Catherine Ghezzi

Unité Inserm U1077, Caen, Lower Normandy, France

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Publications (65)235.68 Total impact

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    ABSTRACT: RNA interference is efficient in vitro studies, and appears as a therapeutic tool of major clinical interest. Nevertheless, the clinical utilisation of siRNAs is restrained by the poor availability of biodistribution data on this new class of pharmaceutics. This study aimed at defining the biodistribution and pharmacokinetics properties of a siRNA directed to the Casein Kinase-2 beta (CK2β) subunit, a potential target in cancer therapy.
    Nuclear Medicine and Biology 04/2015; DOI:10.1016/j.nucmedbio.2015.04.007 · 2.41 Impact Factor
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    ABSTRACT: Background Recent advances in nuclear myocardial perfusion imaging (MPI) have made it possible to develop a dual-isotope protocol for high-speed acquisition with image quality and radiation delivery comparable to that obtained with conventional single isotope protocols. So far, no study has compared dual-isotope high-speed MPI to invasive coronary angiography (ICA) in a large cohort using a Cadmium-zinc-telluride SPECT system. Methods Over a 1-year period (May 2011 to April 2012), 1366 patients underwent dual-isotope high-speed MPI. Patients with ICA within 3 months after dual-isotope high-speed MPI were included together with patients with a low likelihood of coronary artery disease (CAD) in order to assess normalcy rate. Global summed stress score (SSS) and summed rest score (SRS) were calculated, and ICA results were analyzed independently. The main end point was a patient-based assessment of the diagnostic performance of dual-isotope high-speed MPI in detecting or ruling out significant CAD (>70% reduction in lumen diameter). Results Inclusion criteria were fulfilled for 214 patients (143 men; age 60 ± 14 years; ICA, n = 104; low likelihood for CAD, n = 110). An exercise stress test was performed in 62% of patients and a pharmacological stress test was performed with either dipyridamole (32%) or dobutamine (6%). Average examination duration was 22.4 ± 4.5 minutes. Mean SSS, SRS, and SDS were 8.0 ± 4.9, 3.1 ± 4.3, and 5.0 ± 3.2, respectively. Prevalence of angiographic CAD was 75%. ICA detected stenosis in the left main trunk, left anterior descending artery, left circumflex artery, and right coronary artery in 4, 33, 31, and 42 patients, respectively. Sensitivity of dual-isotope high-speed MPI was 94%, normalcy rate was 92%, and accuracy was 83% for detecting CAD. Conclusion Dual-isotope high-speed MPI is reliable at detecting or ruling out CAD. NCT01785589
    Journal of Nuclear Cardiology 11/2014; 22(3). DOI:10.1007/s12350-014-0016-0 · 2.65 Impact Factor
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    European journal of nuclear medicine and molecular imaging 09/2014; 41(12). DOI:10.1007/s00259-014-2917-1 · 5.22 Impact Factor
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    ABSTRACT: Previous works have explained the process of naturally fluorescent proflavine derivatives labelling Abeta deposits in vitro. The present study aimed to further characterize the properties of the proflavine COB231 derivative as a probe. This compound was therefore evaluated on human post-mortem and mice brain slices and in vivo in 18-month-old 3xTgAD mice presenting the main characteristics of Alzheimer's disease (AD). COB231 labelled amyloid plaques on brain slices of AD patients, and 3xTgAD mice at 10 μM and 0.1 μM, respectively. However, no labelling of the neurofibrillary tangle-rich areas was observed either at high concentration or in the brain of fronto-temporal dementia patients. The specificity of this mapping was attested in mice by using Thioflavin S and IMPY as positive controls of amyloid deposits. After intravenous injection of COB231 in old 3xTgAD mice, fluorescent amyloid plaques was detected in the cortex and hippocampus, demonstrating COB231 blood-brain barrier permeability. We also controlled the cellular localisation of COB231 on primary neuronal cultures and showed that COB231 accumulates into the cytoplasm and not into the nucleus. Finally, using a viability assay, we only detected a slight cytotoxic effect of COB231 (<10%) for the highest concentration (100 μM).This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 09/2014; 132(5). DOI:10.1111/jnc.12951 · 4.24 Impact Factor
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    ABSTRACT: Purpose The αvβ3 integrin plays an important role in tumour-induced angiogenesis, tumour proliferation, survival and metastasis. The tetrameric RGD-based peptide, regioselectively addressable functionalized template-(cyclo-[RGDfK])4 (RAFT-RGD), specifically targets the αvβ3 integrin in vitro and in vivo. The aim of this study was to evaluate the therapeutic potential of RAFT-RGD radiolabelled with β− emitters in a nude mouse model of αvβ3 integrin-expressing tumours. Methods Biodistribution and SPECT/CT imaging studies were performed after injection of 90Y-RAFT-RGD or 177Lu-RAFT-RGD in nude mice subcutaneously xenografted with αvβ3 integrin-expressing U-87 MG cells. Experimental targeted radionuclide therapy with 90Y-RAFT-RGD or 177Lu-RAFT-RGD and 90Y-RAFT-RAD or 177Lu-RAFT-RAD (nonspecific controls) was evaluated by intravenous injection of the radionuclides into mice bearing αvβ3 integrin-expressing U-87 MG tumours of different sizes (small or large) or bearing TS/A-pc tumours that do not express αvβ3. Tumour volume doubling time was used to evaluate the efficacy of each treatment. Results Injection of 37 MBq of 90Y-RAFT-RGD into mice with large αvβ3-positive tumours or 37 MBq of 177Lu-RAFT-RGD into mice with small αvβ3-positive tumours caused significant growth delays compared to mice treated with 37 MBq of 90Y-RAFT-RAD or 37 MBq of 177Lu-RAFT-RAD or untreated mice. In contrast, injection of 30 MBq of 90Y-RAFT-RGD had no effect on the growth of αvβ3-negative tumours. Conclusion 90Y-RAFT-RGD and 177Lu-RAFT-RGD are potent agents targeting αvβ3-expressing tumours for internal targeted radiotherapy.
    European journal of nuclear medicine and molecular imaging 08/2014; 42(2). DOI:10.1007/s00259-014-2891-7 · 5.22 Impact Factor
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    ABSTRACT: 99mTc-cAbVCAM1-5, a single-domain antibody fragment directed against mouse or human vascular cell adhesion molecule 1 (VCAM- 1), recently has been proposed as a new imaging agent for the detection of inflamed atherosclerotic lesions. Indeed, in a mouse model of atherosclerosis, 99mTc-cAbVCAM1-5 specifically bound to VCAM- 1-positive lesions, thereby allowing their identification on SPECT images. The purpose of the present study was to investigate 99mTccAbVCAM1- 5 imaging sensitivity using a reference statin therapy.
    Journal of Nuclear Medicine 08/2014; 55(10). DOI:10.2967/jnumed.114.143792 · 5.56 Impact Factor
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    ABSTRACT: Background [18F]-fluorodeoxyglucose (FDG) has been suggested for the clinical and experimental imaging of inflammatory atherosclerotic lesions. Significant FDG uptake in brown adipose tissue (BAT) has been observed both in humans and mice. The objective of the present study was to investigate the influence of periaortic BAT on apolipoprotein E-deficient (apoE−/−) mouse atherosclerotic lesion imaging with FDG. Methods ApoE−/− mice (36±2 weeks-old) were injected with FDG (12±2 MBq). Control animals (Group A, n = 7) were injected conscious and kept awake at room temperature (24°C) throughout the accumulation period. In order to minimize tracer activity in periaortic BAT, Group B (n = 7) and C (n = 6) animals were injected under anaesthesia at 37°C and Group C animals were additionally pre-treated with propranolol. PET/CT acquisitions were performed prior to animal euthanasia and ex vivo analysis of FDG biodistribution. Results Autoradiographic imaging indicated higher FDG uptake in atherosclerotic lesions than in the normal aortic wall (all groups, P<0.05) and the blood (all groups, P<0.01) which correlated with macrophage infiltration (R = 0.47; P<0.001). However, periaortic BAT uptake was either significantly higher (Group A, P<0.05) or similar (Group B and C, P = NS) to that observed in atherosclerotic lesions and was shown to correlate with in vivo quantified aortic FDG activity. Conclusion Periaortic BAT FDG uptake was identified as a confounding factor while using FDG for the non-invasive imaging of mouse atherosclerotic lesions.
    PLoS ONE 07/2014; 9(7):e99441. DOI:10.1371/journal.pone.0099441 · 3.23 Impact Factor
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    ABSTRACT: The great clinical potential of myocardial β-AR imaging has been shown by recent studies evaluating the β-AR-specific, non-selective agent [(11)C]-CGP12177 in the setting of idiopathic-dilated cardiomyopathy, and myocardial infarction. However, the short half-life of (11)C hampers the potential of [(11)C]-CGP12177 for routine clinical use. AMI9 is an analog of the β-adrenoceptor ligand practolol that can readily be labeled using radioactive isotopes of iodine. The present study was aimed at characterizing the in vitro, ex vivo, and in vivo β-AR binding properties of [(125)I]-AMI9.
    Journal of Nuclear Cardiology 05/2014; 21(5). DOI:10.1007/s12350-014-9913-5 · 2.65 Impact Factor
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    ABSTRACT: L-Maurocalcine (L-MCa) is the first reported animal cell-penetrating toxin. Characterizing its cell penetration properties is crucial considering its potential as a vector for the intracellular delivery of drugs. Radiolabeling is a sensitive and quantitative method to follow the cell accumulation of a molecule of interest. An L-MCa analog containing an additional N-terminal tyrosine residue (Tyr-L-MCa) was synthesized, shown to fold and oxidize properly, and successfully radioiodinated to I-125-Tyr-L-MCa. Using various microscopy techniques, the average volume of the rat line F98 glioma cells was evaluated at 8.9 to 18.9 x 10(-7) mu l. I-125-Tyr-L-MCa accumulates within cells with a dose-dependency similar to the one previously published using 5,6-carboxyfluorescein-L-MCa. According to subcellular fractionation of F98 cells, plasma membranes keep less than 3% of the peptide, regardless of the extracellular concentration, while the nucleus accumulates over 75% and the cytosol around 20% of the radioactive material. Taking into account both nuclear and cytosolic fractions, cells accumulate intracellular concentrations of the peptide that are equal to the extracellular concentrations. Estimation of I-125-Tyr-L-MCa cell entry kinetics indicate a first rapid phase with a 5 min time constant for the plasma membrane followed by slower processes for the cytoplasm and the nucleus. Once inside cells, the labeled material no longer escapes from the intracellular environment since 90% of the radioactivity remains 24 h after washout. Dead cells were found to have a lower uptake than live ones. The quantitative information gained herein will be useful for better framing the use of L-MCa in biotechnological applications. This article is part of a Special Issue entitled: Calcium Signaling in Health and Disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau.
    Biochimica et Biophysica Acta 03/2014; 1843(10). DOI:10.1016/j.bbamcr.2014.03.017 · 4.66 Impact Factor
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    ABSTRACT: Mouse models of atherosclerosis are extensively being used to study the mechanisms of atherosclerotic plaque development and the results are frequently extrapolated to humans. However, major differences have been described between murine and human atherosclerotic lesions and the determination of similarities and differences between these species has been largely addressed recently. This study takes over and extends previous studies performed by our group and related to the biomechanical characterization of both mouse and human atherosclerotic lesions. Its main objective was to determine the distribution and amplitude of mechanical stresses including peak cap stress (PCS) in aortic vessels from atherosclerotic apoE(-/-) mice, in order to evaluate whether such biomechanical data would be in accordance with the previously suggested lack of plaque rupture in this model. Successful finite element analysis was performed from the zero-stress configuration of aortic arch sections and mainly indicated (1) the modest role of atherosclerotic lesions in the observed increase in residual parietal stresses in apoE(-/-) mouse vessels and (2) the low amplitude of murine PCS as compared to humans. Overall, the results from the present study support the hypothesis that murine biomechanical properties and artery size confer less propensity to rupture for mouse lesions in comparison with those of humans.
    Journal of Biomechanics 01/2014; DOI:10.1016/j.jbiomech.2014.01.020 · 2.75 Impact Factor
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    ABSTRACT: Mono-and poly-iodinated peptides form frequently during radioiodination procedures. However, the formation of a single species in its mono-iodinated form is essential for quantitative studies such as determination of tissue concentration or image quantification. Therefore, the aim of the present study was to define the optimal experimental conditions in order to exclusively obtain the mono-iodinated form of L-maurocalcine (L-MCa). L-MCa is an animal venom toxin which was shown to act as a cell-penetrating peptide. In order to apply the current direct radioiodination technique using oxidative agents including chloramine T, Iodo-Gen (R) or lactoperoxidase, an analogue of this peptide containing a tyrosine residue (Tyr-L-MCa) was synthesized and was shown to fold/oxidize properly. The enzymatic approach using lactoperoxidase/H2O2 was found to be the best method for radioiodination of Tyr-LMCa. MALDI-TOF mass spectrometry analyses were then used for identification of the chromatographic eluting components of the reaction mixtures. We observed that the production of different radioiodinated species depended upon the reaction conditions. Our results successfully described the experimental conditions of peptide radioiodination allowing the exclusive production of the mono-iodinated form with high radiochemical purity and without the need for a purification step. Mono-radioiodination of L-Tyr-MCa will be crucial for future quantitative studies, investigating the mechanism of cell penetration and in vivo biodistribution.
    Radiochimica Acta 01/2014; 102(11). DOI:10.1515/ract-2013-2238 · 1.41 Impact Factor
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    IEEE NSS-MIC-RTSD, Seoul; 10/2013
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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; 54(8). DOI:10.2967/jnumed.112.115675 · 5.56 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; DOI:10.2174/138161281939131127122054 · 3.29 Impact Factor
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    ABSTRACT: The industrial development of active immunotherapy based on live-attenuated bacterial vectors has matured. We developed a microsyringe for antigen delivery based on the type III secretion system (T3SS) of P. aeruginosa. We applied the "killed but metabolically active" (KBMA) attenuation strategy to make this bacterial vector suitable for human use. We demonstrate that attenuated P. aeruginosa has the potential to deliver antigens to human antigen-presenting cells in vitro via T3SS with considerable attenuated cytotoxicity as compared with the wild-type vector. In a mouse model of cancer, we demonstrate that this KBMA strain, which cannot replicate in its host, efficiently disseminates into lymphoid organs and delivers its heterologous antigen. The attenuated strain effectively induces a cellular immune response to the cancerous cells while lowering the systemic inflammatory response. Hence, a KBMA P. aeruginosa microsyringe is an efficient and safe tool for in vivo antigen delivery.Molecular Therapy (2013); doi:10.1038/mt.2013.41.
    Molecular Therapy 03/2013; 21(5). DOI:10.1038/mt.2013.41 · 6.43 Impact Factor
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    Archives of Cardiovascular Diseases Supplements 01/2013; 5(1):38-39. DOI:10.1016/S1878-6480(13)71047-4
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    Dataset: 2313suppl
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    ABSTRACT: Purpose In vivo imaging of GABAA receptors is essential for the comprehension of psychiatric disorders in which the GABAergic system is implicated. Small animal SPECT provides a modality for in vivo imaging of the GABAergic system in rodents using [123I]Iomazenil, an antagonist of the GABAA receptor. The goal of this work is to describe and evaluate different quantitative reference tissue methods that enable reliable binding potential (BP) estimations in the rat brain to be obtained. Methods Five male Sprague-Dawley rats were used for [123I]Iomazenil brain SPECT scans. Binding parameters were obtained with a 1-tissue compartment model (1TC), a constrained 2-tissue compartment model (2TCc), the two-step Simplified Reference Tissue Model (SRTM2), Logan graphical analysis and analysis of delayed activity images. In addition, we employed Factor Analysis (FA) to deal with noise in data. Results BPND obtained with SRTM2, Logan graphical analysis and delayed activity analysis was highly correlated with BPF values obtained with 2TCc (r = 0.954 and 0.945 respectively, p < 0.0001). Equally significant correlations were found between values obtained with 2TCc and SRTM2 in raw and FA-denoised images (r = 0.961 and 0.909 respectively, p < 0.0001). Scans of at least 100 minutes are required to obtain stable BPND values from raw images while scans of only 70 minutes are sufficient from FA-denoised images. These images are also associated with significantly lower standard errors of 2TCc and SRTM2 BP values. Conclusion Reference tissue methods such as SRTM2 and Logan graphical analysis can provide equally reliable BPND values from rat brain [123I]Iomazenil SPECT. Acquisitions, however, can be much less time-consuming either with analysis of delayed activity obtained from a 20-minute scan 50 min after tracer injection or with FA-denoising of images.
    Nuclear Medicine and Biology 01/2013; DOI:10.1016/j.nucmedbio.2013.11.008 · 2.41 Impact Factor
  • Cancer Science 06/2012; 103(6):Junecover. DOI:10.1111/j.1349-7006.2012.02278.x · 3.53 Impact Factor

Publication Stats

485 Citations
235.68 Total Impact Points

Institutions

  • 2007–2014
    • Unité Inserm U1077
      Caen, Lower Normandy, France
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2003–2014
    • University of Grenoble
      Grenoble, Rhône-Alpes, France
  • 1990–2014
    • University Joseph Fourier - Grenoble 1
      • Laboratoire de Radiopharmaceutiques Biocliniques
      Grenoble, Rhône-Alpes, France
  • 2004
    • Centre Hospitalier Universitaire de Grenoble
      Grenoble, Rhône-Alpes, France