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ABSTRACT: Vascular cell adhesion molecule 1 (VCAM-1) plays a major role in the chronic inflammatory processes involved in vulnerable atherosclerotic plaque development. We previously showed that the (99m)Tc-labeled major histocompatibility complex 1-derived peptide B2702p bound specifically to VCAM-1 and allowed the ex vivo imaging of atherosclerotic lesions in Watanabe heritable hyperlipidemic rabbits. However, B2702p target-to-background ratio was suboptimal for the in vivo imaging of VCAM-1 expression in atherosclerotic lesions. To improve the target-to-background ratio, 20 derivatives of B2702p (B2702p1-B2702p20) were synthesized using the alanine scan methodology. We hypothesized that (99m)Tc-radiolabeled B2702p derivatives might allow the molecular imaging of VCAM-1 expression in an experimental model of atherosclerosis. METHODS: A mouse model of focal atherosclerotic plaque development induced by left carotid artery ligation in apolipoprotein E double-knockout (ApoE(-/-)) mice was used (n = 82). (99m)Tc-B2702p and (99m)Tc-B2702p1-(99m)Tc-B2702p20 were injected intravenously in anesthetized animals 3 wk after the ligation. Whole-body planar imaging was performed for 3 h. SPECT imaging of 6 additional ligated ApoE(-/-) mice was also performed with (99m)Tc-B2702p1. The animals were then euthanized, and the biodistribution of (99m)Tc-labeled peptides was evaluated by γ-well counting of excised organs. Expression of VCAM-1 in the ligated and contralateral carotid arteries was evaluated by immunohistology. RESULTS: Robust VCAM-1 immunostaining was observed in the left carotid atherosclerotic lesions as a consequence of artery ligation, whereas no VCAM-1 expression was detected in the contralateral carotid artery. Among all evaluated peptides, (99m)Tc-B2702p1 exhibited the most favorable properties. By γ-well counting, there was a significant 2.0-fold increase in the (99m)Tc-B2702p1 left-to-right carotid artery activity ratio (2.6 ± 0.6) and a 3.4-fold increase in the left carotid-to-blood activity ratio (1.4 ± 0.4) in comparison to (99m)Tc-B2702p (1.3 ± 0.2 and 0.4 ± 0.1, respectively, P < 0.05 for both comparisons). Similarly, planar image quantification indicated a higher left-to-right carotid activity ratio in (99m)Tc-B2702p1- than in (99m)Tc-B2702p-injected mice (1.2 ± 0.1 vs. 1.0 ± 0.0, respectively, P < 0.05). Finally, a significantly higher (99m)Tc-B2702p1 activity in the left than in the right carotid artery was observed by SPECT imaging (2.2 ± 0.4 vs. 1.4 ± 0.3 cpm/mm(2)/injected dose, respectively, P < 0.05). CONCLUSION: (99m)Tc-B2702p1 is a potentially useful radiotracer for the in vivo molecular imaging of VCAM-1 expression in atherosclerotic plaques.
Journal of Nuclear Medicine 05/2013; · 6.38 Impact Factor
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ABSTRACT: Metabolic disorders such as insulin resistance (IR) and dyslipidemia (DL) might contribute to the induction of diabetic cardiomyopathy (DCM). However, few relevant animal models are currently available for studying the time-course of DCM and evaluating experimental therapeutics. The present study proposes a rodent model of dietary-induced IR combined or not with DL in order to investigate the impact of chronic IR and DL on in vivo myocardial function. Male rats were fed a western-type diet (65% fat; 15% fructose; WD). DL was induced by combining the western diet with i.p. injections of a nonionic surface-active agent (P-407; 0.2 mg/kg, 3 times/wk; P-407). A chow diet was used as control. At 11 and 14 weeks, cardiac function was assessed by echocardiography. Fasting blood glucose increased in WD group while plasma lipids markedly accumulated in P-407 treated rats. Echocardiographic data showed no significant difference in cardiac geometry under basal conditions. Diastolic dysfunction was evidenced at 14 weeks by a significant decrease in E/A ratio in the P-407 group. Moreover, fractional shortening was significantly depressed under dobutamine stress in WD group at 14 weeks whereas systolic dysfunction appeared as early as 11 weeks and worsened at 14 weeks in P-407 animals. Finally, myocardial TNF-alpha tissue content increased in P-407 group. In conclusion, DL exacerbated cardiac lipotoxicity and functional complications associated with IR. This experimental model of combined IR and DL closely mimics the main clinical manifestations of DCM and might therefore constitute a useful tool for the evaluation of pharmacological treatments.
Current pharmaceutical design 04/2013; · 4.41 Impact Factor
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Arnaud Briat,
Christiane H F Wenk,
Mitra Ahmadi,
Michael Claron,
Didier Boturyn,
Véronique Josserand,
Pascal Dumy,
Daniel Fagret,
Jean-Luc Coll, Catherine Ghezzi,
Lucie Sancey,
Jean-Philippe Vuillez
Cancer Science 06/2012; 103(6):Junecover. · 3.33 Impact Factor
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Julien Dimastromatteo,
Laurent M. Riou,
Mitra Ahmadi,
Guillaume Pons,
Eric Pellegrini,
Alexis Broisat,
Lucie Sancey,
Tatiana Gavrilina,
Didier Boturyn,
Pascal Dumy,
Daniel Fagret, Catherine Ghezzi
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ABSTRACT: BackgroundMyocardial angiogenesis following reperfusion of an infarcted area may impact on patient prognosis and pro-angiogenic treatments
are currently evaluated. The non-invasive imaging of angiogenesis would therefore be of potential clinical relevance in these
settings. 99mTc-RAFT-RGD is a novel 99mTc-labeled tracer that targets the αvβ3 integrin. Our objective was to determine whether this tracer was suitable for myocardial angiogenesis imaging.
Methods and ResultsA rat model of reperfused myocardial infarction was employed. Fourteen days following reperfusion, the animals were injected
with 99mTc-RAFT-RGD or with its negative control 99mTc-RAFT-RAD. Fourteen animals were dedicated to autoradiographic imaging, infarct staining, and gamma-well counting of myocardial
activity. In vivo dual-isotope pinhole SPECT imaging of 201Tl and 99mTc-RAFT-RGD or 99mTc-RAFT-RAD was also performed in 11 additional animals. Neovessels were observed by immunostaining in the infarcted and peri-infarct
areas. 99mTc-RAFT-RGD infarct-to-normal ratios by gamma-well counting and ex vivo imaging (2.5±0.6 and 4.9±0.9, respectively) were
significantly higher than those of 99mTc-RAFT-RAD (1.7±0.2 and 2.2±0.4, respectively, P<.05). The infarcted area was readily visible in vivo by SPECT with 99mTc-RAFT-RGD but not with 99mTc-RAFT-RAD (infarct-to-normal zone activity ratio, 2.5±0.6 and 1.7±0.4, respectively, P<.05).
Conclusion
99mTc-RAFT-RGD allowed the experimental in vivo molecular imaging of myocardial angiogenesis.
KeywordsMolecular imaging-angiogenesis-radiopharmaceuticals-biodistribution
Journal of Nuclear Cardiology 04/2012; 17(3):435-443. · 2.67 Impact Factor
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ABSTRACT: PurposeThe molecular imaging of tumour neoangiogenesis currently represents a major field of research for the diagnostic and treatment
strategy of solid tumours. Endothelial cells from tumour neovessels overexpress the αvβ3 integrin, which selectively binds to Arg-Gly-Asp (RGD)-containing peptides. We evaluated the potential of the novel radiotracer
99mTc-RAFT-RGD for the non-invasive molecular imaging of αvβ3 integrin expression in mice models of tumour development.
Methods
99mTc-RAFT-RGD, 99mTc-cRGD (specific control) and 99mTc-RAFT-RAD (non-specific control) were injected intravenously to mice bearing B16F0 or TS/A-pc tumours. In vivo whole-body
tomographic imaging and post-mortem biodistribution studies were performed 60min following tracer injection. Adjacent tumour
slices were used to compare the localisation of neovessels from immunostaining and the pattern of 99mTc-RAFT-RGD uptake from autoradiographic ex vivo imaging.
ResultsBiodistribution studies indicated that 99mTc-RAFT-RGD tumour uptake was significantly higher than that of 99mTc-RAFT-RAD in B16F0 (2.4±0.5 vs 1.0±0.1%ID/g, respectively) and in TS/A-pc tumours (2.7±0.8 vs 0.7±0.1%ID/g, respectively).
Immunohistochemical and autoradiographic studies indicated that 99mTc-RAFT-RGD intratumoural uptake preferentially occurred in angiogenic areas. Tomographic imaging allowed tumour visualisation
following injection of 99mTc-RAFT-RGD and 99mTc-cRGD with similar tumour-to-contralateral muscle (T/CM) ratios in B16F0 and in TS/A-pc tumours whereas 99mTc-RAFT-RAD T/CM ratios did not allow tumour imaging. In accordance with the higher level of αvβ3 integrin expression on TS/A-pc tumours than on B16F0 tumours as determined from western blot and immunoprecipitation analyses,
the 99mTc-RAFT-RGD T/CM ratio was significantly higher in TS/A-pc than in B16F0 tumours.
Conclusion
99mTc-RAFT-RGD allowed the in vivo imaging of αvβ3 integrin tumour expression.
European journal of nuclear medicine and molecular imaging 04/2012; 34(12):2037-2047. · 4.99 Impact Factor
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Alexis Broisat,
Sophie Hernot,
Jakub Toczek,
Jens De Vos,
Laurent M Riou,
Sandrine Martin,
Mitra Ahmadi,
Nicole Thielens,
Ulrich Wernery,
Vicky Caveliers,
Serge Muyldermans,
Tony Lahoutte,
Daniel Fagret, Catherine Ghezzi,
Nick Devoogdt
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ABSTRACT: A noninvasive tool allowing the detection of vulnerable atherosclerotic plaques is highly needed. By combining nanomolar affinities and fast blood clearance, nanobodies represent potential radiotracers for cardiovascular molecular imaging. Vascular cell adhesion molecule-1 (VCAM1) constitutes a relevant target for molecular imaging of atherosclerotic lesions.
We aimed to generate, radiolabel, and evaluate anti-VCAM1 nanobodies for noninvasive detection of atherosclerotic lesions.
Ten anti-VCAM1 nanobodies were generated, radiolabeled with technetium-99m, and screened in vitro on mouse and human recombinant VCAM1 proteins and endothelial cells and in vivo in apolipoprotein E-deficient (ApoE(-/-)) mice. A nontargeting control nanobody was used in all experiments to demonstrate specificity. All nanobodies displayed nanomolar affinities for murine VCAM1. Flow cytometry analyses using human human umbilical vein endothelial cells indicated murine and human VCAM1 cross-reactivity for 6 of 10 nanobodies. The lead compound cAbVCAM1-5 was cross-reactive for human VCAM1 and exhibited high lesion-to-control (4.95±0.85), lesion-to-heart (8.30±1.11), and lesion-to-blood ratios (4.32±0.48) (P<0.05 versus control C57Bl/6J mice). Aortic arch atherosclerotic lesions of ApoE(-/-) mice were successfully identified by single-photon emission computed tomography imaging. (99m)Tc-cAbVCAM1-5 binding specificity was demonstrated by in vivo competition experiments. Autoradiography and immunohistochemistry further confirmed cAbVCAM1-5 uptake in VCAM1-positive lesions.
The (99m)Tc-labeled, anti-VCAM1 nanobody cAbVCAM1-5 allowed noninvasive detection of VCAM1 expression and displayed mouse and human cross-reactivity. Therefore, this study demonstrates the potential of nanobodies as a new class of radiotracers for cardiovascular applications. The nanobody technology might evolve into an important research tool for targeted imaging of atherosclerotic lesions and has the potential for fast clinical translation.
Circulation Research 03/2012; 110(7):927-37. · 9.49 Impact Factor
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Arnaud Briat,
Christiane H F Wenk,
Mitra Ahmadi,
Michael Claron,
Didier Boturyn,
Véronique Josserand,
Pascal Dumy,
Daniel Fagret,
Jean-Luc Coll, Catherine Ghezzi,
Lucie Sancey,
Jean-Philippe Vuillez
[show abstract]
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ABSTRACT: Integrin α(v)β(3) expression is upregulated during tumor growth and invasion in newly formed endothelial cells in tumor neovasculature and in some tumor cells. A tetrameric RGD-based peptide, regioselectively addressable functionalized template-(cyclo-[RGDfK])4 (RAFT-RGD), specifically targets integrin α(v)β(3) in vitro and in vivo. When labeled with indium-111, the RAFT-RGD is partially reabsorbed and trapped in the kidneys, limiting its use for further internal targeted radiotherapy and imaging investigations. We studied the effect of Gelofusine on RAFT-RGD renal retention in tumor-bearing mice. Mice were imaged using single photon emission computed tomography and optical imaging 1 and 24 h following tracer injection. Distribution of RAFT-RGD was further investigated by tissue removal and direct counting of the tracer. Kidney sections were analyzed by confocal microscopy. Gelofusine significantly induced a >50% reduction of the renal reabsorption of (111)In-DOTA-RAFT-RGD and A700-RAFT-RGD, without affecting tumor uptake. Injection of Gelofusine significantly reduced the renal retention of labeled RAFT-RGD, while increasing the tumor over healthy tissue ratio. These results will lead to the development of future therapeutic approaches.
Cancer Science 03/2012; 103(6):1105-10. · 3.33 Impact Factor
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François Lux,
Anna Mignot,
Pierre Mowat,
Cédric Louis,
Sandrine Dufort,
Claire Bernhard,
Franck Denat,
Frédéric Boschetti,
Claire Brunet,
Rodolphe Antoine, [......],
Jean-Luc Coll,
Vasile Stupar,
Emmanuel Barbier,
Chantal Rémy,
Alexis Broisat, Catherine Ghezzi,
Géraldine Le Duc,
Stéphane Roux,
Pascal Perriat,
Olivier Tillement
Angewandte Chemie International Edition 11/2011; 50(51):12299-303. · 13.45 Impact Factor
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ABSTRACT: Post-infarct left ventricular dysfunction and cardiac remodeling are the primary causes of chronic heart failure in industrialized countries. In the present study, we examined the influence of dietary selenium intake on cardiac remodeling after reperfused myocardial infarction and explored one of the possible mechanisms.
Rats were fed a diet containing either 0.05 mg/kg (Low-Se, group of rats receiving the low-selenium diet) or 1.50 mg/kg (group of rats receiving the high-selenium diet) selenium. At the end of the 5th week of the diet, rats were subjected to transient (1 h) coronary ligation followed by 8 days of reperfusion. Infarct size and cardiac passive compliance were increased in the Low-Se group compared with group of rats receiving the high-selenium diet. Similarly, indices of cardiac remodeling (thinning index and expansion index) were more altered in Low-Se hearts. These adverse effects of the Low-Se diet on cardiac remodeling were accompanied by an increase in cardiac TNF-α content, a decreased activity of antioxidant seleno-enzymes and an increase in connexin-43 dephosphorylation.
Dietary selenium intake influences post-infarct cardiac remodeling even when provided within the range of physiological values. Our data suggest that the cardioprotective effect of selenium might be mediated by a reduced oxidative stress, a lower connexin-43 dephosphorylation, and a decreased TNF-α expression.
Molecular Nutrition & Food Research 04/2011; 55(4):522-9. · 4.30 Impact Factor
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ABSTRACT: Despite the fact that mechanical stresses are well recognized as key determinants for atherosclerotic plaque rupture, very little is known about stress amplitude and distribution in atherosclerotic lesions, even in the standard apolipoprotein E (apoE)-/- mouse model of atherosclerosis. Our objectives were to combine immunohistology, atomic force microscopy measurements, and finite element computational analysis for the accurate quantification of stress amplitude and distribution in apoE-/- mouse aortic atherosclerotic lesions.
Residual stresses and strains were released by radially cutting aortic arch segments from 7- to 30-week-old pathological apoE-/- (n=25) and healthy control mice (n=20). Immunohistology, atomic force microscopy, and biomechanical modeling taking into account regional residual stresses and strains were performed. Maximum stress values were observed in the normal arterial wall (276±71 kPa), whereas low values (<20 kPa) were observed in all plaque areas. Stress distribution was not correlated to macrophage infiltration.
Low mechanical stress amplitude was observed in apoE-/- mouse aortic atherosclerotic lesions. This original study provides a basis for further investigations aimed at determining whether low stress levels are responsible for the apparently higher stability of murine aortic atherosclerotic lesions.
Arteriosclerosis Thrombosis and Vascular Biology 03/2011; 31(5):1007-10. · 6.37 Impact Factor
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Julien Dimastromatteo,
Laurent M Riou,
Mitra Ahmadi,
Guillaume Pons,
Eric Pellegrini,
Alexis Broisat,
Lucie Sancey,
Tatiana Gavrilina,
Didier Boturyn,
Pascal Dumy,
Daniel Fagret, Catherine Ghezzi
[show abstract]
[hide abstract]
ABSTRACT: Myocardial angiogenesis following reperfusion of an infarcted area may impact on patient prognosis and pro-angiogenic treatments are currently evaluated. The non-invasive imaging of angiogenesis would therefore be of potential clinical relevance in these settings. (99m)Tc-RAFT-RGD is a novel (99m)Tc-labeled tracer that targets the alpha(v)beta(3) integrin. Our objective was to determine whether this tracer was suitable for myocardial angiogenesis imaging.
A rat model of reperfused myocardial infarction was employed. Fourteen days following reperfusion, the animals were injected with (99m)Tc-RAFT-RGD or with its negative control (99m)Tc-RAFT-RAD. Fourteen animals were dedicated to autoradiographic imaging, infarct staining, and gamma-well counting of myocardial activity. In vivo dual-isotope pinhole SPECT imaging of (201)Tl and (99m)Tc-RAFT-RGD or (99m)Tc-RAFT-RAD was also performed in 11 additional animals. Neovessels were observed by immunostaining in the infarcted and peri-infarct areas. (99m)Tc-RAFT-RGD infarct-to-normal ratios by gamma-well counting and ex vivo imaging (2.5 +/- 0.6 and 4.9 +/- 0.9, respectively) were significantly higher than those of (99m)Tc-RAFT-RAD (1.7 +/- 0.2 and 2.2 +/- 0.4, respectively, P < .05). The infarcted area was readily visible in vivo by SPECT with (99m)Tc-RAFT-RGD but not with (99m)Tc-RAFT-RAD (infarct-to-normal zone activity ratio, 2.5 +/- 0.6 and 1.7 +/- 0.4, respectively, P < .05).
(99m)Tc-RAFT-RGD allowed the experimental in vivo molecular imaging of myocardial angiogenesis.
Journal of Nuclear Cardiology 06/2010; 17(3):435-43. · 2.67 Impact Factor
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Olivier Detante,
Anaïck Moisan,
Julien Dimastromatteo,
Marie-Jeanne Richard,
Laurent Riou,
Emmanuelle Grillon,
Emmanuel Barbier,
Marie-Dominique Desruet,
Florence De Fraipont,
Christoph Segebarth,
Assia Jaillard,
Marc Hommel, Catherine Ghezzi,
Chantal Remy
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ABSTRACT: Human mesenchymal stem cells (hMSC) are a promising source for cell therapy after stroke. To deliver these cells, an IV injection appears safer than a local graft. We aimed to assess the whole-body biodistribution of IV-injected (99m)Tc-HMPAO-labeled hMSC in normal rats (n = 9) and following a right middle cerebral artery occlusion (MCAo, n = 9). Whole-body nuclear imaging, isolated organ counting (at 2 and 20 h after injection) and histology were performed. A higher activity was observed in the right damaged hemisphere of the MCAo group [6.5 +/- 0.9 x 10(-3) % of injected dose (ID)/g] than in the control group (3.6 +/- 1.2 x 10(-3) %ID/g), 20 h after injection. In MCAo rats, right hemisphere activity was higher than that observed in the contralateral hemisphere at 2 h after injection (11.6 +/- 2.8 vs. 9.8 +/- 1.7 x 10(-3) %ID/g). Following an initial hMSC lung accumulation, there was a decrease in pulmonary activity from 2 to 20 h after injection in both groups. The spleen was the only organ in which activity increased between 2 and 20 h. The presence of hMSC was documented in the spleen, liver, lung, and brain following histology. IV-injected hMSC are transiently trapped in the lungs, can be sequestered in the spleen, and are predominantly eliminated by kidneys. After 20 h, more hMSC are found in the ischemic lesion than into the undamaged cerebral tissue. IV delivery of hMSC could be the initial route for a clinical trial of tolerance.
Cell Transplantation 09/2009; 18(12):1369-79. · 5.13 Impact Factor
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ABSTRACT: Angiogenesis plays a central role in tumor growth and metastasis. Quantification or evaluation of angiogenesis is crucial for antiangiogenic therapeutic strategies. Since integrin alpha(v)beta(3) overexpression appears specific of angiogenesis at the adult stage, it became a target of choice over the past decade, and labeled RGD-based compounds, therefore, constitute promising agents for noninvasive tumor visualization and targeting. We evaluated the chemical and biologic properties of a new tetrameric RGD-based tracer named RAFT-RGD. RAFT-RGD was radiolabeled with indium-111, using the chelating agent [(1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid] (DOTA). Labeling reaction parameters, such as time, temperature, solvent, or molar ratio, were investigated in order to optimize the final properties of the labeled RGD peptide. A 97.7% +/- 0.7% binding efficiency was achieved. (111)In-DOTA-RAFT-RGD was injected intravenously in a cohort of alpha(v)beta(3)-positive tumor-bearing nude mice. We noninvasively visualized the in vivo distribution of the tracer, using a small-animal gamma camera. In vivo distribution and stability were also studied after organ removal. In vivo, the radiolabeled peptide showed rapid blood clearance and tumor uptake. Whole-body noninvasive planar imaging allowed tumor visualization from 1 hour postinjection. However, renal uptake must be reduced to increase the therapeutic potential of RAFT-RGD.
Cancer Biotherapy & Radiopharmaceuticals 01/2009; 23(6):691-700. · 1.44 Impact Factor
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[hide abstract]
ABSTRACT: The molecular imaging of tumour neoangiogenesis currently represents a major field of research for the diagnostic and treatment strategy of solid tumours. Endothelial cells from tumour neovessels overexpress the alpha(v)beta(3) integrin, which selectively binds to Arg-Gly-Asp (RGD)-containing peptides. We evaluated the potential of the novel radiotracer (99m)Tc-RAFT-RGD for the non-invasive molecular imaging of alpha(v)beta(3) integrin expression in mice models of tumour development.
(99m)Tc-RAFT-RGD, (99m)Tc-cRGD (specific control) and (99m)Tc-RAFT-RAD (non-specific control) were injected intravenously to mice bearing B16F0 or TS/A-pc tumours. In vivo whole-body tomographic imaging and post-mortem biodistribution studies were performed 60 min following tracer injection. Adjacent tumour slices were used to compare the localisation of neovessels from immunostaining and the pattern of (99m)Tc-RAFT-RGD uptake from autoradiographic ex vivo imaging.
Biodistribution studies indicated that (99m)Tc-RAFT-RGD tumour uptake was significantly higher than that of (99m)Tc-RAFT-RAD in B16F0 (2.4+/-0.5 vs 1.0+/-0.1%ID/g, respectively) and in TS/A-pc tumours (2.7+/-0.8 vs 0.7+/-0.1%ID/g, respectively). Immunohistochemical and autoradiographic studies indicated that (99m)Tc-RAFT-RGD intratumoural uptake preferentially occurred in angiogenic areas. Tomographic imaging allowed tumour visualisation following injection of (99m)Tc-RAFT-RGD and (99m)Tc-cRGD with similar tumour-to-contralateral muscle (T/CM) ratios in B16F0 and in TS/A-pc tumours whereas (99m)Tc-RAFT-RAD T/CM ratios did not allow tumour imaging. In accordance with the higher level of alpha(v)beta(3) integrin expression on TS/A-pc tumours than on B16F0 tumours as determined from western blot and immunoprecipitation analyses, the (99m)Tc-RAFT-RGD T/CM ratio was significantly higher in TS/A-pc than in B16F0 tumours.
(99m)Tc-RAFT-RGD allowed the in vivo imaging of alpha(v)beta(3) integrin tumour expression.
European journal of nuclear medicine and molecular imaging 01/2008; 34(12):2037-47. · 4.99 Impact Factor
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ABSTRACT: Insulin resistance, implying depressed cellular sensitivity to insulin, is a risk factor for type 2 diabetes and cardiovascular disease. This study is the first step towards the development of a technique of insulin resistance measurement in humans with a new tracer of glucose transport, [(123)I]6-deoxy-6-iodo-D-glucose (6DIG).
We investigated 6DIG kinetics in anaesthetised control rats and in three models of insulin-resistant rats: fructose fed, Zucker and ZDF. The study of myocardial 6DIG activity was performed under two conditions: first, 6DIG was injected under the baseline condition and then it was injected after a bolus injection of insulin. After each injection, radioactivity was measured over 45 min by external detection via NaI probes, in the heart and blood. A tri-compartment model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the heart.
These coefficients were significantly increased with insulin in control rats and did not change significantly in insulin-resistant rats. The ratio of the coefficient obtained under insulin to that obtained under basal conditions gave an index of cardiac insulin resistance for each animal. The mean values of these ratios were significantly lower in insulin-resistant than in control rats: 1.16 +/- 0.06 vs 2.28 +/- 0.18 (p < 0.001) for the fructose-fed group, 0.92 +/- 0.05 vs 1.62 +/- 0.25 (p < 0.01) for the Zucker group and 1.34 +/- 0.06 vs 2.01 +/- 0.26 (p < 0.05) for the ZDF group.
These results show that 6DIG could be a useful tracer to image cardiac insulin resistance.
European journal of nuclear medicine and molecular imaging 11/2007; 34(11):1756-64. · 4.99 Impact Factor
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ABSTRACT: Myocardial infarction induces contractile dysfunction and remodeling that can lead to heart failure. Nitric oxide has been proposed as one of the major actors of this pathophysiologic process. We note that N (G)-nitro-L-arginine methyl ester (L-NAME) administration from day 2 to day 7 after myocardial infarction in rats improves stroke volume, preserves cardiac compliance, and reduces infarct expansion. Our observations lead to the hypothesis that the mechanisms by which cytokines contribute to myocardial remodeling and dysfunction in the days after infarction might involve *NO signalling pathways.
Antioxidants and Redox Signaling 07/2007; 9(6):757-63. · 8.46 Impact Factor
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ABSTRACT: Insulin resistance, characterised by an insulin-stimulated glucose transport defect, is an important feature of the pre-diabetic state that has been observed in numerous pathological disorders. The purpose of this study was to assess variations in glucose transport in rats using (125)I-6-deoxy-6-iodo-D-glucose (6DIG), a new tracer of glucose transport proposed as an imaging tool to assess insulin resistance in vivo.
Two protocols were performed, a hyperinsulinaemic-euglycaemic clamp and a normoinsulinaemic-normoglycaemic protocol, in awake control and insulin-resistant fructose-fed rats. The tracer was injected at steady state, and activity in 11 tissues and the blood was assessed ex vivo at several time points. A multicompartmental mathematical model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the organs.
Insulin sensitivity of fructose-fed rats, estimated by the glucose infusion rate, was reduced by 40% compared with control rats. At steady state, 6DIG uptake was significantly stimulated by insulin in insulin-sensitive tissues of control rats (basal versus insulin: diaphragm, p < 0.01; muscle, p<0.05; heart, p<0.001), whereas insulin did not stimulate 6DIG uptake in insulin-resistant fructose-fed rats. Moreover, in these tissues, the fractional transfer coefficients of entrance were significantly increased with insulin in control rats (basal vs insulin: diaphragm, p<0.001; muscle, p<0.001; heart, p<0.01) whereas no significant changes were observed in fructose-fed rats.
This study sets the stage for the future use of 6DIG as a non-invasive means for the evaluation of insulin resistance by nuclear imaging.
European journal of nuclear medicine and molecular imaging 06/2007; 34(5):734-44. · 4.99 Impact Factor
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ABSTRACT: In addition to improving drug solubilization, cyclodextrins (CDs) also affect the biological behavior of the included compound. We evaluated the effects of two natural CDs beta-CD and gamma-CD, and six beta-CD derivatives, Dimeb, Trimeb, SBb, 2-HP, 6AD, and 6 MTU on the biological behavior of (99m)TcN-NOET, a technetium-99m-labeled, lipophilic compound readily detectable through radioactivity assessment. Determination of CDs' affinities for (99m)TcN-NOET indicated that the cavity size of gamma-CD was not suitable for (99m)TcN-NOET inclusion, and that beta-CD derivatization mostly resulted in decreased CDs affinities for (99m)TcN-NOET to various extents compared with the natural beta-CD. In vitro and ex vivo experiments performed on newborn rat cardiomyocytes and isolated perfused rat hearts, respectively, showed 1.7- and 2.3-fold maximal differences in (99m)TcN-NOET cellular and tissue activities. Regression analyzes indicated no significant correlation between these observed biological differences and the affinities of the eight CDs tested for (99m)TcN-NOET or for cellular membranes. In conclusion, CD derivatization often resulted in impaired affinity of the derivatives for the lipophilic compound (99m)TcN-NOET. Moreover, the in vitro and ex vivo biological behavior of (99m)TcN-NOET was greatly affected depending on the CD used for inclusion of the tracer.
European Journal of Pharmaceutics and Biopharmaceutics 10/2005; 61(1-2):40-9. · 4.27 Impact Factor
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ABSTRACT: Pre-diabetic subjects with high insulin secretory capacity have double risk of cardiovascular disease compared with subjects who do not develop insulin-resistance. It is well established that the ability of the myocardium to increase its glycolytic ATP production plays a crucial role in determining cell survival under conditions of ischemia. Up to now, whether the pre-diabetic state reduces the tolerance of the heart to ischemia by affecting its ability to increase its energy production through glycolysis remains unknown. The aim of the present study was to assess whether insulin resistance affects the ability of the myocardium to increase glycolysis under ischemic conditions. Male Wistar rats were fed for 8 weeks a fructose-enriched (33%) diet to induce a pre-diabetic state. Hearts were isolated and subjected to ex-vivo low-flow (2%) ischemia for 30 min. The fructose diet increased sarcolemmal GLUT4 localisation in myocardial cells under basal conditions compared with controls. This effect was not accompanied by increased glucose utilisation. Ischemia induced the translocation of GLUT4 to the plasma membrane in controls but did not significantly modify the distribution of these transporters in pre-diabetic hearts. Glycolytic flux under ischemic conditions was significantly lower in fructose-fed rat hearts compared with controls. The reduction of glycolytic flux during ischemia in fructose-fed rat hearts was not due to metabolic inhibition downstream hexokinase II since no cardiac accumulation of glucose-6-phosphate was detected. In conclusion, our results suggest that the pre-diabetic state reduces the tolerance of the myocardium to ischemia by decreasing glycolytic flux adaptation.
Molecular and Cellular Biochemistry 05/2005; 272(1-2):9-17. · 2.06 Impact Factor
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ABSTRACT: The aim of this study was to assess the biological behavior of new radiolabeled glucose analogues proposed as tracers of glucose uptake in vivo and iodinated in position 3, 4, or 6. Biological results obtained in vitro on adipocytes and erythrocytes and in vivo in mice were compared to those obtained with the gold-standard tracer of glucose uptake, 2-deoxy-D-glucose. None of these molecules had the same biological behavior than 2-deoxy-D-glucose. Therefore, these compounds cannot be considered as tracers of glucose uptake.
Nuclear Medicine and Biology 03/2004; 31(2):241-50. · 3.02 Impact Factor
