation of [^99mTc]Radiolabeled Macrophage Mannose Receptor-Specific Nanobodies for Targeting of Atherosclerotic Lesions in Mice

verfasst von: Gezim Bala, Henri Baudhuin, Isabel Remory, Kris Gillis, Pieterjan Debie, Ahmet Krasniqi, Tony Lahoutte, Geert Raes, Nick Devoogdt, Bernard Cosyns, Sophie Hernot

Erschienen in: Molecular Imaging and Biology | Ausgabe 2/2018

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Abstract

Purpose

Macrophage accumulation characterizes the development of atherosclerotic plaques, and the presence of certain macrophage subsets might be an indicator of plaque phenotype and (in)stability. The macrophage mannose receptor (MMR) is expressed on alternatively activated macrophages and found at sites of intraplaque hemorrhage and neovascularization. It has been proposed as target to identify vulnerable plaques. Therefore, we aimed to assess the feasibility of using anti-MMR nanobodies (Nbs) as molecular tracers for nuclear imaging in an animal model of atherosclerosis.

Procedure

Anti-MMR and control Nb, radiolabeled with Tc-99m, were injected in ApoE^−/− and/or C57Bl/6 mice (n = 6). In vivo competition studies involving pre-injection of excess of unlabeled anti-MMR Nb (n = 3) and injection of anti-MMR Nb in MMR^−/− mice (n = 3) were performed to demonstrate specificity. At 3 h p.i. radioactive uptake in organs, tissues and aorta segments were evaluated. Autoradiography and immunofluorescence were performed on aortic sections.

Results

Significantly higher uptake was observed in all aortic segments of ApoE^−/− mice injected with anti-MMR Nb compared to control Nb (1.36 ± 0.67 vs 0.38 ± 0.13 percent of injected dose per gram (%ID/g), p ≤ 0.001). Surprisingly, high aortic uptake was also observed in C57Bl/6 mice (1.50 ± 0.43%ID/g, p ≥ 0.05 compared to ApoE^−/−), while aortic uptake was reduced to background levels in the case of competition and in MMR^−/− mice (0.46 ± 0.10 and 0.22 ± 0.06%ID/g, respectively; p ≤ 0.001). Therefore, expression of MMR along healthy aortas was suggested. Autoradiography showed no specific radioactive signal within atherosclerotic plaques, but rather localization of the signal along the aorta, correlating with MMR expression in perivascular tissue as demonstrated by immunofluorescence.

Conclusions

No significant uptake of MMR-specific Nb could be observed in atherosclerotic lesions of ApoE^−/− mice in this study. A specific perivascular signal causing a non-negligible background level was demonstrated. This observation should be considered when using MMR as a target in molecular imaging of atherosclerosis, as well as use of translational animal models with vulnerable plaques.

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1.

Quillard T, Libby P (2012) Molecular imaging of atherosclerosis for improving diagnostic and therapeutic development. Circ Res 111:231–244CrossRefPubMedPubMedCentral

2.

Libby P, Ridker PM, Maseri A (2002) Inflammation and atherosclerosis. Circulation 105:1135–1143CrossRefPubMed

3.

Libby P (2012) Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol 32:2045–2051CrossRefPubMedPubMedCentral

4.

Tarkin JM, Joshi FR, Rudd JHF (2014) PET imaging of inflammation in atherosclerosis. Nat Rev Cardiol 11:443–457CrossRefPubMed

5.

Colin S, Chinetti-Gbaguidi G, Staels B (2014) Macrophage phenotypes in atherosclerosis. Immunol Rev 262:153–166CrossRefPubMed

6.

Chinetti-Gbaguidi G, Colin S, Staels B (2015) Macrophage subsets in atherosclerosis. Nat Rev Cardiol 12:10–17CrossRefPubMed

7.

Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23–35CrossRefPubMed

8.

Tahara N, Mukherjee J, de Haas HJ et al (2014) 2-Deoxy-2-[¹⁸F]fluoro-D-mannose positron emission tomography imaging in atherosclerosis. Nat Med 20:215–219CrossRefPubMed

9.

Finn AV, Nakano M, Polavarapu R et al (2012) Hemoglobin directs macrophage differentiation and prevents foam cell formation in human atherosclerotic plaques. J Am Coll Cardiol 59:166–177CrossRefPubMed

10.

Chinetti-Gbaguidi G, Baron M, Bouhlel MA et al (2011) Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARγ and LXRα pathways. Circ Res 108:985–995CrossRefPubMedPubMedCentral

11.

Finn AV, Saeed O, Virmani R (2012) Macrophage subsets in human atherosclerosis. Circ Res 110:1–8CrossRef

12.

Chinetti-Gbaguidi G, Staels B (2012) Response to the letter by Finn et al. Circ Res 110:e65–e66CrossRef

13.

Kim EJ, Kim S, Seo HS et al (2016) Novel PET imaging of atherosclerosis with ⁶⁸Ga-labeled NOTA-neomannosylated human serum albumin. J Nucl Med 57:1792–1797CrossRefPubMed

14.

Kim JB, Park K, Ryu J et al (2016) Intravascular optical imaging of high-risk plaques in vivo by targeting macrophage mannose receptors. Sci Rep 6:22608CrossRefPubMedPubMedCentral

15.

Movahedi K, Schoonooghe S, Laoui D et al (2012) Nanobody-based targeting of the macrophage mannose receptor for effective in vivo imaging of tumor-associated macrophages. Cancer Res 72:4165–4177CrossRefPubMed

16.

Blykers A, Schoonooghe S, Xavier C et al (2015) PET imaging of macrophage mannose receptor-expressing macrophages in tumor stroma using ¹⁸F-radiolabeled camelid single-domain antibody fragments. J Nucl Med 56:1265–1271CrossRefPubMed

17.

Put S, Schoonooghe S, Devoogdt N et al (2013) SPECT imaging of joint inflammation with nanobodies targeting the macrophage mannose receptor in a mouse model for rheumatoid arthritis. J Nucl Med 54:807–814CrossRefPubMed

18.

Broisat A, Hernot S, Toczek J et al (2012) Nanobodies targeting mouse/human VCAM1 for the nuclear imaging of atherosclerotic lesions. Circ Res 110:927–937CrossRefPubMedPubMedCentral

19.

Vaneycken I, Devoogdt N, Van Gassen N et al (2011) Preclinical screening of anti-HER2 nanobodies for molecular imaging of breast cancer. FASEB J 25:2433–2446CrossRefPubMed

20.

Bala G, Blykers A, Xavier C et al (2016) Targeting of vascular cell adhesion molecule-1 by ¹⁸F-labelled nanobodies for PET/CT imaging of inflamed atherosclerotic plaques. Eur Hear J - Cardiovasc Imaging 17:1001–1008CrossRef

21.

De Vos J, Mathijs I, Xavier C et al (2014) Specific targeting of atherosclerotic plaques in ApoE−/− mice using a new camelid sdAb binding the vulnerable plaque marker LOX-1. Mol Imaging Biol 16:690–698CrossRefPubMed

22.

Zheng F, Devoogdt N, Sparkes A et al (2015) Monitoring liver macrophages using nanobodies targeting Vsig4: concanavalin A induced acute hepatitis as paradigm. Immunobiology 220:200–209CrossRefPubMed

23.

Keyaerts M, Xavier C, Heemskerk J et al (2016) Phase I study of ⁶⁸Ga-HER2-nanobody for PET/CT assessment of HER2 expression in breast carcinoma. J Nucl Med 57:27–33CrossRefPubMed

24.

Xavier C, Devoogdt N, Hernot S et al (2012) Site-specific labeling of his-tagged Nanobodies with ^99mTc: a practical guide. Methods Mol Biol 911:485–490CrossRefPubMed

25.

Stöger JL, Gijbels MJJ, van der Velden S et al (2012) Distribution of macrophage polarization markers in human atherosclerosis. Atherosclerosis 225:461–468CrossRefPubMed

26.

Schwartz CJ, Mitchell JR (1962) Cellular infiltration of the human arterial adventitia associated with atheromatous plaques. Circulation 26:73–78CrossRefPubMed

27.

Linehan SA, Martínez-Pomares L, Stahl PD, Gordon S (1999) Mannose receptor and its putative ligands in normal murine lymphoid and nonlymphoid organs: in situ expression of mannose receptor by selected macrophages, endothelial cells, perivascular microglia, and mesangial cells, but not dendritic cells. J Exp Med 189:1961–1972CrossRefPubMedPubMedCentral

28.

Lardenoye JH, Delsing DJ, de Vries MR et al (2000) Accelerated atherosclerosis by placement of a perivascular cuff and a cholesterol-rich diet in ApoE*3Leiden transgenic mice. Circ Res 87:248–253CrossRefPubMed

29.

Zhang S, Picard MH, Vasile E et al (2005) Diet-induced occlusive coronary atherosclerosis, myocardial infarction, cardiac dysfunction, and premature death in scavenger receptor class B type I-deficient, hypomorphic apolipoprotein ER61 mice. Circulation 111:3457–3464CrossRefPubMed

30.

Van der Donckt C, Van Herck JL, Schrijvers DM et al (2015) Elastin fragmentation in atherosclerotic mice leads to intraplaque neovascularization, plaque rupture, myocardial infarction, stroke, and sudden death. Eur Heart J 36:1049–1058CrossRefPubMed

Titel: Evaluation of [99mTc]Radiolabeled Macrophage Mannose Receptor-Specific Nanobodies for Targeting of Atherosclerotic Lesions in Mice
verfasst von: Gezim Bala
Henri Baudhuin
Isabel Remory
Kris Gillis
Pieterjan Debie
Ahmet Krasniqi
Tony Lahoutte
Geert Raes
Nick Devoogdt
Bernard Cosyns
Sophie Hernot
Publikationsdatum: 01.04.2018
Verlag: Springer US
Erschienen in: Molecular Imaging and Biology / Ausgabe 2/2018
Print ISSN: 1536-1632
Elektronische ISSN: 1860-2002
DOI: https://doi.org/10.1007/s11307-017-1117-3

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