172 results on '"Mather SJ"'
Search Results
2. Hybridization and cell uptake studies with radiolabelled antisense oligonucleotides
- Author
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M. A. Stalteri and Mather Sj
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Base Sequence ,Oligonucleotide ,Chemistry ,Cell ,Genes, myc ,Technetium ,Biological Transport ,General Medicine ,Molecular biology ,In vitro ,Cell Line ,Oligodeoxyribonucleotides, Antisense ,Rats ,Kinetics ,medicine.anatomical_structure ,In vivo ,Cell culture ,Gene expression ,medicine ,Animals ,Radiology, Nuclear Medicine and imaging ,RNA, Messenger ,Fibroblast ,Phosphorus Radioisotopes ,Intracellular - Abstract
Background Radiolabelled antisense oligonucleotides have been proposed as radiopharmaceuticals for imaging changes in the level of gene expression in vivo. This paper describes a study of the uptake of radiolabelled oligonucleotides in cell lines expressing different levels of the target mRNA. Methods A 15-mer phosphorodiester deoxyoligonucleotide antisense to c-myc was labelled with 99m Tc and 32 P. Hybridization and stability studies were performed in vitro. Cell uptake studies were carried out in a c-myc expressing transformed rat embryonic fibroblast cell-line, TGR-1, and a knock-out cell line HO15.19 which does not express c-myc. Results The oligonucleotides were efficiently labelled with both radionuclides and retained their ability to hybridize with their complementary mRNA when extracted from cell lines. The radiolabelled oligonucleotides were stable for a few hours in human serum. No statistically significant difference was found between the uptake of radioactivity by the two cell lines. Conclusions Although able to bind efficiently to their target in cell-free systems, radiolabelled oligonucleotides may be prevented from performing effectively as radiopharmaceutical vectors by the barriers imposed by cell membranes and/or intracellular metabolism.
- Published
- 2001
3. Radiolabelled peptides - promises and pitfalls
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Mather Sj
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Chemistry ,Neoplasms ,Indium Radioisotopes ,Humans ,Radiology, Nuclear Medicine and imaging ,Receptors, Somatostatin ,General Medicine ,Radiopharmaceuticals ,Peptides ,Radionuclide Imaging ,Somatostatin - Published
- 2000
4. Detection of pancreatic insulitis by 99mTc-IL2 scintigraphy in newly diagnosed type 1 dabetes patients: prediction of response to immunotherapy
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Chianelli, M, Parisella, Mg, Mather, Sj, Visalli, N, Annovazzi, A, Giacalone, P, Capriotti, Gabriela, Corsetti, F, Pozzilli, P, and Signore, Alberto
- Published
- 2000
5. Genetic engineering of pharmacologically regulated T cells, specific for breast cancer target antigens
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Wilkie, S, primary, Burbridge, S, additional, Davies, DM, additional, Chiapero-Stanke, L, additional, Foster, J, additional, Mather, SJ, additional, and Maher, J, additional
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- 2010
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6. 99mTc-labelled SM3 in the preoperative evaluation of axillary lymph nodes and primary breast cancer with change detection statistical processing as an aid to tumour detection
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Biassoni, L, primary, Granowska, M, additional, Carroll, MJ, additional, Mather, SJ, additional, Howell, R, additional, Ellison, D, additional, MacNeill, FA, additional, Wells, CA, additional, Carpenter, R, additional, and Britton, KE, additional
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- 1998
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7. Insertion of a lysosomal enzyme cleavage site into the sequence of a radiolabeled neuropeptide influences cell trafficking in vitro and in vivo.
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Naqvi SA, Matzow T, Finucane C, Nagra SA, Ishfaq MM, Mather SJ, Sosabowski J, Naqvi, Syed Ali Raza, Matzow, Torkjel, Finucane, Ciara, Nagra, Saeed A, Ishfaq, Malik M, Mather, Stephen J, and Sosabowski, Jane
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- 2010
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8. Radiopharmaceutical licensing revisited
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Mather Sj
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Text mining ,business.industry ,Computer science ,Radiology, Nuclear Medicine and imaging ,General Medicine ,Nuclear Medicine ,Legislation, Drug ,business ,Data science ,United Kingdom - Published
- 1993
9. Synthesis of Tc-99m-Hynic-interleukin-12, a new radiopharmaceutical for imaging Th-1-lymphocytes
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Annovazzi, A., Mather, Sj, Cornelissen, B., Slegers, G., D Alessandria, C., Bonanno, E., Mattei, M., Scopinaro, F., and Alberto Signore
10. Tc(99m)-EDDA/HYNIC-Tyr(3)-octreotide: Pharmacokinetics in rats and comparison with In(111)-DTPA-octreotide
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Laznicek, M., Alice Laznickova, Decristoforo, C., and Mather, Sj
11. Structural-dependent elimination of the small peptide complexes with 99mTc
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Trejtnar, F., Laznicek, M., Alice Laznickova, and Mather, Sj
12. Pharmacokinetics and renal handling of Tc-99m-labeled peptides
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Trejtnar, F., Milan Laznicek, Laznickova, A., and Mather, Sj
13. Selective inhibition of prostaglandin biosynthesis by gold salts and phenylbutazone
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Stone, KJ, primary, Mather, SJ, additional, and Gibson, PP, additional
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- 1975
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14. Obstructive sleep apnea risk factors and symptoms in children with a known parental obstructive sleep apnea diagnosis.
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Campbell AJ, Mather SJ, and Elder DE
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- Child, Humans, Overweight, Parents, Polysomnography, Risk Factors, Sleep Apnea, Obstructive diagnosis, Sleep Apnea, Obstructive epidemiology
- Abstract
Objective: To document symptoms and risk factors of obstructive sleep apnea (OSA) in children who have a parent diagnosed with OSA and compare them to an age and sex matched sample where parents are low risk for OSA., Methods: We recruited 25 children with a parent diagnosed with OSA (P-OSA) and 29 age and gender matched children from the community whose parents scored low risk for OSA (P-NOSA). Comparisons were made using the OSA-18 questionnaire, anthropometric measurements, and mallampati score. Statistical analysis included t-tests for OSA-18 score and BMI measures and non parametric analysis for mallampati score. OSA-18 domain scores were analysed using T-test and Bonferroni correction for multiple comparisons., Results: Fifty-six percent of the P-OSA group had a mallampati score of III/IV compared to 11% in the P-NOSA sample (p = 0.005). There was a significant difference in BMI between the P-OSA sample (mean ± SD 19.5 ± 5.7 kg/m
2 ) and the P-NOSA sample (16.95 ± 2.08 kg/m2 , p = 0.002). Forty-four percent of P-OSA children were found to be either overweight or obese (BMI z-score). None of the P-NOSA children fell into this category. No significant difference was found between the P-OSA and P-NOSA samples on the OSA-18 score (P-OSA 36.5 ± 8.1, P-NOSA 29.2 ± 9.1, p = 0.07). Five children in the P-OSA sample scored >60 but no P-NOSA children scored >60., Conclusions: This study suggests that children with a parent diagnosed with OSA are more likely to have risk factors of pediatric OSA compared to age and sex matched children of parents without OSA but do not have more symptoms., (Copyright © 2021 Elsevier B.V. All rights reserved.)- Published
- 2021
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15. High-throughput high-volume nuclear imaging for preclinical in vivo compound screening § .
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Macholl S, Finucane CM, Hesterman J, Mather SJ, Pauplis R, Scully D, Sosabowski JK, and Jouannot E
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Background: Preclinical single-photon emission computed tomography (SPECT)/CT imaging studies are hampered by low throughput, hence are found typically within small volume feasibility studies. Here, imaging and image analysis procedures are presented that allow profiling of a large volume of radiolabelled compounds within a reasonably short total study time. Particular emphasis was put on quality control (QC) and on fast and unbiased image analysis., Methods: 2-3 His-tagged proteins were simultaneously radiolabelled by
99m Tc-tricarbonyl methodology and injected intravenously (20 nmol/kg; 100 MBq; n = 3) into patient-derived xenograft (PDX) mouse models. Whole-body SPECT/CT images of 3 mice simultaneously were acquired 1, 4, and 24 h post-injection, extended to 48 h and/or by 0-2 h dynamic SPECT for pre-selected compounds. Organ uptake was quantified by automated multi-atlas and manual segmentations. Data were plotted automatically, quality controlled and stored on a collaborative image management platform. Ex vivo uptake data were collected semi-automatically and analysis performed as for imaging data., Results: >500 single animal SPECT images were acquired for 25 proteins over 5 weeks, eventually generating >3500 ROI and >1000 items of tissue data. SPECT/CT images clearly visualized uptake in tumour and other tissues even at 48 h post-injection. Intersubject uptake variability was typically 13% (coefficient of variation, COV). Imaging results correlated well with ex vivo data., Conclusions: The large data set of tumour, background and systemic uptake/clearance data from 75 mice for 25 compounds allows identification of compounds of interest. The number of animals required was reduced considerably by longitudinal imaging compared to dissection experiments. All experimental work and analyses were accomplished within 3 months expected to be compatible with drug development programmes. QC along all workflow steps, blinding of the imaging contract research organization to compound properties and automation provide confidence in the data set. Additional ex vivo data were useful as a control but could be omitted from future studies in the same centre. For even larger compound libraries, radiolabelling could be expedited and the number of imaging time points adapted to increase weekly throughput. Multi-atlas segmentation could be expanded via SPECT/MRI; however, this would require an MRI-compatible mouse hotel. Finally, analysis of nuclear images of radiopharmaceuticals in clinical trials may benefit from the automated analysis procedures developed.- Published
- 2017
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16. Evaluation and comparison of a new DOTA and DTPA-bombesin agonist in vitro and in vivo in low and high GRPR expressing prostate and breast tumor models.
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Pujatti PB, Foster JM, Finucane C, Hudson CD, Burnet JC, Pasqualoto KFM, Mengatti J, Mather SJ, de Araújo EB, and Sosabowski JK
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- Animals, Bombesin chemistry, Cell Line, Tumor, Drug Stability, Female, Heterografts, Humans, In Vitro Techniques, Indium Radioisotopes, Male, Mice, SCID, Neoplasm Transplantation, Radionuclide Imaging, Tissue Distribution, Bombesin analogs & derivatives, Breast Neoplasms diagnostic imaging, Breast Neoplasms metabolism, Heterocyclic Compounds, 1-Ring, Pentetic Acid analogs & derivatives, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms metabolism, Radiopharmaceuticals chemistry, Receptors, Bombesin metabolism
- Abstract
We evaluated and compared a new bombesin analog [Tyr-Gly5, Nle(14)]-BBN(6-14) conjugated to DOTA or DTPA and radiolabeled with In-111 in low and high GRPR expressing tumor models. Both peptides were radiolabeled with high radiochemical purity and specific activity. In vitro assays on T-47D, LNCaP and PC-3 cells showed that the affinity of peptides is similar and a higher binding and internalization of DOTA-peptide to PC-3 cells was observed. Both peptides could target PC-3 and LNCaP tumors in vivo and both tumor types could be visualized by microSPECT/CT., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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17. GRP receptor imaging of prostate cancer using [(99m)Tc]Demobesin 4: a first-in-man study.
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Mather SJ, Nock BA, Maina T, Gibson V, Ellison D, Murray I, Sobnack R, Colebrook S, Wan S, Halberrt G, Szysko T, Powles T, and Avril N
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- Aged, Bombesin pharmacokinetics, Humans, Male, Middle Aged, Tomography, Emission-Computed, Single-Photon, Tomography, X-Ray Computed, Whole Body Imaging, Bombesin analogs & derivatives, Organotechnetium Compounds pharmacokinetics, Prostatic Neoplasms diagnostic imaging, Radiopharmaceuticals pharmacokinetics, Receptors, Bombesin metabolism
- Abstract
Purpose: We explored the imaging of bombesin receptors and evaluated the clinical use of [(99m)Tc]Demobesin 4 ([(99m)Tc]DB4) in prostate cancer patients., Procedures: [(99m)Tc]DB4 was prepared according to Good Manufacturing Practice. Patients with prostate cancer underwent serial planar and SPECT imaging up to 3 h after administration. Blood and urine samples were taken to assess pharmacokinetics., Results: [(99m)Tc]DB4 is safe and clears rapidly from the bloodstream via the kidneys resulting in low background activity. The tracer binds strongly to the gastrin-releasing peptide receptor (GRPR) in vivo as indicated by the high uptake in the pancreas seen in all patients. In patients who had undergone hormone therapy, [(99m)Tc]DB4 did not efficiently image metastatic prostate cancer. In contrast, in newly diagnosed patients local disease was visualised., Conclusions: The GRPR is an unsuitable target for imaging refractory prostate cancer but may be useful in untreated disease. [(99m)Tc]DB4 is a promising radiopharmaceutical which merits further exploration in this specific group of patients.
- Published
- 2014
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18. PET and SPECT imaging of a radiolabeled minigastrin analogue conjugated with DOTA, NOTA, and NODAGA and labeled with (64)Cu, (68)Ga, and (111)In.
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Roosenburg S, Laverman P, Joosten L, Cooper MS, Kolenc-Peitl PK, Foster JM, Hudson C, Leyton J, Burnet J, Oyen WJ, Blower PJ, Mather SJ, Boerman OC, and Sosabowski JK
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- Animals, Cell Line, Tumor, Chelating Agents chemistry, Female, Humans, Inhibitory Concentration 50, Mice, Mice, SCID, Multimodal Imaging, Neoplasm Transplantation, Peptides chemistry, Positron-Emission Tomography, Radiopharmaceuticals chemistry, Receptor, Cholecystokinin B metabolism, Tomography, Emission-Computed, Single-Photon, Tomography, X-Ray Computed, Acetates pharmacology, Copper Radioisotopes chemistry, Gallium Radioisotopes chemistry, Gastrins chemistry, Heterocyclic Compounds pharmacology, Heterocyclic Compounds, 1-Ring pharmacology, Indium Radioisotopes chemistry
- Abstract
Cholecystokinin-2 (CCK-2) receptors, overexpressed in cancer types such as small cell lung cancers (SCLC) and medullary thyroid carcinomas (MTC), may serve as targets for peptide receptor radionuclide imaging. A variety of CCK and gastrin analogues has been developed, but a major drawback is metabolic instability or high kidney uptake. The minigastrin analogue PP-F11 has previously been shown to be a promising peptide for imaging of CCK-2 receptor positive tumors and was therefore further evaluated. The peptide was conjugated with one of the macrocyclic chelators DOTA, NOTA, or NODAGA. The peptide conjugates were then radiolabeled with either (68)Ga, (64)Cu, or (111)In. All (radio)labeled compounds were evaluated in vitro (IC50) and in vivo (biodistribution and PET/CT and SPECT/CT imaging). IC50 values were in the low nanomolar range for all compounds (0.79-1.51 nM). In the biodistribution studies, (68)Ga- and (111)In-labeled peptides showed higher tumor-to-background ratios than the (64)Cu-labeled compounds. All tested radiolabeled compounds clearly visualized the CCK2 receptor positive tumor in PET or SPECT imaging. The chelator did not seem to affect in vivo behavior of the peptide for (111)In- and (68)Ga-labeled peptides. In contrast, the biodistribution of the (64)Cu-labeled peptides showed high uptake in the liver and in other organs, most likely caused by high blood levels, probably due to dissociation of (64)Cu from the chelator and subsequent transchelation to proteins. Based on the present study, (68)Ga-DOTA-PP-F11 might be a promising radiopharmaceutical for PET/CT imaging of CCK2 receptor expressing tumors such as MTC and SCLC. Clinical studies are warranted to investigate the potential of this tracer.
- Published
- 2014
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19. The relationship between the diameter of chemically-functionalized multi-walled carbon nanotubes and their organ biodistribution profiles in vivo.
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Wang JT, Fabbro C, Venturelli E, Ménard-Moyon C, Chaloin O, Da Ros T, Methven L, Nunes A, Sosabowski JK, Mather SJ, Robinson MK, Amadou J, Prato M, Bianco A, Kostarelos K, and Al-Jamal KT
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- Animals, Diagnostic Imaging methods, Drug Delivery Systems, Mice, Microscopy, Electron, Transmission, Particle Size, Surface Plasmon Resonance, Tissue Distribution, Immunoglobulin Fab Fragments metabolism, Immunoglobulin G metabolism, Nanotubes, Carbon chemistry
- Abstract
Carbon nanotubes (CNTs) exhibit unique properties which have led to their applications in the biomedical field as novel delivery systems for diagnosis and therapy purposes. We have previously reported that the degree of functionalization of CNTs is a key factor determining their biological behaviour. The present study broadens the spectrum by investigating the impact of the diameter of CNTs using two series of multi-walled CNTs (MWNTs) with distinct differences in their diameters. Both MWNTs were doubly functionalized by 1,3-dipolar cycloaddition and amidation reactions, allowing the appended functional groups to be further conjugated with radionuclide chelating moieties and antibodies or antibody fragments. All constructs possessed comparable degree of functionalization and were characterized by thermogravimetric analysis, transmission electron microscopy, gel electrophoresis and surface plasmon resonance. The MWNT conjugates were radio-labelled with indium-111, which thereby enabled in vivo single photon emission computed tomography/computed tomography (SPECT/CT) imaging and organ biodistribution study using γ-scintigraphy. The narrow MWNTs (average diameter: 9.2 nm) demonstrated enhanced tissue affinity including non-reticular endothelial tissues compared to the wider MWNTs (average diameter: 39.5 nm). The results indicate that the higher aspect ratio of narrow MWNTs may be beneficial for their future biological applications due to higher tissue accumulation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
- Full Text
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20. Resistance to the tyrosine kinase inhibitor axitinib is associated with increased glucose metabolism in pancreatic adenocarcinoma.
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Hudson CD, Hagemann T, Mather SJ, and Avril N
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- Adenocarcinoma enzymology, Adenocarcinoma pathology, Animals, Axitinib, Cell Membrane drug effects, Cell Membrane metabolism, Cell Proliferation drug effects, Cell Shape drug effects, Cell Survival drug effects, Clone Cells, Enzyme Activation drug effects, G2 Phase Cell Cycle Checkpoints drug effects, Glucose Transporter Type 1 metabolism, Heterocyclic Compounds, 3-Ring pharmacology, Humans, Imidazoles pharmacology, Indazoles pharmacology, Mice, Mitosis drug effects, Pancreatic Neoplasms enzymology, Pancreatic Neoplasms pathology, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-akt metabolism, Adenocarcinoma drug therapy, Adenocarcinoma metabolism, Drug Resistance, Neoplasm drug effects, Glucose metabolism, Imidazoles therapeutic use, Indazoles therapeutic use, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms metabolism
- Abstract
Alterations in energy (glucose) metabolism are key events in the development and progression of cancer. In pancreatic adenocarcinoma (PDAC) cells, we investigated changes in glucose metabolism induced by resistance to the receptor tyrosine kinase inhibitor (RTKI) axitinib. Here, we show that human cell lines and mouse PDAC cell lines obtained from the spontaneous pancreatic cancer mouse model (Kras(G12D)Pdx1-cre) were sensitive to axitinib. The anti-proliferative effect was due to a G2/M block resulting in loss of 70-75% cell viability in the most sensitive PDAC cell line. However, a surviving sub-population showed a 2- to 3-fold increase in [C-14]deoxyglucose ([C-14]DG) uptake. This was sustained in axitinib-resistant cell lines, which were derived from parental PDAC. In addition to the axitinib-induced increase in [C-14]DG uptake, we observed a translocation of glucose transporter-1 (Glut-1) transporters from cytosolic pools to the cell surface membrane and a 2-fold increase in glycolysis rates measured by the extracellular acidification rate (ECAR). We demonstrated an axitinib-induced increase in phosphorylated Protein Kinase B (pAkt) and by blocking pAkt with a phosphatidylinositol-3 kinase (PI3K) inhibitor we reversed the Glut-1 translocation and restored sensitivity to axitinib treatment. Combination treatment with both axitinib and Akt inhibitor in parental pancreatic cell line resulted in a decrease in cell viability beyond that conferred by single therapy alone. Our study shows that PDAC resistance to axitinib results in increased glucose metabolism mediated by activated Akt. Combining axitinib and an Akt inhibitor may improve treatment in PDAC.
- Published
- 2014
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21. Magnetically Decorated Multi-Walled Carbon Nanotubes as Dual MRI and SPECT Contrast Agents.
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Wang JT, Cabana L, Bourgognon M, Kafa H, Protti A, Venner K, Shah AM, Sosabowski J, Mather SJ, Roig A, Ke X, Tendeloo GV, de Rosales RTM, Tobias G, and Al-Jamal KT
- Abstract
Carbon nanotubes (CNTs) have been proposed as one of the most promising nanomaterials to be used in biomedicine for their applications in drug/gene delivery as well as biomedical imaging. The present study developed radio-labeled iron oxide decorated multi-walled CNTs (MWNT) as dual magnetic resonance (MR) and single photon emission computed tomography (SPECT) imaging agents. Hybrids containing different amounts of iron oxide were synthesized by in situ generation. Physicochemical characterisations revealed the presence of superparamagnetic iron oxide nanoparticles (SPION) granted the magnetic properties of the hybrids. Further comprehensive examinations including high resolution transmission electron microscopy (HRTEM), fast Fourier transform simulations (FFT), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) assured the conformation of prepared SPION as γ-Fe
2 O3 . High r2 relaxivities were obtained in both phantom and in vivo MRI compared to the clinically approved SPION Endorem® . The hybrids were successfully radio-labeled with technetium-99m through a functionalized bisphosphonate and enabled SPECT/CT imaging and γ-scintigraphy to quantitatively analyze the biodistribution in mice. No abnormality was found by histological examination and the presence of SPION and MWNT were identified by Perls stain and Neutral Red stain, respectively. TEM images of liver and spleen tissues showed the co-localization of SPION and MWNT within the same intracellular vesicles, indicating the in vivo stability of the hybrids after intravenous injection. The results demonstrated the capability of the present SPION-MWNT hybrids as dual MRI and SPECT contrast agents for in vivo use.- Published
- 2014
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22. Identification of ZDHHC14 as a novel human tumour suppressor gene.
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Yeste-Velasco M, Mao X, Grose R, Kudahetti SC, Lin D, Marzec J, Vasiljević N, Chaplin T, Xue L, Xu M, Foster JM, Karnam SS, James SY, Chioni AM, Gould D, Lorincz AT, Oliver RT, Chelala C, Thomas GM, Shipley JM, Mather SJ, Berney DM, Young BD, and Lu YJ
- Subjects
- Acyltransferases metabolism, Animals, Apoptosis, Cell Line, Tumor, Cell Proliferation, Cell Survival, Down-Regulation, Gene Deletion, Gene Expression Profiling methods, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Male, Mice, Mice, Nude, Neoplasms, Germ Cell and Embryonal enzymology, Neoplasms, Germ Cell and Embryonal pathology, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Prostatic Neoplasms enzymology, Prostatic Neoplasms pathology, Prostatic Neoplasms prevention & control, RNA Interference, Testicular Neoplasms enzymology, Testicular Neoplasms pathology, Time Factors, Transfection, Tumor Burden, Acyltransferases genetics, Genes, Tumor Suppressor, Neoplasms, Germ Cell and Embryonal genetics, Prostatic Neoplasms genetics, Testicular Neoplasms genetics
- Abstract
Genomic changes affecting tumour suppressor genes are fundamental to cancer. We applied SNP array analysis to a panel of testicular germ cell tumours to search for novel tumour suppressor genes and identified a frequent small deletion on 6q25.3 affecting just one gene, ZDHHC14. The expression of ZDHHC14, a putative protein palmitoyltransferase with unknown cellular function, was decreased at both RNA and protein levels in testicular germ cell tumours. ZDHHC14 expression was also significantly decreased in a panel of prostate cancer samples and cell lines. In addition to our findings of genetic and protein expression changes in clinical samples, inducible overexpression of ZDHHC14 led to reduced cell viability and increased apoptosis through the classic caspase-dependent apoptotic pathway and heterozygous knockout of ZDHHC14 increased [CORRECTED] cell colony formation ability. Finally, we confirmed our in vitro findings of the tumour suppressor role of ZDHHC14 in a mouse xenograft model, showing that overexpression of ZDHHC14 inhibits tumourigenesis. Thus, we have identified a novel tumour suppressor gene that is commonly down-regulated in testicular germ cell tumours and prostate cancer, as well as given insight into the cellular functional role of ZDHHC14, a potential protein palmitoyltransferase that may play a key protective role in cancer., (© 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)
- Published
- 2014
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23. Generation and characterization of a diabody targeting the αvβ6 integrin.
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Kogelberg H, Miranda E, Burnet J, Ellison D, Tolner B, Foster J, Picón C, Thomas GJ, Meyer T, Marshall JF, Mather SJ, and Chester K
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- Animals, Antibody Specificity, Antigens, Neoplasm metabolism, Cell Line, Female, Gene Expression Regulation, Neoplastic, Humans, Immunoglobulin Fragments chemistry, Integrins metabolism, Isotope Labeling, Mice, Pichia genetics, Recombinant Proteins chemistry, Skin Neoplasms metabolism, Technetium chemistry, Antigens, Neoplasm immunology, Immunoglobulin Fragments genetics, Immunoglobulin Fragments immunology, Integrins immunology, Protein Engineering, Recombinant Proteins genetics, Recombinant Proteins immunology
- Abstract
The αvβ6 integrin is up-regulated in cancer and wound healing but it is not generally expressed in healthy adult tissue. There is increasing evidence that it has a role in cancer progression and will be a useful target for antibody-directed cancer therapies. We report a novel recombinant diabody antibody fragment that targets specifically αvβ6 and blocks its function. The diabody was engineered with a C-terminal hexahistidine tag (His tag), expressed in Pichia pastoris and purified by IMAC. Surface plasmon resonance (SPR) analysis of the purified diabody showed affinity in the nanomolar range. Pre-treatment of αvβ6-expressing cells with the diabody resulted in a reduction of cell migration and adhesion to LAP, demonstrating biological function-blocking activity. After radio-labeling, using the His-tag for site-specific attachment of (99m)Tc, the diabody retained affinity and targeted specifically to αvβ6-expressing tumors in mice bearing isogenic αvβ6 +/- xenografts. Furthermore, the diabody was specifically internalized into αvβ6-expressing cells, indicating warhead targeting potential. Our results indicate that the new αvβ6 diabody has a range of potential applications in imaging, function blocking or targeted delivery/internalization of therapeutic agents.
- Published
- 2013
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24. Structural guided scaffold phage display libraries as a source of bio-therapeutics.
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Man YK, DiCara D, Chan N, Vessillier S, Mather SJ, Rowe ML, Howard MJ, Marshall JF, and Nissim A
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- Algorithms, Amino Acid Sequence, Animals, Antigens, Neoplasm genetics, Antigens, Neoplasm metabolism, Binding Sites, Female, Humans, Integrins genetics, Integrins metabolism, Ligands, Magnetic Resonance Spectroscopy, Mice, Mice, Nude, Models, Molecular, Molecular Sequence Data, Oligopeptides genetics, Oligopeptides metabolism, Protein Binding, Protein Structure, Secondary, Protein Structure, Tertiary, Single-Chain Antibodies metabolism, Single-Chain Antibodies pharmacology, Structural Homology, Protein, Tumor Burden drug effects, Xenograft Model Antitumor Assays, Antigens, Neoplasm chemistry, Integrins chemistry, Oligopeptides chemistry, Peptide Library, Single-Chain Antibodies chemistry
- Abstract
We have developed a structurally-guided scaffold phage display strategy for identification of ligand mimetic bio-therapeutics. As a proof of concept we used the ligand of integrin αvβ6, a tumour cell surface receptor and a major new target for imaging and therapy of many types of solid cancer. NMR structure analysis showed that RGD-helix structures are optimal for αvβ6 ligand-interaction, so we designed novel algorithms to generate human single chain fragment variable (scFv) libraries with synthetic VH-CDR3 encoding RGD-helix hairpins with helices of differing pitch, length and amino acid composition. Study of the lead scFv clones D25scFv and D34scFv and their corresponding VH-CDR3 derived peptides, D25p and D34p, demonstrated: specific binding to recombinant and cellular αvβ6; inhibition of αvβ6-dependent cell and ligand adhesion, αvβ6-dependent cell internalisation; and selective retention by αvβ6-expressing, but not αvβ6-negative, human xenografts. NMR analysis established that both the D25p and D34p retained RGD-helix structures confirming the success of the algorithm. In conclusion, scFv libraries can be engineered based on ligand structural motifs to increase the likelihood of developing powerful bio-therapeutics.
- Published
- 2013
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25. Novel indium-111 labeled gastrin peptide analogues (MG-CL1-4): synthesis and quality control.
- Author
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Naqvi SA, Khan ZA, Nagra SA, Yar M, Sherazi TA, Shahzad SS, Shah SQ, Mahmood N, Ishfaq MM, and Mather SJ
- Subjects
- Gastrins blood, Gastrins standards, Humans, Hydrogen-Ion Concentration, Oxidation-Reduction, Protein Stability, Quality Control, Temperature, Time Factors, Gastrins chemical synthesis, Indium Radioisotopes, Isotope Labeling standards
- Abstract
Radiolabeled neuropeptides are widely investigated to diagnose and therapy of tumors. These peptides get internalization after binding with particular receptors at the surface of cells and finally move to lysosome. Internalization into tumor cells helps in mapping the infected site. Minigastrin peptide analogues (MG-CL1-4) were synthesised and labeled with 111-In radioisotope under different sets of conditions for imaging CCk-2 receptor bearing tumors. Different parameters such as temperature (80-100°C), pH (4-12), incubation time (5-30 minutes) and dilution effect were investigated to get the maximum labeling yield and stability. The results indicated that MG-CL1-4 is successfully labeled with indium-111 at pH 4.5 with heating at 98°C for 15 minute. At these conditions i.e. heating, pH and incubation minimum oxidized and maximum labeling yield, more than 94 %, was obtained. The labeling stability was studied by incubating the radiolabeled complex for predefined time points in PBSA and blood serum. Results show that more than 90% radiolabeled MG-CL1-4 remained intact.
- Published
- 2013
26. Targeted delivery of cytokine therapy to rheumatoid tissue by a synovial targeting peptide.
- Author
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Wythe SE, DiCara D, Taher TE, Finucane CM, Jones R, Bombardieri M, Man YK, Nissim A, Mather SJ, Chernajovsky Y, and Pitzalis C
- Subjects
- Animals, Disease Models, Animal, Humans, Mice, Mice, SCID, Multimodal Imaging, Peptides administration & dosage, Positron-Emission Tomography, Synovial Membrane drug effects, Synovial Membrane metabolism, Tomography, X-Ray Computed, Transplantation, Heterologous, Arthritis, Rheumatoid drug therapy, Cytokines administration & dosage, Drug Delivery Systems methods, Immunotherapy methods, Interleukin-4 administration & dosage, Recombinant Fusion Proteins administration & dosage
- Abstract
Objectives: The synovial endothelium targeting peptide (SyETP) CKSTHDRLC has been identified previously and was shown to preferentially localise to synovial xenografts in the human/severe combined immunodeficient (SCID) mouse chimera model of rheumatoid arthritis (RA). The objective of the current work was to generate SyETP-anti-inflammatory-cytokine fusion proteins that would deliver bioactive cytokines specifically to human synovial tissue., Methods: Fusion proteins consisting of human interleukin (IL)-4 linked via a matrix metalloproteinase (MMP)-cleavable sequence to multiple copies of either SyETP or scrambled control peptide were expressed in insect cells, purified by Ni-chelate chromatography and bioactivity tested in vitro. The ability of SyETP to retain bioactive cytokine in synovial but not control skin xenografts in SCID mice was determined by in vivo imaging using nano-single-photon emission computed tomography-computed tomography (nano-SPECT-CT) and measuring signal transducer and activator of transcription 6 (STAT6) phosphorylation in synovial grafts following intravenous administration of the fusion protein., Results: In vitro assays confirmed that IL-4 and the MMP-cleavable sequence were functional. IL-4-SyETP augmented production of IL-1 receptor antagonist (IL-1ra) by fibroblast-like synoviocytes (FLS) stimulated with IL-1β in a dose-dependent manner. In vivo imaging showed that IL-4-SyETP was retained in synovial but not in skin tissue grafts and the period of retention was significantly enhanced through increasing the number of SyETP copies from one to three. Finally, retention correlated with increased bioactivity of the cytokine as quantified by STAT6 phosphorylation in synovial grafts., Conclusions: The present work demonstrates that SyETP specifically delivers fused IL-4 to human rheumatoid synovium transplanted into SCID mice, thus providing a proof of concept for peptide-targeted tissue-specific immunotherapy in RA. This technology is potentially applicable to other biological treatments providing enhanced potency to inflammatory sites and reducing systemic toxicity.
- Published
- 2013
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27. Contrasting effects of sunitinib within in vivo models of metastasis.
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Welti JC, Powles T, Foo S, Gourlaouen M, Preece N, Foster J, Frentzas S, Bird D, Sharpe K, van Weverwijk A, Robertson D, Soffe J, Erler JT, Pili R, Springer CJ, Mather SJ, and Reynolds AR
- Subjects
- Animals, Mice, Mice, Inbred BALB C, Positron-Emission Tomography, Sunitinib, Tomography, X-Ray Computed, Antineoplastic Agents therapeutic use, Indoles therapeutic use, Neoplasm Metastasis drug therapy, Pyrroles therapeutic use
- Abstract
Sunitinib is a potent and clinically approved tyrosine kinase inhibitor that can suppress tumour growth by inhibiting angiogenesis. However, conflicting data exist regarding the effects of this drug on the growth of metastases in preclinical models. Here we use 4T1 and RENCA tumour cells, which both form lung metastases in Balb/c mice, to re-address the effects of sunitinib on the progression of metastatic disease in mice. We show that treatment of mice with sunitinib prior to intravenous injection of tumour cells can promote the seeding and growth of 4T1 lung metastases, but not RENCA lung metastases, showing that this effect is cell line dependent. However, increased metastasis occurred only upon administration of a very high sunitinib dose, but not when lower, clinically relevant doses were used. Mechanistically, high dose sunitinib led to a pericyte depletion effect in the lung vasculature that correlated with increased seeding of metastasis. By administering sunitinib to mice after intravenous injection of tumour cells, we demonstrate that while sunitinib does not inhibit the growth of 4T1 lung tumour nodules, it does block the growth of RENCA lung tumour nodules. This contrasting response was correlated with increased myeloid cell recruitment and persistent vascularisation in 4T1 tumours, whereas RENCA tumours recruited less myeloid cells and were more profoundly devascularised upon sunitinib treatment. Finally, we show that progression of 4T1 tumours in sunitinib treated mice results in increased hypoxia and increased glucose metabolism in these tumours and that this is associated with a poor outcome. Taken together, these data suggest that the effects of sunitinib on tumour progression are dose-dependent and tumour model-dependent. These findings have relevance for understanding how anti-angiogenic agents may influence disease progression when used in the adjuvant or metastatic setting in cancer patients.
- Published
- 2012
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28. Pathogen identification by nuclear imaging--almost there?
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Agrawal SG and Mather SJ
- Subjects
- Animals, Female, Male, Radionuclide Imaging, Aspergillus fumigatus metabolism, Gallium Radioisotopes, Pulmonary Aspergillosis diagnostic imaging, Pulmonary Aspergillosis metabolism, Siderophores pharmacokinetics
- Published
- 2012
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29. Flexible targeting of ErbB dimers that drive tumorigenesis by using genetically engineered T cells.
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Davies DM, Foster J, Van Der Stegen SJ, Parente-Pereira AC, Chiapero-Stanke L, Delinassios GJ, Burbridge SE, Kao V, Liu Z, Bosshard-Carter L, Van Schalkwyk MC, Box C, Eccles SA, Mather SJ, Wilkie S, and Maher J
- Subjects
- Animals, Breast Neoplasms immunology, Breast Neoplasms therapy, Cell Line, Tumor, Female, Genetic Engineering, Head and Neck Neoplasms immunology, Head and Neck Neoplasms therapy, Humans, Interleukin-4 immunology, Interleukin-4 metabolism, Mice, Mice, SCID, Receptor, ErbB-2 chemistry, Receptor, ErbB-2 metabolism, Receptors, Antigen genetics, Receptors, Antigen metabolism, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, T-Lymphocytes immunology, Transduction, Genetic, Xenograft Model Antitumor Assays, Cell Transformation, Neoplastic genetics, Protein Multimerization drug effects, Receptor, ErbB-2 genetics, T-Lymphocytes metabolism
- Abstract
Pharmacological targeting of individual ErbB receptors elicits antitumor activity, but is frequently compromised by resistance leading to therapeutic failure. Here, we describe an immunotherapeutic approach that exploits prevalent and fundamental mechanisms by which aberrant upregulation of the ErbB network drives tumorigenesis. A chimeric antigen receptor named T1E28z was engineered, in which the promiscuous ErbB ligand, T1E, is fused to a CD28 + CD3ζ endodomain. Using a panel of ErbB-engineered 32D hematopoietic cells, we found that human T1E28z⁺ T cells are selectively activated by all ErbB1-based homodimers and heterodimers and by the potently mitogenic ErbB2/3 heterodimer. Owing to this flexible targeting capability, recognition and destruction of several tumor cell lines was achieved by T1E28⁺ T cells in vitro, comprising a wide diversity of ErbB receptor profiles and tumor origins. Furthermore, compelling antitumor activity was observed in mice bearing established xenografts, characterized either by ErbB1/2 or ErbB2/3 overexpression and representative of insidious or rapidly progressive tumor types. Together, these findings support the clinical development of a broadly applicable immunotherapeutic approach in which the propensity of solid tumors to dysregulate the extended ErbB network is targeted for therapeutic gain.
- Published
- 2012
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30. Length-dependent retention of carbon nanotubes in the pleural space of mice initiates sustained inflammation and progressive fibrosis on the parietal pleura.
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Murphy FA, Poland CA, Duffin R, Al-Jamal KT, Ali-Boucetta H, Nunes A, Byrne F, Prina-Mello A, Volkov Y, Li S, Mather SJ, Bianco A, Prato M, Macnee W, Wallace WA, Kostarelos K, and Donaldson K
- Subjects
- Animals, Cell Proliferation, Epithelium pathology, Fibrosis, Lymph Nodes pathology, Mediastinum pathology, Mice, Nanotubes, Carbon ultrastructure, Nanowires ultrastructure, Particle Size, Pleura ultrastructure, Pleural Cavity ultrastructure, Time Factors, Tomography, Emission-Computed, Single-Photon, Tomography, X-Ray Computed, Disease Progression, Inflammation complications, Inflammation pathology, Nanotubes, Carbon chemistry, Pleura pathology, Pleural Cavity pathology
- Abstract
The fibrous shape of carbon nanotubes (CNTs) raises concern that they may pose an asbestos-like inhalation hazard, leading to the development of diseases, especially mesothelioma. Direct instillation of long and short CNTs into the pleural cavity, the site of mesothelioma development, produced asbestos-like length-dependent responses. The response to long CNTs and long asbestos was characterized by acute inflammation, leading to progressive fibrosis on the parietal pleura, where stomata of strictly defined size limit the egress of long, but not short, fibers. This was confirmed by demonstrating clearance of short, but not long, CNT and nickel nanowires and by visualizing the migration of short CNTs from the pleural space by single-photon emission computed tomographic imaging. Our data confirm the hypothesis that, although a proportion of all deposited particles passes through the pleura, the pathogenicity of long CNTs and other fibers arises as a result of length-dependent retention at the stomata on the parietal pleura., (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
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31. Quantitative Accuracy of Low-Count SPECT Imaging in Phantom and In Vivo Mouse Studies.
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Finucane CM, Murray I, Sosabowski JK, Foster JM, and Mather SJ
- Abstract
We investigated the accuracy of a single photon emission computed tomography (SPECT) system in quantifying a wide range of radioactivity concentrations using different scan times in both phantom and animal models. A phantom containing various amounts of In-111 or Tc-99m was imaged until the activity had decayed close to background levels. Scans were acquired for different durations, employing different collimator pinhole sizes. VOI analysis was performed to quantify uptake in the images and the values compared to the true activity. The phantom results were then validated in tumour-bearing mice. The use of an appropriate calibration phantom and disabling of a background subtraction feature meant that absolute errors were within 12% of the true activity. Furthermore, a comparison of in vivo imaging and biodistribution studies in mice showed a correlation of 0.99 for activities over the 200 kBq to 5 MBq range. We conclude that the quantitative information provided by the NanoSPECT camera is accurate and allows replacement of dissection studies for assessment of radiotracer biodistribution in mouse models.
- Published
- 2011
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32. Radiopeptide internalisation and externalization assays: cell viability and radioligand integrity.
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Naqvi SA, Sosabowski JK, Nagra SA, Ishfaq MM, Mather SJ, and Matzow T
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- Animals, Cell Line, Tumor, Cell Survival drug effects, Endocytosis physiology, Exocytosis physiology, Gastrins chemistry, Gastrins pharmacology, Indium Radioisotopes chemistry, Indium Radioisotopes pharmacology, Organometallic Compounds chemical synthesis, Organometallic Compounds pharmacology, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Radiopharmaceuticals chemical synthesis, Radiopharmaceuticals pharmacology, Rats, Gastrins pharmacokinetics, Indium Radioisotopes pharmacokinetics, Organometallic Compounds pharmacokinetics, Pancreatic Neoplasms radiotherapy, Radiopharmaceuticals pharmacokinetics
- Abstract
Various aspects of radiopeptide receptor-mediated cell internalisation and externalization assays were assessed, including the integrity of externalized peptides and the effect of varying the pH and incubation time of the acid wash step (to remove surface receptor-bound ligand) on efficacy and cell viability. The observed intact proportion of externalized peptide was 5-10%, and acid wash buffers with pH 2.8 or below were found to be detrimental to cell viability and integrity, particularly following prolonged incubation times., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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33. Synthesis and optimization of the labeling procedure of 99mTc-HYNIC-interleukin-2 for in vivo imaging of activated T lymphocytes.
- Author
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D'Alessandria C, di Gialleonardo V, Chianelli M, Mather SJ, de Vries EF, Scopinaro F, Dierck RA, and Signore A
- Subjects
- Animals, Chromatography, Liquid, Humans, Mice, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Tissue Distribution, Interleukin-2 chemistry, Lymphocyte Activation, Organotechnetium Compounds chemistry, T-Lymphocytes immunology
- Abstract
Introduction: We have previously described the labeling of interleukin-2 (IL2) with (123)I and (99m)Tc-N(3)S. Both radiopharmaceuticals were successfully applied in humans to image several inflammatory lesions and autoimmune diseases characterized by tissue infiltrating lymphocytes expressing the IL2 receptor (CD25). However, both radiopharmaceuticals had some specific disadvantages, such as cost and time of synthesis., Materials and Methods: Here, we describe a new improved method for labeling interleukin-2 with (99m)Tc using HYNIC-NHS and tricine as coligand. Several optimizations of reagent concentrations and labeling conditions were performed in order to standardize the procedure. After labeling, IL2 was purified by tC2 reverse-phase chromatography and tested in vitro and in vivo, in mice and in a normal volunteer. Results showed that this labeling procedure is cheap, fast, reliable, and reproducible, leading to a product with high specific activity (153 µCi/µg), high stability and capable of binding in vitro to CD25 positive cells. In vivo biodistribution in mice and human volunteer did not show any significant different from (99m)Tc-N(3)S-IL2., Conclusion: In conclusion, the optimization of (99m)Tc-HYNIC-IL2 has a great advantage in terms of cost and time of production and a simple kit formulation can be considered for routine application to study patients affected by autoimmune diseases, graft rejection, or other chronic inflammatory disorders.
- Published
- 2010
- Full Text
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34. High-resolution in vivo imaging of breast cancer by targeting the pro-invasive integrin alphavbeta6.
- Author
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Saha A, Ellison D, Thomas GJ, Vallath S, Mather SJ, Hart IR, and Marshall JF
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- Animals, Female, Humans, Indium Radioisotopes metabolism, Indium Radioisotopes pharmacokinetics, Mammary Neoplasms, Experimental metabolism, Mice, Mice, Inbred Strains, Neoplasm Transplantation, Pentetic Acid pharmacokinetics, Peptide Fragments metabolism, Peptide Fragments pharmacokinetics, Positron-Emission Tomography methods, Radiopharmaceuticals pharmacokinetics, Tissue Distribution, Tomography, Emission-Computed, Single-Photon methods, Transplantation, Heterologous, Tumor Cells, Cultured, Antigens, Neoplasm metabolism, Integrins metabolism, Mammary Neoplasms, Experimental diagnostic imaging
- Abstract
The integrin alphavbeta6 is expressed only on epithelia and then usually only during processes of tissue remodelling including cancer, where its high expression correlates with reduced survival. Thus, alphavbeta6 represents an important target for imaging and therapy of cancer and new molecular-specific targeting agents are required. We have developed A20FMDV2, a peptide derived from the VP1 coat protein of foot-and-mouth-disease virus that binds specifically and stably to alphavbeta6. Using a newly generated pair of isogenic human cell lines that differ only in alphavbeta6 expression, it was shown, using biodistribution and SPECT imaging, that indium-111-labelled A20FMDV2 locates specifically to alphavbeta6-expressing tissues in vivo, achieving at least seven-times higher retention in alphavbeta6-positive than in alphavbeta6-negative tumours. In further studies with MCF10.DCIS.COM and MCF10A.CA1a breast carcinoma cell lines, which express alphavbeta6 endogenously, the radiopeptide achieved similar levels of tumour retention and permitted excellent discriminatory imaging of tumours. Thus, A20FMDV2 can be used for molecular-specific targeting of alphavbeta6 for imaging in vivo the often more aggressive, alphavbeta6-positive cancers. In the future, A20FMDV2 could serve also to deliver therapy to these same cancers.
- Published
- 2010
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35. Filled and glycosylated carbon nanotubes for in vivo radioemitter localization and imaging.
- Author
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Hong SY, Tobias G, Al-Jamal KT, Ballesteros B, Ali-Boucetta H, Lozano-Perez S, Nellist PD, Sim RB, Finucane C, Mather SJ, Green ML, Kostarelos K, and Davis BG
- Subjects
- Acetylglucosamine metabolism, Carbohydrate Metabolism, Glycosylation, Humans, Isotope Labeling methods, Microscopy, Electron, Scanning Transmission methods, Nanotechnology methods, Oxidation-Reduction, Radioisotopes metabolism, Radioisotopes pharmacokinetics, Stomach diagnostic imaging, Thyroid Gland diagnostic imaging, Tissue Distribution, Tomography, X-Ray Computed methods, Nanotechnology trends, Nanotubes, Carbon chemistry
- Abstract
Functionalization of nanomaterials for precise biomedical function is an emerging trend in nanotechnology. Carbon nanotubes are attractive as multifunctional carrier systems because payload can be encapsulated in internal space whilst outer surfaces can be chemically modified. Yet, despite potential as drug delivery systems and radiotracers, such filled-and-functionalized carbon nanotubes have not been previously investigated in vivo. Here we report covalent functionalization of radionuclide-filled single-walled carbon nanotubes and their use as radioprobes. Metal halides, including Na(125)I, were sealed inside single-walled carbon nanotubes to create high-density radioemitting crystals and then surfaces of these filled-sealed nanotubes were covalently modified with biantennary carbohydrates, improving dispersibility and biocompatibility. Intravenous administration of Na(125)I-filled glyco-single-walled carbon nanotubes in mice was tracked in vivo using single-photon emission computed tomography. Specific tissue accumulation (here lung) coupled with high in vivo stability prevented leakage of radionuclide to high-affinity organs (thyroid/stomach) or excretion, and resulted in ultrasensitive imaging and delivery of unprecedented radiodose density. Nanoencapsulation of iodide within single-walled carbon nanotubes enabled its biodistribution to be completely redirected from tissue with innate affinity (thyroid) to lung. Surface functionalization of (125)I-filled single-walled carbon nanotubes offers versatility towards modulation of biodistribution of these radioemitting crystals in a manner determined by the capsule that delivers them. We envisage that organ-specific therapeutics and diagnostics can be developed on the basis of the nanocapsule model described here.
- Published
- 2010
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36. 188Re(CO)3-dipicolylamine-alendronate: a new bisphosphonate conjugate for the radiotherapy of bone metastases.
- Author
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Torres Martin de Rosales R, Finucane C, Foster J, Mather SJ, and Blower PJ
- Subjects
- Alendronate chemical synthesis, Alendronate chemistry, Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Diphosphonates chemical synthesis, Diphosphonates chemistry, Female, Humans, Mice, Mice, Inbred BALB C, Radioisotopes chemistry, Radioisotopes pharmacokinetics, Radiopharmaceuticals chemical synthesis, Radiopharmaceuticals chemistry, Rhenium chemistry, Alendronate pharmacokinetics, Antineoplastic Agents pharmacokinetics, Bone Neoplasms radiotherapy, Bone Neoplasms secondary, Diphosphonates pharmacokinetics, Radiopharmaceuticals pharmacokinetics, Rhenium pharmacokinetics
- Abstract
The palliation of pain due to bone metastases using targeted compounds containing beta-emitters such as rhenium-188 ((188)Re) is an accepted and effective form of treatment. Here, we describe the efficient synthesis and preclinical evaluation of (188)Re(CO)(3)-dipicolylamine(DPA)-alendronate, a novel bifunctional bisphosphonate for the palliative treatment of bone metastases. (188)Re(CO)(3)-DPA-alendronate can be easily synthesized with high specific activities and yields (18.8 GBq/mg, radiochemical yield > or =96%) in two steps using kit-based methodology, and in contrast with the clinically approved bisphosphonate (186/188)Re-HEDP, it forms inert, single species that have been well-characterized. In vivo imaging and biodistribution studies demonstrate that (188)Re(CO)(3)-DPA-alendronate is superior to (188)Re-HEDP in targeting and accumulating in areas of high metabolic bone activity while having low soft-tissue uptake. In addition to these studies, a simple and convenient new method for purifying its precursor, fac-[(188)Re(CO)(3)(H(2)O)(3)](+), is described.
- Published
- 2010
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37. Molecular imaging of inflammation/infection: nuclear medicine and optical imaging agents and methods.
- Author
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Signore A, Mather SJ, Piaggio G, Malviya G, and Dierckx RA
- Subjects
- Animals, Humans, Infections metabolism, Infections pathology, Inflammation metabolism, Inflammation pathology, Molecular Probes chemistry, Molecular Probes metabolism, Infections diagnosis, Inflammation diagnosis, Molecular Imaging methods, Nuclear Medicine methods, Optical Phenomena
- Published
- 2010
- Full Text
- View/download PDF
38. The qualified person in radiopharmacy.
- Author
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Mather SJ, Maltby P, Ellis B, O'Docherty M, Lewington V, Nunan T, Khan S, and Hodges N
- Subjects
- Clinical Trials as Topic standards, Education, Pharmacy, Humans, Models, Organizational, Pharmacists, Pharmacy standards, Radiation Monitoring standards, United Kingdom, Radiation Monitoring methods, Radiopharmaceuticals therapeutic use, Radiotherapy standards
- Published
- 2010
- Full Text
- View/download PDF
39. Automated radiolabelling of monoclonal antibodies with the Modular Lab system.
- Author
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Ellison D, Kaufman J, and Mather SJ
- Subjects
- Chromatography, High Pressure Liquid, Indium chemistry, Radioisotopes, Antibodies, Monoclonal chemistry, Automation, Isotope Labeling methods
- Abstract
Automation of radiopharmaceutical preparation represents a way of reducing radiation doses to operators and providing good manufacturing practice-compliant manufacture of radiopharmaceuticals. Although widely adopted for PET radiochemical synthesis, such methods have not widely been used for the preparation of therapeutic radiopharmaceuticals. Here we describe an evaluation of an automated system for the preparation of radiolabelled antibodies. A labelling method based on the Modular Lab system was developed and applied to the radiolabelling of the monoclonal antibody conjugate, YAML568-CHX'A-DTPA, with indium-111. Antibodies were labelled using both manual and automated means and analysed by high-performance liquid chromatography and thin-layer chromatography methods. Radiochemical purities achieved using automation (mean 98%) were slightly lower than those achieved manually (mean 99%); however, the radiochemical purity obtained was reproducible and well within the set specification of greater than 95%. The Modular Lab system can be used to automate the radiolabelling of monoclonal antibody-chelate conjugates with metallic isotopes such as indium for the potential application for therapeutic radionuclide therapy.
- Published
- 2010
- Full Text
- View/download PDF
40. Targeting of CCK-2 receptor-expressing tumors using a radiolabeled divalent gastrin peptide.
- Author
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Sosabowski JK, Matzow T, Foster JM, Finucane C, Ellison D, Watson SA, and Mather SJ
- Subjects
- Amino Acid Sequence, Animals, Cell Line, Tumor, Female, Gastrins pharmacokinetics, Heterocyclic Compounds, 1-Ring chemistry, Isotope Labeling, Mice, Neoplasms diagnostic imaging, Neoplasms genetics, Protein Stability, Protein Transport, Rats, Tissue Distribution, Tomography, Emission-Computed, Single-Photon, Tomography, X-Ray Computed, Gastrins chemistry, Gastrins metabolism, Gene Expression Regulation, Neoplastic, Neoplasms metabolism, Receptor, Cholecystokinin B metabolism
- Abstract
Unlabelled: Gastrin/cholecystokinin subtype 2 receptors (CCK-2Rs) are overexpressed in several tumor types and are, thus, a potential target for peptide receptor radionuclide therapy (PRRT) of cancer. To improve the in vivo performance of CCK-2R binding peptides, we have previously synthesized and screened a series of divalent gastrin peptides for improved biochemical and biologic characteristics. In this study, we explore in more detail the most promising of these compounds and compare its performance with a previously described monomeric peptide., Methods: From six (111)In-labeled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-conjugated divalent gastrin peptides based on the C-terminal sequence of minigastrin, the maleimide-linked compound DOTA-GSC(succinimidopropionyl-EAYGWNleDF-NH(2))-EAYGWNleDF-NH(2) (MGD5) was selected. The in vitro stability, receptor binding, and internalization of (111)In-MGD5 were studied and compared with those of monomer compound (111)In-APH070. In vivo biodistribution and imaging using a SPECT/CT camera were also performed., Results: More than 90% of the labeled divalent peptide remained intact after 20 h of incubation in plasma. The inhibitory concentration of 50% of the divalent peptide was 1.0 versus 5.6 nM for the monomer, and the dissociation constant was 0.7 versus 2.9 nM. The rate of internalization of the divalent peptide was twice that of the monomer. Tumor uptake of the divalent peptide in vivo was about 6 times that of the monomer. The rate of washout of the divalent peptide from the tumor was lower than that of the monomer., Conclusion: Dimerization of the CCK-2R binding site results in an increase in binding affinity and an increase in tumor uptake both in vitro and in vivo. It is likely that these increases would result in improved tumor-targeting efficiency in patients with CCK-2R-positive tumors.
- Published
- 2009
- Full Text
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41. Bifunctional bisphosphonate complexes for the diagnosis and therapy of bone metastases.
- Author
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Torres Martin de Rosales R, Finucane C, Mather SJ, and Blower PJ
- Subjects
- Animals, Female, Humans, Magnetic Resonance Spectroscopy, Mice, Mice, Inbred BALB C, Molecular Structure, Organotechnetium Compounds therapeutic use, Radionuclide Imaging, Bone Neoplasms diagnosis, Bone Neoplasms diagnostic imaging, Bone Neoplasms drug therapy, Diphosphonates therapeutic use, Organotechnetium Compounds chemistry, Radiopharmaceuticals chemical synthesis, Radiopharmaceuticals chemistry, Radiopharmaceuticals therapeutic use, Rhenium chemistry
- Abstract
Easily synthesised and structurally well-defined novel imaging/therapeutic radiopharmaceutical agents for bone metastases are described.
- Published
- 2009
- Full Text
- View/download PDF
42. Cyclic minigastrin analogues for gastrin receptor scintigraphy with technetium-99m: preclinical evaluation.
- Author
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von Guggenberg E, Sallegger W, Helbok A, Ocak M, King R, Mather SJ, and Decristoforo C
- Subjects
- Amino Acid Sequence, Animals, Drug Evaluation, Preclinical, Female, Gastrins pharmacokinetics, Isotope Labeling, Mice, Mice, Inbred BALB C, Molecular Sequence Data, Neoplasms, Experimental metabolism, Tissue Distribution, Gastrins chemical synthesis, Radiopharmaceuticals chemical synthesis, Receptor, Cholecystokinin B analysis, Technetium
- Abstract
Two cyclized minigastrin analogues for gastrin receptor scintigraphy were synthesized and derivatized with HYNIC at the N-terminus for labeling with 99mTc. Radiolabeling efficiency, stability, cell internalization, and receptor binding on CCK-2 receptor expressing AR42J cells were studied and the biodistribution evaluated in tumor bearing nude mice, including NanoSPECT/CT imaging. Metabolites in urine, liver, and kidneys were analyzed by radio-HPLC. Radiolabeled cyclic MG showed high stability in vitro and receptor mediated uptake in AR42J cells. In the animal tumor model, fast renal clearance and low nonspecific uptake in most organs were observed. A tumor uptake >3% was calculated ex vivo 1 h p.i. for both 99mTc-EDDA-HYNIC-cyclo-MG1 and 99mTc-EDDA-HYNIC-cyclo-MG2. In an imaging study with 99mTc-EDDA-HYNIC-cyclo-MG1, the tumor was clearly visualized. The metabolite analysis indicated rapid enzymatic degradation in vivo.
- Published
- 2009
- Full Text
- View/download PDF
43. Radiopharmaceutical clinical trials - dose is more than sieverts and becquerels.
- Author
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Ballinger JR, Mather SJ, and O'Doherty MJ
- Subjects
- Clinical Trials as Topic economics, Clinical Trials as Topic legislation & jurisprudence, Clinical Trials as Topic standards, Humans, Radiopharmaceuticals economics, Clinical Trials as Topic methods, Radiation Dosage, Radiopharmaceuticals administration & dosage
- Published
- 2009
- Full Text
- View/download PDF
44. Technetium-binding in labelled HYNIC-peptide conjugates: role of coordinating amino acids.
- Author
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Surfraz MB, King R, Mather SJ, Biagini S, and Blower PJ
- Subjects
- Animals, Cattle, Glutamic Acid chemistry, Glycine analogs & derivatives, Glycine chemistry, Histidine chemistry, Niacinamide chemistry, Spectrometry, Mass, Electrospray Ionization, Hydrazines chemistry, Niacinamide analogs & derivatives, Peptides chemistry, Serum Albumin, Bovine chemistry, Technetium chemistry
- Abstract
Electrospray mass spectrometry (ESMS) of certain peptides labelled with (99m)Tc via hydrazinonicotinamide (HYNIC) with tricine as co-ligand shows one Tc-bound tricine, whereas typically two are observed. We speculated that this was due to coordination of a neighbouring histidine (His) or glutamate (Glu). To investigate this possibility, several short peptides incorporating lysine (HYNIC), with and without His and Glu at different positions in the sequence, were radiolabelled with (99m)Tc, using tricine, ethylenediaminediacetic acid (EDDA) and nicotinic acid as co-ligands. The products were examined by HPLC-ESMS, cysteine challenge and bovine serum albumin (BSA) challenge. Peptides with His nearby on either side of lysine (HYNIC) contained only one tricine and showed markedly enhanced structural homogeneity and stability to cysteine challenge and BSA binding, except those with His located at the N-terminus. Peptides without His, or with neighbouring N-terminal His, contained two tricines and were less stable to cysteine challenge and BSA binding. Glu participated in Tc-binding but did not enhance stability. We conclude that neighbouring His or Glu side chains coordinate to Tc and this could alter peptide or protein conformation. Inclusion of His in a neighbouring position to lysine (HYNIC) enhances stability, improves homogeneity and reduces the demand of the metal center for binding to additional co-ligands.
- Published
- 2009
- Full Text
- View/download PDF
45. 99mTc-HYNIC-Gastrin Peptides: Assisted Coordination of 99mTc by Amino Acid Side Chains Results in Improved Performance Both In Vitro and In Vivo.
- Author
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King R, Surfraz MB, Finucane C, Biagini SC, Blower PJ, and Mather SJ
- Subjects
- Amino Acids chemistry, Animals, Isotope Labeling methods, Metabolic Clearance Rate, Mice, Mice, Nude, Oligopeptides chemical synthesis, Oligopeptides pharmacokinetics, Organ Specificity, Organometallic Compounds chemical synthesis, Organometallic Compounds pharmacokinetics, Organotechnetium Compounds chemical synthesis, Organotechnetium Compounds pharmacokinetics, Radionuclide Imaging, Radiopharmaceuticals chemical synthesis, Tissue Distribution, Image Enhancement methods, Pancreatic Neoplasms diagnostic imaging, Pancreatic Neoplasms metabolism, Radiopharmaceuticals pharmacokinetics
- Abstract
Unlabelled: The aim of this study was to determine the effects of assisted coordination by amino acids such as histidine and glutamic acid on the function of (99m)Tc-labeled gastrin peptide-hydrazinonicotinamide (HYNIC) conjugates and their ability to target cholecystokinin-R in small-animal models., Methods: Three peptide-HYNIC conjugates containing the -AYGWMDF-NH2 C-terminal sequence and combinations of histidine, glutamic acid, and glycine were synthesized, radiolabeled with (99m)Tc/(99)Tc using either tricine or ethylenediaminediacetic acid as a coligand, and analyzed by the high-performance liquid chromatography and liquid chromatography-mass spectrometric techniques. Stability, receptor binding, and internalization and in vivo targeting in AR42J-bearing mice were assessed., Results: When radiolabeling was performed using tricine as a coligand, the insertion of a histidine residue near the HYNIC residue resulted in the displacement of one molecule of tricine from the coordination sphere, a reduction in the number of radiolabeled species formed, an improvement in the in vitro stability, an increase in the rate of radiopeptide internalization, and a significant improvement in tumor uptake in vivo. When radiolabeling was performed using ethylenediaminediacetic acid as a coligand, no effect on coligand binding, homogeneity, or in vitro stability was observed but a significant improvement in the internalization in vitro and tumor uptake in vivo was again found. All of the complexes formed showed similar receptor affinity in competitive radioligand binding assays., Conclusion: The insertion of histidine into the sequence of peptide-HYNIC conjugates can result in more stable, more homogeneous complexes that show improvements in tumor-targeting performance both in vitro and in vivo.
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- 2009
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46. Cancer-specific transgene expression mediated by systemic injection of nanoparticles.
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Chisholm EJ, Vassaux G, Martin-Duque P, Chevre R, Lambert O, Pitard B, Merron A, Weeks M, Burnet J, Peerlinck I, Dai MS, Alusi G, Mather SJ, Bolton K, Uchegbu IF, Schatzlein AG, and Baril P
- Subjects
- Animals, Colloids chemistry, DNA genetics, Dendrimers chemistry, Drug Stability, Female, Fourier Analysis, HeLa Cells, Humans, Light, Macrophages drug effects, Macrophages metabolism, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Nude, Microscopy, Electron, Transmission methods, Plasmids chemistry, Plasmids genetics, Scattering, Radiation, Transplantation, Heterologous, DNA chemistry, Gene Transfer Techniques, Nanoparticles chemistry, Polypropylenes chemistry
- Abstract
The lack of safe and efficient systemic gene delivery vectors has largely reduced the potential of gene therapy in the clinic. Previously, we have reported that polypropylenimine dendrimer PPIG3/DNA nanoparticles are capable of tumor transfection upon systemic administration in tumor-bearing mice. To be safely applicable in the clinic, it is crucial to investigate the colloidal stability of nanoparticles and to monitor the exact biodistribution of gene transfer in the whole body of the live subject. Our biophysical characterization shows that dendrimers, when complexed with DNA, are capable of forming spontaneously in solution a supramolecular assembly that possesses all the features required to diffuse in experimental tumors through the enhanced permeability and retention effect. We show that these nanoparticles are of sizes ranging from 33 to 286 nm depending on the DNA concentration, with a colloidal stable and well-organized fingerprint-like structure in which DNA molecules are condensed with an even periodicity of 2.8 nm. Whole-body nuclear imaging using small-animal nano-single-photon emission computed tomography/computer tomography scanner and the human Na/I symporter (NIS) as reporter gene shows unique and highly specific tumor targeting with no detection of gene transfer in any of the other tissues of tumor-bearing mice. Tumor-selective transgene expression was confirmed by quantitative reverse transcription-PCR at autopsy of scanned animals, whereas genomic PCR showed that the tumor sites are the predominant sites of nanoparticle accumulation. Considering that NIS imaging of transgene expression has been recently validated in humans, our data highlight the potential of these nanoparticles as a new formulation for cancer gene therapy.
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- 2009
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47. 99mTc-interleukin-2 scintigraphy in normal subjects and in patients with autoimmune thyroid diseases: a feasibility study.
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Chianelli M, Mather SJ, Grossman A, Sobnak R, Fritzberg A, Britton KE, and Signore A
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- Adult, Case-Control Studies, Feasibility Studies, Female, Granulocytes drug effects, Granulocytes metabolism, Humans, Kinetics, Lymphocytes drug effects, Lymphocytes metabolism, Male, Metabolic Clearance Rate, Radiation Dosage, Radionuclide Imaging, Tissue Distribution, Autoimmune Diseases diagnostic imaging, Interleukin-2 pharmacokinetics, Interleukin-2 toxicity, Organotechnetium Compounds pharmacokinetics, Organotechnetium Compounds toxicity, Thyroid Diseases diagnostic imaging
- Abstract
Purpose: Radiolabelled interleukin-2 is a radiopharmaceutical used for the study of chronic inflammatory processes. (123)I-labelled interleukin-2 has successfully been used in a large number of patients affected by several immune-mediated diseases. (123)I, however, is expensive and not readily available. We have, therefore, developed a method for labelling interleukin-2 with (99m)Tc to high specific activity based on the use of an N(3)S bifunctional chelating agent. In this paper, we describe the results obtained with (99m)Tc-interleukin-2 in a series of eight normal subjects and of 12 patients with autoimmune thyroid diseases., Methods: Biodistribution, pharmacokinetics, haematological and systemic toxicity, radiation absorbed dose and in vivo targeting were studied., Results: Results showed rapid plasma clearance of (99m)Tc-interleukin-2 with retention mainly in the kidneys. Biodistribution and kinetics were similar to that observed for (123)I-interleukin-2. No acute systemic toxicity was found; a small decrease in peripheral blood lymphocytes was observed in the first hours only in patients, but it was mild and transient. (99m)Tc-interleukin-2 accumulated, to varying extents, in the thyroid of all patients affected by autoimmune thyroid diseases but not in the thyroid of normal subjects. The effective dose equivalent of a diagnostic activity of (99m)Tc-interleukin-2 (185 MBq) was 1.35 mSv. No correlation was observed between thyroid autoantibodies and uptake of (99m)Tc-interleukin-2., Conclusions: The use of (99m)Tc-interleukin-2 is safe and simple; the favourable dosimetry and biodistribution and the rapid clearance make it potentially useful for the study of chronic inflammatory diseases such as autoimmune thyroid disease.
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- 2008
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48. IAEA Technical Report Series.
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Mather SJ and Mansi L
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- 2008
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49. Retargeting of human T cells to tumor-associated MUC1: the evolution of a chimeric antigen receptor.
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Wilkie S, Picco G, Foster J, Davies DM, Julien S, Cooper L, Arif S, Mather SJ, Taylor-Papadimitriou J, Burchell JM, and Maher J
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- Carbohydrate Metabolism, Cells, Cultured, Cytotoxicity, Immunologic immunology, Homeodomain Proteins immunology, Humans, Immunoglobulin D immunology, Mucin-1 genetics, Neoplasms genetics, Neoplasms immunology, Protein Binding, Protein Engineering, Receptors, Antigen genetics, Mucin-1 immunology, Mucin-1 metabolism, Neoplasms metabolism, Receptors, Antigen immunology, Receptors, Antigen metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism
- Abstract
MUC1 is a highly attractive immunotherapeutic target owing to increased expression, altered glycosylation, and loss of polarity in >80% of human cancers. To exploit this, we have constructed a panel of chimeric Ag receptors (CAR) that bind selectively to tumor-associated MUC1. Two parameters proved crucial in optimizing the CAR ectodomain. First, we observed that the binding of CAR-grafted T cells to anchored MUC1 is subject to steric hindrance, independent of glycosylation status. This was overcome by insertion of the flexible and elongated hinge found in immunoglobulins of the IgD isotype. Second, CAR function was highly dependent upon strong binding capacity across a broad range of tumor-associated MUC1 glycoforms. This was realized by using an Ab-derived single-chain variable fragment (scFv) cloned from the HMFG2 hybridoma. To optimize CAR signaling, tripartite endodomains were constructed. Ultimately, this iterative design process yielded a potent receptor termed HOX that contains a fused CD28/OX40/CD3zeta endodomain. HOX-expressing T cells proliferate vigorously upon repeated encounter with soluble or membrane-associated MUC1, mediate production of proinflammatory cytokines (IFN-gamma and IL-17), and elicit brisk killing of MUC1(+) tumor cells. To test function in vivo, a tumor xenograft model was derived using MDA-MB-435 cells engineered to coexpress MUC1 and luciferase. Mice bearing an established tumor were treated i.p. with a single dose of engineered T cells. Compared with control mice, this treatment resulted in a significant delay in tumor growth as measured by serial bioluminescence imaging. Together, these data demonstrate for the first time that the near-ubiquitous MUC1 tumor Ag can be targeted using CAR-grafted T cells.
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- 2008
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50. Pancreatic scintigraphy with 99mTc-interleukin-2 at diagnosis of type 1 diabetes and after 1 year of nicotinamide therapy.
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Chianelli M, Parisella MG, Visalli N, Mather SJ, D'Alessandria C, Pozzilli P, and Signore A
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- Adolescent, Adult, Child, Follow-Up Studies, Humans, Radionuclide Imaging, Diabetes Mellitus, Type 1 diagnostic imaging, Diabetes Mellitus, Type 1 drug therapy, Interleukin-2, Niacinamide therapeutic use, Organotechnetium Compounds, Pancreas diagnostic imaging
- Abstract
Background: To evaluate the clinical utility of pancreatic scintigraphy with 99mTc-interleukin-2 to identify Type 1 diabetic patients with pancreatic inflammation at diagnosis., Methods: 99mTc-interleukin-2 scintigraphy was performed on 42 newly diagnosed Type 1 diabetic patients, before and after 1 year of treatment with nicotinamide (25 or 50 mg/kg/day) in addition to intensive insulin therapy. Metabolic status was monitored every 3 months for 1 year. Sixteen normal subjects were studied as control., Results: Significant pancreatic accumulation of 99mTc-interleukin-2 was found in 31% of the patients at the time of diagnosis. Patients positive or negative for pancreatic accumulation of interleukin-2 scintigraphy did not show any difference in metabolic or immunologic parameters at diagnosis. Positive patients, however, showed higher C-peptide values at 3 months and lower insulin requirement at 1 year, compared to negative patients (insulin requirement (IR): 0.33+/-0.11 vs 0.67+/-0.24 IU/kg/day, positive vs negative patients; p=0.0001); patients positive to IL2 scintigraphy treated with nicotinamide at 25 mg/kg were the only group showing a significant reduction in IR 1 year after diagnosis (IRt0: 0.53+/-0.30 vs IRt12: 0.28+/-0.07 IU/kg/day; p=0.013). After 1 year, all the positive patients showed a significant decrease in pancreatic uptake of 99mTc-interleukin-2 (P/B: 7.87+/-2.28 at diagnosis vs 5.00+/-1.23 after 1 year; p<0.0001 paired t-test)., Conclusion: 99mTc-interleukin-2 scintigraphy at diagnosis of Type 1 diabetes may identify patients with pancreatic inflammation. In such patients, treated with nicotinamide at 25 mg/kg, insulin requirement and pancreatic inflammation after 1 year were significantly reduced suggesting that IL2 scintigraphy may be of potential use for assessing the autoimmune phenomena in endocrine pancreas., (Copyright (c) 2007 John Wiley & Sons, Ltd.)
- Published
- 2008
- Full Text
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