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Imaging of atherosclerosis, targeting LFA-1 on inflammatory cells with 111In-DANBIRT.

ABSTRACT: BACKGROUND:111In-DOTA-butylamino-NorBIRT (DANBIRT) is a novel radioligand which binds to Leukocyte Function-associated Antigen-1 (LFA-1), expressed on inflammatory cells. This study evaluated 111In-DANBIRT for the visualization of atherosclerotic plaque inflammation in mice. METHODS AND RESULTS:ApoE-/- mice, fed an atherogenic diet up to 20 weeks (n = 10), were imaged by SPECT/CT 3 hours post injection of 111In-DANBIRT (~ 200 pmol, ~ 40 MBq). Focal spots of 111In-DANBIRT were visible in the aortic arch of all animals, with an average Target-to-Background Ratio (TBR) of 1.7 ± 0.5. In vivo imaging results were validated by ex vivo SPECT/CT imaging, with a TBR up to 11.5 (range 2.6 to 11.5). Plaques, identified by Oil Red O lipid-staining on excised arteries, co-localized with 111In-DANBIRT uptake as determined by ex vivo autoradiography. Subsequent histological processing and in vitro autoradiography confirmed 111In-DANBIRT uptake at plaque areas containing CD68 expressing macrophages and LFA-1 expressing inflammatory cells. Ex vivo incubation of a human carotid endarterectomy specimen with 111In-DANBIRT (~ 950 nmol, ~ 190 MBq) for 2 hours showed heterogeneous plaque uptake on SPECT/CT, after which immunohistochemical analysis demonstrated co-localization of 111In-DANBIRT uptake and CD68 and LFA-1 expressing cells. CONCLUSIONS:Our results indicate the potential of radiolabeled DANBIRT as a relevant imaging radioligand for non-invasive evaluation of atherosclerotic inflammation.

SUBMITTER: Meester EJ

PROVIDER: S-EPMC6775031 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Imaging of atherosclerosis, targeting LFA-1 on inflammatory cells with <sup>111</sup>In-DANBIRT.

Meester E J EJ Krenning B J BJ de Blois R H RH Norenberg J P JP de Jong M M Bernsen M R MR Van der Heiden K K

Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology 20180313 5

<h4>Background</h4><sup>111</sup>In-DOTA-butylamino-NorBIRT (DANBIRT) is a novel radioligand which binds to Leukocyte Function-associated Antigen-1 (LFA-1), expressed on inflammatory cells. This study evaluated <sup>111</sup>In-DANBIRT for the visualization of atherosclerotic plaque inflammation in mice.<h4>Methods and results</h4>ApoE<sup>-/-</sup> mice, fed an atherogenic diet up to 20 weeks (n = 10), were imaged by SPECT/CT 3 hours post injection of <sup>111</sup>In-DANBIRT (~ 200 pmol, ~ 40 ...[more]

PMID: 29536351

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Project description:Atherosclerosis-related morbidity and mortality remain a global concern. Atherosclerotic disease follows a slow and silent progression, and the transition from early-stage lesions to vulnerable plaques remains difficult to diagnose. Inflammation is a key component of the development of atherosclerotic plaque and consequent life-threatening complications. This study assessed 111In-DANBIRT as an in vivo, noninvasive SPECT/CT imaging probe targeting an inflammatory marker, Lymphocyte Function Associated Antigen-1 (LFA-1), in atherosclerotic plaques. Methods. Selective binding of 111In-DANBIRT was assessed using Sprague-Dawley rats exposed to filtered air and ozone (1 ppm) by inhalation for 4 hours to induce a circulating leukocytosis and neutrophilia in peripheral blood. After 24 hours, whole blood was collected and incubated with radiolabeled DANBIRT (68Ga-DANBIRT and 111In-DANBIRT). Isolated cell component smeared slides using cytospin technique were stained with Wright-Giemsa stain. Apolipoprotein E-deficient (apoE-/-) mice were fed either a normal diet or a high-fat diet (HFD) for 8 weeks. Longitudinal SPECT/CT imaging was performed 3 hours after administration at baseline, 4, and 8 weeks of HFD diet, followed by tissue harvesting for biodistribution, serum lipid analysis, and histology. 3D autoradiography was performed in both groups 24 hours after administration of 111In-DANBIRT. Results. Increased specific uptake of radiolabeled DANBIRT by neutrophils in the ozone-exposed group was evidenced by the acute immune response due to 4-hour ozone exposure. Molecular imaging performed at 3 hours using SPECT/CT imaging evidenced an exponential longitudinal increase in 111In-DANBIRT uptake in atherosclerosis lesions in HFD-fed mice compared to normal-diet-fed mice. Such results were consistent with increased immune response to vascular injury in cardiovascular and also immune tissues, correlated by 24 hours after administration of 3D autoradiography. Histologic analysis confirmed atherosclerotic disease progression with an increased vascular lesion area in HFD-fed mice compared to normal-diet-fed mice. Conclusion. 111In-DANBIRT is a promising molecular imaging probe to assess inflammation in evolving atheroma and atherosclerotic plaque.

Project description:UNLABELLED:Atherosclerosis is inherently an inflammatory process that is strongly affected by the chemokine-chemokine receptor axes regulating the trafficking of inflammatory cells at all stages of the disease. Of the chemokine receptor family, some specifically upregulated on macrophages play a critical role in plaque development and may have the potential to track plaque progression. However, the diagnostic potential of these chemokine receptors has not been fully realized. On the basis of our previous work using a broad-spectrum peptide antagonist imaging 8 chemokine receptors together, the purpose of this study was to develop a targeted nanoparticle for sensitive and specific detection of these chemokine receptors in both a mouse vascular injury model and a spontaneously developed mouse atherosclerosis model. METHODS:The viral macrophage inflammatory protein-II (vMIP-II) was conjugated to a biocompatible poly(methyl methacrylate)-core/polyethylene glycol-shell amphiphilic comblike nanoparticle through controlled conjugation and polymerization before radiolabeling with (64)Cu for PET imaging in an apolipoprotein E-deficient (ApoE(-/-)) mouse vascular injury model and a spontaneous ApoE(-/-) mouse atherosclerosis model. Histology, immunohistochemistry, and real-time reverse transcription polymerase chain reaction were performed to assess the plaque progression and upregulation of chemokine receptors. RESULTS:The chemokine receptor-targeted (64)Cu-vMIP-II-comb showed extended blood retention and improved biodistribution. PET imaging showed specific tracer accumulation at plaques in ApoE(-/-) mice, confirmed by competitive receptor blocking studies and assessment in wild-type mice. Histopathologic characterization showed the progression of plaque including size and macrophage population, corresponding to the elevated concentration of chemokine receptors and more importantly increased PET signals. CONCLUSION:This work provides a useful nanoplatform for sensitive and specific detection of chemokine receptors to assess plaque progression in mouse atherosclerosis models.

Project description:BACKGROUND:4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid (GSAO) when conjugated at the ?-glutamyl residue with fluorophores and radio-isotopes is able to image dead and dying cells in vitro and in vivo by binding to intracellular 90-kDa heat shock proteins (hsp90) when cell membrane integrity is compromised. The ability to image cell death has potential clinical impact especially for early treatment response assessment in oncology. This work aims to assess the biodistribution and tumour uptake of diethylene triamine pentaacetic acid GSAO labelled with 111In ([111In]In-DTPA-GSAO) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid GSAO labelled with 67Ga ([67Ga]Ga-DOTA-GSAO) in a murine subcutaneous tumour xenograft model and estimate dosimetry of [67Ga]Ga-DOTA-GSAO. RESULTS:There was good tumour uptake of both [111In]In-DTPA-GSAO and [67Ga]Ga-DOTA-GSAO (2.44?±?0.26% injected activity per gramme of tissue (%IA/g) and 2.75?±?0.34?%IA/g, respectively) in Balb c nu/nu mice bearing subcutaneous tumour xenografts of a human metastatic prostate cancer cell line (PC3M-luc-c6). Peak tumour uptake occurred at 2.7?h post injection. [111In]In-DTPA-GSAO and [67Ga]Ga-DOTA-GSAO demonstrated increased uptake in the liver (4.40?±?0.86?%IA/g and 1.72?±?0.27?%IA/g, respectively), kidneys (16.54?±?3.86?%IA/g and 8.16?±?1.33?%IA/g) and spleen (6.44?±?1.24?%IA/g and 1.85?±?0.44?%IA/g); however, uptake in these organs was significantly lower with [67Ga]Ga-DOTA-GSAO (p?=?0.006, p?=?0.017 and p?=?0.003, respectively). Uptake of [67Ga]Ga-DOTA-GSAO into tumour was higher than all organs except the kidneys. There was negligible uptake in the other organs. Excretion of [67Ga]Ga-DOTA-GSAO was more rapid than [111In]In-DTPA-GSAO. Estimated effective dose of [67Ga]Ga-DOTA-GSAO for an adult male human was 1.54?×?10-?2?mSv/MBq. CONCLUSIONS:[67Ga]Ga-DOTA-GSAO demonstrates higher specific uptake in dead and dying cells within tumours and lower uptake in normal organs than [111In]In-DTPA-GSAO. [67Ga]Ga-DOTA-GSAO may be potentially useful for imaging cell death in vivo. Dosimetry estimates for [67Ga]Ga-DOTA-GSAO are acceptable for future human studies. This work also prepares for development of 68Ga GSAO radiopharmaceuticals.

Dataset Information

Imaging of atherosclerosis, targeting LFA-1 on inflammatory cells with 111In-DANBIRT.

Publications

Imaging of atherosclerosis, targeting LFA-1 on inflammatory cells with <sup>111</sup>In-DANBIRT.

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