scholarly journals Evaluation of [68Ga]Ga-DOTA-TCTP-1 for the Detection of Metalloproteinase 2/9 Expression in Mouse Atherosclerotic Plaques

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3168 ◽  
Author(s):  
Max Kiugel ◽  
Sanna Hellberg ◽  
Meeri Käkelä ◽  
Heidi Liljenbäck ◽  
Tiina Saanijoki ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Tracer Uptake ◽  
Atherosclerotic Plaques ◽  
Positron Emission ◽  
Pre Treatment ◽  
Targeting Peptide ◽  
Gallium 68

Background: The expression of matrix metalloproteinases 2/9 (MMP-2/9) has been implicated in arterial remodeling and inflammation in atherosclerosis. We evaluated a gallium-68 labeled peptide for the detection of MMP-2/9 in atherosclerotic mouse aorta. Methods: We studied sixteen low-density lipoprotein receptor deficient mice (LDLR-/-ApoB100/100) kept on a Western-type diet. Distribution of intravenously-injected MMP-2/9-targeting peptide, [68Ga]Ga-DOTA-TCTP-1, was studied by combined positron emission tomography (PET) and contrast-enhanced computed tomography (CT). At 60 min post-injection, aortas were cut into cryosections for autoradiography analysis of tracer uptake, histology, and immunohistochemistry. Zymography was used to assess MMP-2/9 activation and pre-treatment with MMP-2/9 inhibitor to assess the specificity of tracer uptake. Results: Tracer uptake was not visible by in vivo PET/CT in the atherosclerotic aorta, but ex vivo autoradiography revealed 1.8 ± 0.34 times higher tracer uptake in atherosclerotic plaques than in normal vessel wall (p = 0.0029). Tracer uptake in plaques correlated strongly with the quantity of Mac-3-positive macrophages (R = 0.91, p < 0.001), but weakly with MMP-9 staining (R = 0.40, p = 0.099). Zymography showed MMP-2 activation in the aorta, and pre-treatment with MMP-2/9 inhibitor decreased tracer uptake by 55% (p = 0.0020). Conclusions: The MMP-2/9-targeting [68Ga]Ga-DOTA-TCTP-1 shows specific uptake in inflamed atherosclerotic lesions; however, a low target-to-background ratio precluded in vivo vascular imaging. Our results suggest, that the affinity of gelatinase imaging probes should be steered towards activated MMP-2, to reduce the interference of circulating enzymes on the target visualization in vivo.

Development of Nanoparticle Probes for In Vivo Imaging of Atherosclerotic Plaques

2012 ◽  
Author(s):  
Zihao Zhang ◽  
Sheng Tong ◽  
Gang Bao
Keyword(s):  
Surface Defects ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Necrotic Core ◽  
Intraplaque Hemorrhage ◽  
Atherosclerotic Plaques ◽  
Nanoparticle Probes ◽  
Arterial Lumen ◽  
Inflammatory Macrophage

Atherosclerosis, the formation of fatty plaques in the arterial lumen, is mediated by inflammatory macrophage infiltration in the lesion and ingestion of low-density lipoprotein (LDL), forming foam cells. Its progression will likely form a large necrotic core and fibrotic cap surface defects. The resulting intraplaque hemorrhage causes red blood cell infiltration and hemoglobin abundance, which oxidizes LDL to form cholesterol crystal aggregates (1). Hemorrhagic plaques could rupture and form artery-blocking emboli. Thus, it is critical to develop a tool to detect and locate unstable hemorrhagic plaques in live specimens.

In vivo and in vitro evidence for the glycoxidation of low density lipoprotein in human atherosclerotic plaques

2000 ◽  
Vol 150 (2) ◽  
pp. 343-355 ◽  
Author(s):  
Yoshinobu Imanaga ◽  
Noriyuki Sakata ◽  
Shigeo Takebayashi ◽  
Akira Matsunaga ◽  
Jun Sasaki ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Atherosclerotic Plaques ◽  
Low Density

Genistein inhibits the development of atherosclerosis via inhibiting NF-κB and VCAM-1 expression in LDLR knockout mice

2008 ◽  
Vol 86 (11) ◽  
pp. 777-784 ◽  
Author(s):  
Juejin Wang ◽  
Rongjian Zhang ◽  
Youhua Xu ◽  
Hong Zhou ◽  
Bin Wang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Knockout Mice ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Atherosclerotic Plaques ◽  
Sod Activity ◽  
Density Lipoprotein Receptor ◽  
Total Antioxidant ◽  
Antioxidative Ability

Diet can be an important factor that influences risks for cardiovascular disease. Genistein (4′,5,7-trihydroxyisoflavone), rich in soy, is one candidate that may benefit the cardiovascular system. Here, we explored the effect of genistein in atherosclerosis (AS) development in an in vivo mouse model. Low-density lipoprotein receptor (LDLR) knockout mice were allocated to control, model, and genistein groups. Our results showed that genistein significantly reduced the formation and development of atherosclerotic plaques ((4.68 ± 1.18) ×106 versus (6.65 ± 1.51) ×106 µm2, p < 0.05). In the genistein group, compared with the model group, total antioxidant capacity (TAC) level was 85.5 ± 15.6 versus 203.4 ± 32.6 mmol/L (p < 0.01); malondialdehyde (MDA) level was 3.79 ± 0.28 versus 3.06 ± 0.31 mmol/L (p < 0.01), and superoxide dismutase (SOD) activity was 86.1 ± 6.1 versus 139.1 ± 25.1 U/mL (p < 0.01). Therefore, genistein was able to enhance serum antioxidative ability in our mouse model. Genistein had no influence, however, on serum cholesterol and lipid profiles. Genistein also markedly downregulated the expression of nuclear factor (NF)-κB and vascular cell adhesion molecule (VCAM)-1 in aortas of mice (p < 0.05). These observations suggest that genistein may inhibit AS in LDLR−/− mice via enhancing serum antioxidation and downregulating NF-κB and VCAM-1 expression in the aorta.

scholarly journals Positron Emission Tomography Imaging of Macrophages in Atherosclerosis with 18F-GE-180, a Radiotracer for Translocator Protein (TSPO)

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Sanna Hellberg ◽  
Heidi Liljenbäck ◽  
Olli Eskola ◽  
Veronique Morisson-Iveson ◽  
Matthew Morrison ◽  
...  
Keyword(s):  
Vessel Wall ◽  
Ex Vivo ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Positron Emission Tomography Imaging ◽  
Translocator Protein ◽  
Atherosclerotic Plaques ◽  
Third Generation ◽  
Tissue Samples ◽  
Contrast Enhanced Ct

Intraplaque inflammation plays an important role in the progression of atherosclerosis. The 18 kDa translocator protein (TSPO) expression is upregulated in activated macrophages, representing a potential target to identify inflamed atherosclerotic plaques. We preclinically evaluated 18F-GE-180, a novel third-generation TSPO radioligand, in a mouse model of atherosclerosis. Methods. Nine hypercholesterolemic mice deficient in low density lipoprotein receptor and apolipoprotein B48 (LDLR−/−ApoB100/100) and six healthy C57BL/6N mice were injected with 10 MBq of 18F-GE-180. Specificity of binding was demonstrated in three LDLR−/−ApoB100/100 mice by injection of nonradioactive reference compound of 18F-GE-180 before 18F-GE-180. Dynamic 30-minute PET was performed followed by contrast-enhanced CT, and the mice were sacrificed at 60 minutes after injection. Tissue samples were obtained for ex vivo biodistribution measurements, and aortas were cut into serial cryosections for digital autoradiography. The presence of macrophages and TSPO was studied by immunohistochemistry. The 18F-GE-180 retention in plaque areas with different macrophage densities and lesion-free vessel wall were compared. Results. The LDLR−/−ApoB100/100 mice showed large, inflamed plaques in the aorta. Autoradiography revealed significantly higher 18F-GE-180 retention in macrophage-rich plaque areas than in noninflamed areas (count densities 150 ± 45 PSL/mm2 versus 51 ± 12 PSL/mm2, p<0.001). Prominent retention in the vessel wall without plaque was also observed (220 ± 41 PSL/mm2). Blocking with nonradioactive GE-180 diminished the difference in count densities between macrophage-rich and noninflamed areas in atherosclerotic plaques and lowered the count density in vessel wall without plaque. Conclusion. 18F-GE-180 shows specific uptake in macrophage-rich areas of atherosclerotic plaques in mice. However, retention in atherosclerotic lesions does not exceed that in lesion-free vessel wall. The third-generation TSPO radioligand 18F-GE-180 did not show improved characteristics for imaging atherosclerotic plaque inflammation compared to previously studied TSPO-targeting tracers.

scholarly journals [68Ga]Ga-DFO-c(RGDyK): Synthesis and Evaluation of Its Potential for Tumor Imaging in Mice

2021 ◽  
Vol 22 (14) ◽  
pp. 7391
Author(s):  
Sona Krajcovicova ◽  
Andrea Daniskova ◽  
Katerina Bendova ◽  
Zbynek Novy ◽  
Miroslav Soural ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Imaging ◽  
Ex Vivo ◽  
Cell Uptake ◽  
Αvβ3 Integrin ◽  
In Vitro Characterization ◽  
Positron Emission ◽  
Gallium 68

Angiogenesis has a pivotal role in tumor growth and the metastatic process. Molecular imaging was shown to be useful for imaging of tumor-induced angiogenesis. A great variety of radiolabeled peptides have been developed to target αvβ3 integrin, a target structure involved in the tumor-induced angiogenic process. The presented study aimed to synthesize deferoxamine (DFO)-based c(RGD) peptide conjugate for radiolabeling with gallium-68 and perform its basic preclinical characterization including testing of its tumor-imaging potential. DFO-c(RGDyK) was labeled with gallium-68 with high radiochemical purity. In vitro characterization including stability, partition coefficient, protein binding determination, tumor cell uptake assays, and ex vivo biodistribution as well as PET/CT imaging was performed. [68Ga]Ga-DFO-c(RGDyK) showed hydrophilic properties, high stability in PBS and human serum, and specific uptake in U-87 MG and M21 tumor cell lines in vitro and in vivo. We have shown here that [68Ga]Ga-DFO-c(RGDyK) can be used for αvβ3 integrin targeting, allowing imaging of tumor-induced angiogenesis by positron emission tomography.

Endogenous biosynthesis of thromboxane and prostacyclin in 2 distinct murine models of atherosclerosis

Blood ◽  
2000 ◽  
Vol 96 (12) ◽  
pp. 3823-3826 ◽  
Author(s):  
Domenico Praticò ◽  
Tillmann Cyrus ◽  
Hongwei Li ◽  
Garret A. FitzGerald
Keyword(s):  
Ex Vivo ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Thromboxane B2 ◽  
Murine Models ◽  
En Face ◽  
Density Lipoprotein Receptor ◽  
Potent Vasoconstrictor ◽  
Deficient Mice

Abstract Thromboxane A2 is a potent vasoconstrictor and platelet agonist; prostacyclin is a potent platelet inhibitor and vasodilator. Altered biosynthesis of these eicosanoids is a feature of human hypercholesterolemia and atherosclerosis. This study examined whether in 2 murine models of atherosclerosis their levels are increased and correlated with the evolution of the disease. Urinary 2,3-dinor thromboxane B2 and 2,3-dinor-6-keto prostaglandin F1α, metabolites of thromboxane and prostacyclin, respectively, were assayed in apoliprotein E (apoE)-deficient mice on chow and low-density lipoprotein receptor (LDLR)-deficient mice on chow and a Western-type diet. Atherosclerosis lesion area was measured by en face method. Both eicosanoids increased in apoE-deficient mice on chow and in LDLR-deficient mice on a high-fat diet, but not in LDLR-deficient mice on chow by the end of the study. Aspirin suppressed ex vivo platelet aggregation, serum thromboxane B2, and 2,3-dinor thromboxane B2, and significantly reduced the excretion of 2,3-dinor-6-keto prostaglandin F1α in these animals. This study demonstrates that thromboxane as well as prostacyclin biosynthesis is increased in 2 murine models of atherogenesis and is secondary to increased in vivo platelet activation. Assessment of their generation in these models may afford the basis for future studies on the functional role of these eicosanoids in the evolution and progression of atherosclerosis.

Ex vivo low-density lipoprotein oxidizability and in vivo lipid peroxidation in patients on CAPD

2001 ◽  
Vol 59 (s78) ◽  
pp. 128-136 ◽  
Author(s):  
Johannes M. Roob ◽  
Thomas Rabold ◽  
Marianne Hayn ◽  
Gholamali Khoschsorur ◽  
Ulrike Resch ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Ex Vivo ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density

Endogenous biosynthesis of thromboxane and prostacyclin in 2 distinct murine models of atherosclerosis

Blood ◽  
2000 ◽  
Vol 96 (12) ◽  
pp. 3823-3826 ◽  
Author(s):  
Domenico Praticò ◽  
Tillmann Cyrus ◽  
Hongwei Li ◽  
Garret A. FitzGerald
Keyword(s):  
Ex Vivo ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Thromboxane B2 ◽  
Murine Models ◽  
En Face ◽  
Density Lipoprotein Receptor ◽  
Potent Vasoconstrictor ◽  
Deficient Mice

Thromboxane A2 is a potent vasoconstrictor and platelet agonist; prostacyclin is a potent platelet inhibitor and vasodilator. Altered biosynthesis of these eicosanoids is a feature of human hypercholesterolemia and atherosclerosis. This study examined whether in 2 murine models of atherosclerosis their levels are increased and correlated with the evolution of the disease. Urinary 2,3-dinor thromboxane B2 and 2,3-dinor-6-keto prostaglandin F1α, metabolites of thromboxane and prostacyclin, respectively, were assayed in apoliprotein E (apoE)-deficient mice on chow and low-density lipoprotein receptor (LDLR)-deficient mice on chow and a Western-type diet. Atherosclerosis lesion area was measured by en face method. Both eicosanoids increased in apoE-deficient mice on chow and in LDLR-deficient mice on a high-fat diet, but not in LDLR-deficient mice on chow by the end of the study. Aspirin suppressed ex vivo platelet aggregation, serum thromboxane B2, and 2,3-dinor thromboxane B2, and significantly reduced the excretion of 2,3-dinor-6-keto prostaglandin F1α in these animals. This study demonstrates that thromboxane as well as prostacyclin biosynthesis is increased in 2 murine models of atherogenesis and is secondary to increased in vivo platelet activation. Assessment of their generation in these models may afford the basis for future studies on the functional role of these eicosanoids in the evolution and progression of atherosclerosis.

scholarly journals LDL receptor-peptide conjugate as in vivo tool for specific targeting of pancreatic ductal adenocarcinoma

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Angélina Acier ◽  
Magali Godard ◽  
Fanny Gassiot ◽  
Pascal Finetti ◽  
Marion Rubis ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Near Infrared ◽  
Low Density Lipoprotein ◽  
Survival Rates ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
Targeting Peptide

AbstractDespite clinical advances in diagnosis and treatment, pancreatic ductal adenocarcinoma (PDAC) remains the third leading cause of cancer death, and is still associated with poor prognosis and dismal survival rates. Identifying novel PDAC-targeted tools to tackle these unmet clinical needs is thus an urgent requirement. Here we use a peptide conjugate that specifically targets PDAC through low-density lipoprotein receptor (LDLR). We demonstrate by using near-infrared fluorescence imaging the potential of this conjugate to specifically detect and discriminate primary PDAC from healthy organs including pancreas and from benign mass-forming chronic pancreatitis, as well as detect metastatic pancreatic cancer cells in healthy liver. This work paves the way towards clinical applications in which safe LDLR-targeting peptide conjugate promotes tumor-specific delivery of imaging and/or therapeutic agents, thereby leading to substantial improvements of the PDAC patient’s outcome.

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