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1.
J Nucl Med ; 60(10): 1380-1387, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-30850498

RESUMEN

Shank-associated RH domain-interacting protein (SHARPIN) is a cytosolic protein that plays a key role in activation of nuclear factor κ-light-chain enhancer of activated B cells and regulation of inflammation. Furthermore, SHARPIN controls integrin-dependent cell adhesion and migration in several normal and malignant cell types, and loss of SHARPIN correlates with increased integrin activity in mice. Arginyl-glycyl-aspartic acid (RGD), a cell adhesion tripeptide motif, is an integrin recognition sequence that facilitates PET imaging of integrin upregulation during tumor angiogenesis. We hypothesized that increased integrin activity due to loss of SHARPIN protein would affect the uptake of αvß3-selective cyclic, dimeric peptide 68Ga-DOTA-E[c(RGDfK)]2, where E[c(RGDfk)]2 = glutamic acid-[cyclo(arginyl-glycyl-aspartic acid-D-phenylalanine-lysine)], both in several tissue types and in the tumor microenvironment. To test this hypothesis, we used RGD-based in vivo PET imaging to evaluate wild-type (wt) and SHARPIN-deficient mice (Sharpincpdm , where cpdm = chronic proliferative dermatitis in mice) with and without melanoma tumor allografts. Methods:Sharpincpdm mice with spontaneous null mutation in the Sharpin gene and their wt littermates with or without B16-F10-luc melanoma tumors were studied by in vivo imaging and ex vivo measurements with cyclic-RGD peptide 68Ga-DOTA-E[c(RGDfK)]2 After the last 68Ga-DOTA-E[c(RGDfK)]2 peptide PET/CT, tumors were cut into cryosections for autoradiography, histology, and immunohistochemistry. Results: The ex vivo uptake of 68Ga-DOTA-E[c(RGDfK)]2 in the mouse skin and tumor was significantly higher in Sharpincpdm mice than in wt mice. B16-F10-luc tumors were detected 4 d after inoculation, without differences in volume or blood flow between the mouse strains. PET imaging with 68Ga-DOTA-E[c(RGDfK)]2 peptide at day 10 after inoculation revealed significantly higher uptake in the tumors transplanted into Sharpincpdm mice than in wt mice. Furthermore, tumor vascularization was increased in the Sharpincpdm mice. Conclusion:Sharpincpdm mice demonstrated increased integrin activity and vascularization in B16-F10-luc melanoma tumors, as demonstrated by RGD-based in vivo PET imaging. These data indicate that SHARPIN, a protein previously associated with increased cancer growth and metastasis, may also have important regulatory roles in controlling the tumor microenvironment.


Asunto(s)
Complejos de Coordinación/química , Integrina alfaVbeta3/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos Cíclicos/química , Secuencias de Aminoácidos , Animales , Adhesión Celular , Movimiento Celular , Dermatitis/diagnóstico por imagen , Femenino , Inmunohistoquímica , Inflamación , Masculino , Melanoma/diagnóstico por imagen , Melanoma Experimental , Ratones , Ratones Endogámicos C57BL , Microscopía Fluorescente , Mutación , Metástasis de la Neoplasia , Trasplante de Neoplasias , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias Cutáneas/diagnóstico por imagen , Regulación hacia Arriba
2.
Molecules ; 23(2)2018 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-29385091

RESUMEN

Amino acid residues 283-297 from sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) form a cyclic peptide ligand targeting vascular adhesion protein-1 (VAP-1). VAP-1 is associated with the transfer of leukocytes from blood to tissues upon inflammation. Therefore, analogs of Siglec-9 peptide are good candidates for visualizing inflammation non-invasively using positron emission tomography (PET). Gallium-68-labeled 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid (DOTA)-conjugated Siglec-9 has been evaluated extensively for this purpose. Here, we explored two alternative strategies for radiolabeling Siglec-9 peptide using a 1,4,7-triazacyclononane-triacetic acid (NOTA)-chelator to bind [68Ga]Ga or [18F]AlF. The radioligands were evaluated by in vivo PET imaging and ex vivo γ-counting of turpentine-induced sterile skin/muscle inflammation in Sprague-Dawley rats. Both tracers showed clear accumulation in the inflamed tissues. The whole-body biodistribution patterns of the tracers were similar.


Asunto(s)
Antígenos CD , Radioisótopos de Flúor , Isótopos de Galio , Compuestos Heterocíclicos , Marcaje Isotópico/métodos , Tomografía de Emisión de Positrones/métodos , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico , Animales , Antígenos CD/química , Antígenos CD/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos con 1 Anillo , Ratas , Ratas Sprague-Dawley , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/química , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/farmacología
3.
Arthritis Res Ther ; 19(1): 254, 2017 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-29166944

RESUMEN

BACKGROUND: In the present study, we sought to evaluate the feasibility of targeting vascular adhesion protein-1 (VAP-1) by positron emission tomography (PET) for the longitudinal quantitative assessment of Borrelia burgdorferi infection-induced inflammation in mice. METHODS: Mice with B. burgdorferi infection-induced arthritis were studied. During a 7-week follow-up period, the progression of arthritis was monitored weekly with 68Ga-DOTA-Siglec-9 PET/computed tomography (CT) and measurement of tibiotarsal joint swellings. A subgroup of infected mice was treated with ceftriaxone. Finally, histopathological assessment of joint inflammation was performed and VAP-1 expression in joints were determined. RESULTS: Explicit joint swelling and 68Ga-DOTA-Siglec-9 uptake could be demonstrated in the affected joints from B. burgdorferi-infected mice. By contrast, no obvious accumulation of 68Ga-DOTA-Siglec-9 was detected in joints of uninfected mice. The maximum swelling and highest uptake in the affected joints were observed 4 weeks after the infection. 68Ga-DOTA-Siglec-9 uptake in joints correlated with joint swelling (P < 0.0001) and histopathological scoring of inflammation (P = 0.020). Despite short-term antibiotic treatment, the arthritis persisted, and the PET signal remained as high as in nontreated mice. Immunohistochemistry revealed strong-to-moderate expression of VAP-1 in the synovium of B. burgdorferi-infected mice, while only weak expression of VAP-1 was detected in uninfected mice. CONCLUSIONS: The present study showed that 68Ga-DOTA-Siglec-9 can detect B. burgdorferi infection-induced arthritis in mice. Furthermore, longitudinal PET/CT imaging allowed monitoring of arthritis development over time.


Asunto(s)
Amina Oxidasa (conteniendo Cobre)/biosíntesis , Artritis/diagnóstico por imagen , Moléculas de Adhesión Celular/biosíntesis , Enfermedad de Lyme/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Animales , Antibacterianos/farmacología , Artritis/tratamiento farmacológico , Artritis/microbiología , Borrelia burgdorferi/efectos de los fármacos , Borrelia burgdorferi/fisiología , Ceftriaxona/farmacología , Modelos Animales de Enfermedad , Radioisótopos de Galio/metabolismo , Interacciones Huésped-Patógeno , Humanos , Inmunohistoquímica , Enfermedad de Lyme/tratamiento farmacológico , Enfermedad de Lyme/microbiología , Ratones , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/metabolismo
4.
Contrast Media Mol Imaging ; 2017: 7645070, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29463960

RESUMEN

Sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) is a ligand of inflammation-inducible vascular adhesion protein-1 (VAP-1). We compared 68Ga-DOTA- and 18F-fluorodeoxyribose- (FDR-) labeled Siglec-9 motif peptides for PET imaging of inflammation. Methods. Firstly, we examined 68Ga-DOTA-Siglec-9 and 18F-FDR-Siglec-9 in rats with skin/muscle inflammation. We then studied 18F-FDR-Siglec-9 for the detection of inflamed atherosclerotic plaques in mice and compared it with previous 68Ga-DOTA-Siglec-9 results. Lastly, we estimated human radiation dosimetry from the rat data. Results. In rats, 68Ga-DOTA-Siglec-9 (SUV, 0.88 ± 0.087) and 18F-FDR-Siglec-9 (SUV, 0.77 ± 0.22) showed comparable (P = 0.29) imaging of inflammation. In atherosclerotic mice, 18F-FDR-Siglec-9 detected inflamed plaques with a target-to-background ratio (1.6 ± 0.078) similar to previously tested 68Ga-DOTA-Siglec-9 (P = 0.35). Human effective dose estimates for 68Ga-DOTA-Siglec-9 and 18F-FDR-Siglec-9 were 0.024 and 0.022 mSv/MBq, respectively. Conclusion. Both tracers are suitable for PET imaging of inflammation. The easier production and lower cost of 68Ga-DOTA-Siglec-9 present advantages over 18F-FDR-Siglec-9, indicating it as a primary choice for clinical studies.


Asunto(s)
Dermatitis/diagnóstico por imagen , Fluorodesoxiglucosa F18/farmacología , Radioisótopos de Galio/farmacología , Miositis/diagnóstico por imagen , Compuestos Organometálicos/farmacología , Tomografía de Emisión de Positrones/métodos , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/farmacología , Animales , Inflamación/diagnóstico por imagen , Miositis/diagnóstico , Radiometría , Ratas , Ratas Sprague-Dawley
5.
Sci Rep ; 6: 35089, 2016 10 12.
Artículo en Inglés | MEDLINE | ID: mdl-27731409

RESUMEN

Given the important role of inflammation and the potential association of the leukocyte trafficking-associated adhesion molecule vascular adhesion protein 1 (VAP-1) with atherosclerosis, this study examined whether functional VAP-1 is expressed in atherosclerotic lesions and, if so, whether it could be targeted by positron emission tomography (PET). First, immunohistochemistry revealed that VAP-1 localized to endothelial cells of intra-plaque neovessels in human carotid endarterectomy samples from patients with recent ischemic symptoms. In low-density lipoprotein receptor-deficient mice expressing only apolipoprotein B100 (LDLR-/-ApoB100/100), VAP-1 was expressed on endothelial cells lining inflamed atherosclerotic lesions; normal vessel walls in aortas of C57BL/6N control mice were VAP-1-negative. Second, we discovered that the focal uptake of VAP-1 targeting sialic acid-binding immunoglobulin-like lectin 9 based PET tracer [68Ga]DOTA-Siglec-9 in atherosclerotic plaques was associated with the density of activated macrophages (r = 0.58, P = 0.022). As a final point, we found that the inhibition of VAP-1 activity with small molecule LJP1586 decreased the density of macrophages in inflamed atherosclerotic plaques in mice. Our results suggest for the first time VAP-1 as a potential imaging target for inflamed atherosclerotic plaques, and corroborate VAP-1 inhibition as a therapeutic approach in the treatment of atherosclerosis.


Asunto(s)
Amina Oxidasa (conteniendo Cobre)/metabolismo , Moléculas de Adhesión Celular/metabolismo , Placa Aterosclerótica/metabolismo , Adulto , Animales , Antígenos CD/metabolismo , Apolipoproteína B-100/metabolismo , Estenosis Carotídea/diagnóstico por imagen , Estenosis Carotídea/metabolismo , Estenosis Carotídea/patología , Femenino , Radioisótopos de Galio , Compuestos Heterocíclicos con 1 Anillo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Ensayo de Unión Radioligante , Receptores de LDL/deficiencia , Receptores de LDL/genética , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/metabolismo
6.
ACS Med Chem Lett ; 7(9): 826-30, 2016 Sep 08.
Artículo en Inglés | MEDLINE | ID: mdl-27660685

RESUMEN

Recently mannan from Saccharomyces cerevisiae has been shown to be able to induce psoriasis and psoriatic arthritis in mice, and the phenotypes resemble the corresponding human diseases. To investigate the pathological processes, we set out to label mannan with fluorine-18 ((18)F) and study the (18)F-labeled mannan in vitro and in vivo with positron emission tomography (PET). Accordingly, mannan has been transformed into (18)F-fluoromannan with (18)F-bicyclo[6.1.0]nonyne. In mouse aorta, the binding of [(18)F]fluoromannan to the atherosclerotic lesions was clearly visualized and was significantly higher compared to blocking assays (P < 0.001) or healthy mouse aorta (P < 0.001). In healthy rats the [(18)F]fluoromannan radioactivity accumulated largely in the macrophage-rich organs such as liver, spleen, and bone marrow and the excess excreted in urine. Furthermore, the corresponding (19)F-labeled mannan has been used to induce psoriasis and psoriatic arthritis in mice, which indicates that the biological function of mannan is preserved after the chemical modifications.

8.
Mol Pharm ; 13(7): 2588-95, 2016 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-27218688

RESUMEN

A bis(phosphonate) conjugate of 2'-O-methyl oligoribonucleotide (microRNA-21) was synthesized and used as a bone-targeting carrier in the systemic delivery of a (68)Ga-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-chelated 2'-O-methyl oligoribonucleotide (anti-microRNA-21). The whole-body biodistribution of the double helical RNA was monitored by positron emission tomography (PET), which verified the expected bis(phosphonate)-induced bone accumulation in healthy rats.


Asunto(s)
Radioisótopos de Galio/química , Tomografía de Emisión de Positrones/métodos , ARN/análisis , Animales , Quelantes/química , Compuestos Heterocíclicos/química , Masculino , ARN Interferente Pequeño/química , Ratas , Ratas Sprague-Dawley
9.
Arthritis Res Ther ; 17: 308, 2015 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-26530096

RESUMEN

INTRODUCTION: Vascular adhesion protein-1 (VAP-1) is an adhesion molecule, which upon inflammation is rapidly translocated from intracellular sources to the endothelial cell surface. We have recently discovered that sialic acid- binding immunoglobulin-like lectin 9 (Siglec-9) is a leukocyte ligand of VAP-1 and that 68Ga-labeled Siglec-9 motif peptide facilitates in vivo imaging of inflammation. This study evaluated the feasibility of 68Ga-DOTA-Siglec-9 positron emission tomography (PET) for the assessment of synovitis. METHODS: Rabbits with synovial inflammation were injected with 18F-FDG or 68Ga-DOTA-Siglec-9 and studied by gamma counting and autoradiography. Certain rabbits were also examined with magnetic resonance imaging (MRI). After PET imaging, rabbits were intravenously administered with anti-VAP-1 antibody to evaluate luminal expression of VAP-1 by immunohistochemistry. Finally, binding of Siglec-9 peptide and VAP-1 positive vessels were evaluated by double staining of rheumatoid arthritis synovium. RESULTS: Intra-articular injection of hemagglutinin induced mild synovial inflammation in rabbit knee with luminal expression of VAP-1. Synovitis was clearly visualized by 68Ga-DOTA-Siglec-9 PET in addition to 18F-FDG-PET and MRI. Compared with the 18F-FDG, the ex vivo inflamed-to-control synovium ratio of 68Ga-DOTA-Siglec-9 was similar (1.7 ± 0.4 vs. 1.5 ± 0.2, P = 0.32). Double staining revealed that Siglec-9 peptide binds to VAP-1 positive vessels in human rheumatoid synovium. CONCLUSION: Ga-DOTA-Siglec-9 PET tracer detected VAP-1 positive vasculature in the mild synovitis of rabbits comparable with 18F-FDG, suggesting its potential for in vivo imaging of synovial inflammation in patients with rheumatic diseases.


Asunto(s)
Radioisótopos de Galio , Tomografía de Emisión de Positrones/métodos , Radiofármacos , Sinovitis/diagnóstico por imagen , Amina Oxidasa (conteniendo Cobre)/química , Amina Oxidasa (conteniendo Cobre)/metabolismo , Animales , Antígenos CD/química , Antígenos CD/metabolismo , Artritis Reumatoide/diagnóstico por imagen , Moléculas de Adhesión Celular/química , Moléculas de Adhesión Celular/metabolismo , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Radioisótopos de Galio/química , Compuestos Heterocíclicos con 1 Anillo/química , Humanos , Inmunohistoquímica , Masculino , Estabilidad Proteica , Conejos , Radiofármacos/química , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/química , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/metabolismo
10.
EJNMMI Res ; 5(1): 117, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26183032

RESUMEN

BACKGROUND: This study evaluated the absorption, distribution, and excretion of Gallium-68 ((68)Ga) radionuclide after a single intravenous (i.v.) injection of (68)Ge/(68)Ga generator eluate in healthy rats. Additionally, human radiation doses were estimated from the rat data. METHODS: Twenty-one female and 21 male Sprague-Dawley rats were i.v. injected with 47 ± 4 MBq of (68)Ge/(68)Ga generator eluate, and the radioactivity of excised organs was measured using a gamma counter at 5, 30, 60, 120, or 180 min afterwards (n = 3-7 for each time point). The radioactivity concentration and plasma pharmacokinetic parameters were calculated. Subsequently, the estimates for human radiation dosimetry were determined. Additionally, 4 female and 5 male rats were positron emission tomography (PET) imaged for in vivo visualization of biodistribution. RESULTS: (68)Ga radioactivity was cleared relatively slowly from blood circulation and excreted into the urine, with some retention in the liver and spleen. Notably, the (68)Ga radioactivity in female genital organs, i.e., the uterus and ovaries, was considerable higher compared with male genitals. Extrapolating from the female and male rat (68)Ga data, the estimated effective dose was 0.0308 mSv/MBq for a 57-kg woman and 0.0191 mSv/MBq for a 70-kg man. CONCLUSIONS: The estimated human radiation burden of the (68)Ge/(68)Ga generator eluate was slightly higher for females and similar for males as compared with somatostatin receptor ligands (68)Ga-DOTANOC, (68)Ga-DOTATOC, and (68)Ga-DOTATATE, which is probably due to the retention in the liver and spleen. Our results revealed some differences between female and male rat data, which, at least in part, may be explained by the small sample size.

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