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1.
Mol Imaging Biol ; 21(3): 538-548, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30218389

RESUMO

PURPOSE: Apoptosis may be an indication of success therapy, and precise detection of apoptosis can provide instructional suggestions in the therapy management of malignant tumors. PROCEDURES: We used CNE-1 cell lines for in vitro experiments, and colony formation assay, CCK-8 assay, cell apoptosis analysis, and western blotting were performed. For in vivo experiments, subcutaneous xenotransplanted tumor models of CNE-1 in nude mice were established. Then, small animal positron emission tomography/X-ray computed tomography (PET/CT) images were acquired by tail intravenous injection of 2-(5-[18F]fluoropentyl)-2-methyl-malonic acid ([18F]ML-10) or 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) before and 24 h and 48 h after treatment. Moreover, expression of epidermal growth factor receptor (EGFR), Ki-67, Glut-1, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) was examined by immunohistochemical examination. Tumor volumes of mice were recorded every 2 days. RESULTS: In the presence of Cetuximab, the number of colonies of CNE-1 cells decreased significantly after irradiation at 1 and 2 Gy. In addition, Cetuximab increased the radiation-induced cytotoxicity and apoptosis of CNE-1 cells. Mechanistic studies demonstrated that Cetuximab enhanced radiosensitivity by suppressing the EGFR/PI3-K/AKT pathway. In PET/CT imaging, the tumors showed clear uptake of [18F]ML-10 at 24 h and 48 h after combined treatment, and the value of tumor/muscle (T/M) and SUVmax (the max of standard uptake value) was significantly higher than those of the other three groups. The T/M of [18F]ML-10 uptake showed a positive correlation of 0.926 with the apoptosis index (P < 0.001). However, the uptake of [18F]FDG in tumors exhibited no trend among the four groups. The T/M of [18F]FDG revealed a positive correlation of 0.926 with Glut-1 intensity (P < 0.001). CONCLUSIONS: Our work revealed that Cetuximab could increase the radiosensitivity of CNE-1 cells both in vitro and in vivo. Apoptosis imaging with [18F]ML-10 PET/CT is a promising modality for application in the response prediction of nasopharyngeal carcinoma.


Assuntos
Cetuximab/uso terapêutico , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/radioterapia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cetuximab/farmacologia , Terapia Combinada , Receptores ErbB/metabolismo , Feminino , Fluordesoxiglucose F18/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Humanos , Ácido Metilmalônico/análogos & derivados , Ácido Metilmalônico/química , Camundongos Endogâmicos BALB C , Camundongos Nus , Carcinoma Nasofaríngeo/diagnóstico por imagem , Carcinoma Nasofaríngeo/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaio Tumoral de Célula-Tronco
2.
Mol Imaging Biol ; 21(3): 491-499, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30167994

RESUMO

PURPOSE: The purpose of this study was to assess the potential utility of small-molecule apoptotic radiotracer, 2-(5-[18F]fluoropentyl)-2-methyl malonic acid ([18F]ML-10), for positron emission tomography (PET)/computed tomography (CT) monitoring the progression of pulmonary fibrosis in a rat model. PROCEDURES: Male Sprague-Dawley rats were used to establish a rat model of pulmonary fibrosis by means of bleomycin (BLM) administration; control rats received saline (n = 12 per group). PET/CT with [18F]ML-10 and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) was performed in two groups at different stages of pulmonary fibrosis. The fibrotic response and the cell apoptosis were assessed with histologic examination. Differences in the apoptosis rate, fibrotic activity, and the lung uptake of [18F]ML-10 and [18F]FDG between two groups were determined with Student t test. RESULTS: Compared with control group, BLM group showed a higher lung uptake of [18F]ML-10 at all imaging time points (all P < 0.001). During the fibrotic phase of this disease model (days 21 and 28), the lung uptake of [18F]ML-10 was higher than that of [18F]FDG in the BLM group (all P < 0.001). Moreover, accumulation of [18F]ML-10 in the lung tissues increased in proportion to the apoptosis rate (R2 = 0.9863, P < 0.0001) and fibrotic activity (R2 = 0.9631, P < 0.0001) of rat pulmonary fibrosis. Conversely, no correlation between [18F]FDG uptake and fibrotic activity was found. CONCLUSIONS: [18F]ML-10 PET/CT enabled monitoring the progression of rat pulmonary fibrosis, whereas [18F]FDG PET/CT could not. Implications for noninvasive diagnosis of pulmonary fibrosis, assessment of fibrotic activity, and evaluation of antifibrotic therapy are expected.


Assuntos
Apoptose , Tomografia por Emissão de Pósitrons , Fibrose Pulmonar/diagnóstico por imagem , Fibrose Pulmonar/patologia , Compostos Radiofarmacêuticos/química , Animais , Bleomicina , Colágeno/metabolismo , Fluordesoxiglucose F18/química , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Ácido Metilmalônico/análogos & derivados , Ácido Metilmalônico/química , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Ratos Sprague-Dawley
3.
Mol Imaging ; 17: 1536012118795728, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30348035

RESUMO

OBJECTIVE: To investigate the value of 2-(3-[18F]fluoropropyl)-2-methyl-malonic acid ([18F]ML-8) positron emission tomography (PET) imaging of rat pulmonary fibrosis. METHODS: Male Sprague-Dawley rats were divided into 2 groups, including pulmonary fibrosis model group and control group. The rat model was established by an intratracheal instillation of bleomycin (BLM). Control rats were treated with saline. Positron emission tomography/computed tomography (CT) with [18F]ML-8 or 18F-fluorodeoxyglucose ([18F]FDG) was performed on 2 groups. After PET/CT imaging, lung tissues were collected for histologic examination. Data were analyzed and comparisons between 2 groups were performed using Student t test. RESULTS: Bleomycin-treated rats showed a higher lung uptake of [18F]ML-8 than control rats ( P < .05). In BLM-treated rats, the lung to muscle relative uptake ratio of [18F]ML-8 was also higher than that of [18F]FDG ( P < .05). Pathological examination showed overproliferation of fibroblasts and deposition of collagen in lungs from BLM-treated rats. Compared to control rats, BLM-treated rats had higher lung hydroxyproline content ( P < .05). Immunofluorescence staining indicated more apoptotic cells in BLM-treated rats than those in control rats. Moreover, the apoptosis rate of lung tissues obtained from BLM-treated rats was higher than that from control rats ( P < .05). CONCLUSIONS: 2-(3-[18F]fluoropropyl)-2-methyl-malonic acid PET/CT could be used for noninvasive diagnosis of pulmonary fibrosis in a rat model.


Assuntos
Apoptose , Ácido Metilmalônico/análogos & derivados , Tomografia por Emissão de Pósitrons , Fibrose Pulmonar/diagnóstico por imagem , Fibrose Pulmonar/patologia , Animais , Fluordesoxiglucose F18/química , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Ácido Metilmalônico/química , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Ratos Sprague-Dawley
4.
Sci Rep ; 7(1): 17153, 2017 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-29215055

RESUMO

Together, the three human rhinovirus (RV) species are the most frequent cause of the common cold. Because of their high similarity with other viral species of the genus Enterovirus, within the large family Picornaviridae, studies on RV infectious activities often offer a less pathogenic model for more aggressive enteroviruses, e.g. poliovirus or EV71. Picornaviruses enter via receptor mediated endocytosis and replicate in the cytosol. Most of them depend on functional F-actin, Rab proteins, and probably motor proteins. To assess the latter, we evaluated the role of myosin light chain kinase (MLCK) and two myosin V isoforms (Va and Vb) in RV-B14 infection. We report that ML-9, a very specific MLCK inhibitor, dramatically reduced RV-B14 entry. We also demonstrate that RV-B14 infection in cells expressing dominant-negative forms of myosin Va and Vb was impaired after virus entry. Using immunofluorescent localization and immunoprecipitation, we show that myosin Va co-localized with RV-B14 exclusively after viral entry (15 min post infection) and that myosin Vb was present in the clusters of newly synthesized RNA in infected cells. These clusters, observed at 180 min post infection, are reminiscent of replication sites. Taken together, these results identify myosin light chain kinase, myosin Va and myosin Vb as new players in RV-B14 infection that participate directly or indirectly in different stages of the viral cycle.


Assuntos
Infecções por Enterovirus/prevenção & controle , Ácido Metilmalônico/análogos & derivados , Cadeias Pesadas de Miosina/antagonistas & inibidores , Miosina Tipo V/antagonistas & inibidores , Quinase de Cadeia Leve de Miosina/antagonistas & inibidores , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Infecções por Enterovirus/metabolismo , Infecções por Enterovirus/virologia , Células HeLa , Humanos , Ácido Metilmalônico/farmacologia , Fosforilação , Rhinovirus/efeitos dos fármacos , Rhinovirus/fisiologia
5.
Mol Imaging ; 16: 1536012116685941, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28654376

RESUMO

PURPOSE: We investigated 2-(5-fluoro-pentyl)-2-methyl-malonic acid (18F-ML-10) positron emission tomography (PET) imaging of apoptosis posttherapy to determine optimal timing for predicting chemotherapy response in a mouse head/neck xenograft cancer model. PROCEDURES: BALB/c nude mice (4-8 weeks old) were implanted with UM-SCC-22B tumors. The treatment group received 2 doses of doxorubicin (10 mg/kg, days 0, 2). Small animal 18F-ML-10 PET/computed tomography was performed before and on days 1, 3, and 7 postchemotherapy. Using regions of interest around tumors, 18F-ML-10 uptake change was measured as %ID/g and uptake relative to liver. Terminal Uridine Nick-End Labeling (TUNEL) immunohistochemistry assay was performed using tumor samples of baseline and on days 1, 3, and 7 posttreatment. RESULTS: Treated mice demonstrated increased 18F-ML-10 uptake compared to baseline and controls, and 10 of 13 mice showed tumor volume decreases. All control mice showed tumor volume increases. Tumor-to-liver (T/L) ratios from the control group mice did not show significant change from baseline ( P > .05); however, T/L ratios of the treatment group showed significant 18F-ML-10 uptake differences from baseline compared to days 3 and 7 posttreatment ( P < .05), but no significant difference at 1 day posttreatment. CONCLUSION: 2-(5-Fluoro-pentyl)-2-methyl-malonic acid PET imaging has the potential for early assessment of treatment-induced apoptosis. Timing and image analysis strategies may require optimization, depending on the type of tumor and cancer treatment.


Assuntos
Apoptose/fisiologia , Fluordesoxiglucose F18/análise , Ácido Metilmalônico/análogos & derivados , Tomografia por Emissão de Pósitrons/métodos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Feminino , Humanos , Imuno-Histoquímica , Ácido Metilmalônico/análise , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Tomografia Computadorizada por Raios X , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Appl Radiat Isot ; 123: 49-53, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28236717

RESUMO

[18F]ML-10 (2-(5-[18F]fluoro-pentyl)-2-methylmalonic acid) is a small molecule positron emission tomography (PET) probe for apoptosis imaging. Automated synthesis of [18F]ML-10 was developed by using two different purification methods through a direct saponification procedure on a modified commercial [18F]Fluoro-2-Deoxyglucose ([18F]FDG) synthesizer. C18 purification method 1: The final [18F]ML-10 solution containing ethanol was obtained with radiochemical yields of 60±5% (n=5) at the end of bombardment (EOB) and radiochemical purity of 98% in 35min. Al2O3 and SCX purification method 2: To avoid possible side effects of a conventional ethanol-containing formulation, an new ethanol-free solution of [18F]ML-10 was also developed, the radiochemical yields was 50±5% (n=5, EOB) within 45min and the radiochemical purity was 98%.


Assuntos
Radioisótopos de Flúor/química , Ácido Metilmalônico/análogos & derivados , Compostos Radiofarmacêuticos/síntese química , Animais , Apoptose , Técnicas de Química Sintética/instrumentação , Desenho de Equipamento , Fluordesoxiglucose F18/síntese química , Fluordesoxiglucose F18/química , Humanos , Ácido Metilmalônico/síntese química , Ácido Metilmalônico/química , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Tecnologia Radiológica/instrumentação
7.
FEBS Lett ; 590(24): 4507-4518, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27859061

RESUMO

The cysteine peptidase cathepsin K is a potent collagenolytic enzyme and a promising target for the treatment of osteoporosis. Here, we characterize its allosteric fine-tuning via a recently identified allosteric site. We show that compound NSC94914 binds this site and acts as a specific partial inhibitor of the collagenolytic activity of cathepsin K. We link the functional differences between NSC94914 and known effectors (compound NSC11345 and glycosaminoglycans) to their different modes of interaction with the site. We characterize the allosteric site by site-directed mutagenesis and show that it is involved in specific regulation of the collagenolytic activity of cathepsin K.


Assuntos
Benzoatos/química , Catepsina K/química , Glicosaminoglicanos/química , Ácido Metilmalônico/análogos & derivados , Inibidores de Proteases/química , Regulação Alostérica , Sítio Alostérico , Catepsina K/antagonistas & inibidores , Catepsina K/genética , Catepsina K/metabolismo , Colágeno/química , Colágeno/metabolismo , Cristalografia por Raios X , Elastina/química , Elastina/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Humanos , Hidrólise , Cinética , Modelos Moleculares , Mutagênese Sítio-Dirigida , Mutação , Domínios Proteicos , Estrutura Secundária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato
8.
Oncotarget ; 7(15): 20743-52, 2016 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-26942701

RESUMO

Previous studies have reported that the radiosensitivity is associated with apoptosis. Hereby, we aimed to investigate the value of 18F-ML-10 PET/CT, which selectively targeted cells undergoing apoptosis, in predicting radiosensitivity of human nasopharyngeal carcinoma (NPC) xenografts. We used CNE1 (highly differentiated) and CNE2 (poorly differentiated) NPC cell lines to construct tumor models, which had very different radiosensitivities. After irradiation, the volumes of CNE2 tumors decreased significantly while those of CNE1 tumors increased. In 18F-ML-10 imaging, the values of tumor/muscle (T/M) between CNE1 and CNE2 mice were statistically different at both 24 h and 48 h after irradiation. Besides, ΔT/M1-0 and ΔT/M2-0 of CNE2 mice were higher than those of CNE1 mice, demonstrating obvious discrepancy. Furthermore, we observed obvious changes of radioactive distribution in CNE2 group. On the contrary, T/M of 18F-FDG in irradiation group revealed no obvious change in both CNE1 and CNE2 groups. In conclusion, 18F-ML-10 animal PET/CT showed its potential to predict radiosensitivity in NPC.


Assuntos
Carcinoma de Células Escamosas/patologia , Carcinoma/patologia , Ácido Metilmalônico/análogos & derivados , Neoplasias Nasofaríngeas/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Cintilografia/métodos , Animais , Apoptose , Carcinoma/diagnóstico por imagem , Carcinoma/metabolismo , Carcinoma/radioterapia , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/radioterapia , Proliferação de Células , Humanos , Masculino , Ácido Metilmalônico/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/diagnóstico por imagem , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/radioterapia , Tolerância a Radiação , Compostos Radiofarmacêuticos/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Mol Imaging Biol ; 18(1): 117-26, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26013478

RESUMO

PURPOSE: The first biological evaluation of two potent fluorine-18 radiolabelled inhibitors of caspase-3/7 was achieved in a cerebral stroke rat model to visualize apoptosis. PROCEDURES: In vivo characteristics of isatins [(18)F]-2 and [(18)F]-3 were studied and compared by µPET to previously described 1-[4-(2-[(18)F]fluoroethyl)benzyl]-5-(2-methoxymethylpyrrolidin-1-ylsulfonyl)isatin ([(18)F]-1) and to 2-(5-[(18)F]fluoropentyl)-2-methyl-malonic acid ([(18)F]ML-10) used as a reference radiotracer in a rat stroke model. RESULTS: [(18)F]-2 and [(18)F]-3 were radiolabelled with high radiochemical purity and high specific radioactivity. Radioactivity uptakes in ischemic and contralateral brain regions were weak for the three radiolabelled isatins and lower for [(18)F]ML-10. In µPET, time activity curves showed significant uptake differences between both regions of interest for [(18)F]-1 after 45 min. No differences were observed for [(18)F]ML-10. CONCLUSIONS: Radiolabelled isatins are more promising radiotracers to image apoptosis than [(18)F]ML-10 in this stroke animal model without craniectomy. In particular, [(18)F]-1 presented significant uptake in apoptotic area 45 min after administration.


Assuntos
Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Inibidores de Caspase/farmacologia , Ácido Metilmalônico/análogos & derivados , Imagem Molecular/métodos , Compostos Radiofarmacêuticos/farmacologia , Acidente Vascular Cerebral/diagnóstico por imagem , Animais , Inibidores de Caspase/sangue , Inibidores de Caspase/farmacocinética , Modelos Animais de Doenças , Isatina/química , Isatina/farmacologia , Masculino , Ácido Metilmalônico/farmacocinética , Ácido Metilmalônico/farmacologia , Cintilografia , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/farmacocinética , Ratos Sprague-Dawley , Acidente Vascular Cerebral/patologia , Distribuição Tecidual/efeitos dos fármacos
10.
Mol Imaging ; 14: 433-42, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26431738

RESUMO

[18F]ML-10 (2-(5-fluoro-pentyl)-2-methylmalonic acid) is a positron emission tomography (PET) radiotracer that accumulates in cells presenting apoptosis-specific membrane alterations. The aim of this study was to test whether [18F]ML-10 allows for the detection of apoptotic cells located in atherosclerotic plaques in rabbits. Atherosclerotic plaques were induced in the aortas of five rabbits, and five additional rabbits were used as controls. Activity in the aortas was quantified in vivo and ex vivo. The localization of [18F]ML-10 to the aortic wall was identified by autoradiography. Average target to background ratios measured in vivo by PET were higher in the aortas of atherosclerotic rabbits compared with those of control rabbits (2.00 ± 0.52 vs 1.22 ± 0.30; p < .05). Differences in [18F]ML-10 uptake between atherosclerotic and control aortas were confirmed ex vivo by PET and gamma counting (23.9 ± 11.2 vs 1.1 ± 2.4 counts/pixel; p <.05; 3.6 ± 2.0 vs 0.05 ± 0.05 % of injected activity/g; p < .05, respectively). Strong correlation was observed between the accumulation of [18F]ML-10 in aortic segments as detected by autoradiography and the number of apoptotic cells on corresponding histologic sections (r2 = .75; p < .05). In this study, we found that atherosclerotic plaques rich in apoptotic cells can be detected with [18F]ML-10 and PET.


Assuntos
Aterosclerose/diagnóstico por imagem , Aterosclerose/patologia , Ácido Metilmalônico/análogos & derivados , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/metabolismo , Animais , Aorta/diagnóstico por imagem , Aorta/patologia , Modelos Animais de Doenças , Radioisótopos de Flúor , Injeções , Masculino , Ácido Metilmalônico/metabolismo , Coelhos
11.
Biomed Res Int ; 2015: 317403, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25977920

RESUMO

In this paper, a novel small-molecular apoptotic PET imaging probe, (18)F-ML-8 with a malonate motif structure, is presented and discussed. After study, the small tracer that belongs to a member of ApoSense family is proved to be capable of imaging merely apoptotic regions in the CTX treated tumor-bearing mice. The experimental result is further confirmed by in vitro cell binding assays and TUNEL staining assay. As a result, (18)F-ML-8 could be used for noninvasive visualization of apoptosis induced by antitumor chemotherapy.


Assuntos
Apoptose/efeitos dos fármacos , Ciclofosfamida/farmacologia , Ácido Metilmalônico/análogos & derivados , Ácido Metilmalônico/farmacologia , Imagem Molecular/métodos , Tomografia por Emissão de Pósitrons/métodos , Animais , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Marcação In Situ das Extremidades Cortadas , Injeções Intravenosas , Células Jurkat , Ácido Metilmalônico/administração & dosagem , Ácido Metilmalônico/síntese química , Ácido Metilmalônico/química , Ácido Metilmalônico/isolamento & purificação , Camundongos Nus , Distribuição Tecidual
12.
Brain Behav ; 4(2): 312-5, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24683522

RESUMO

OBJECTIVES: The authors present the first use of the novel positron emission tomography (PET) apoptosis tracer (18)F-labeled 2-(5-fluoro-pentyl)-2-methyl-malonic acid ((18)F-ML-10) for early-therapy response assessment of a newly diagnosed glioblastoma multiforme (GBM) patient. CASE REPORT: A 71-year-old male with a newly diagnosed GBM received (18)F-ML-10 PET scans prior to therapy initiation (baseline) and after completing 3 weeks of whole-brain radiation therapy with concomitant temozolomide chemotherapy (early-therapy assessment, ETA). The baseline (18)F-ML-10 PET scan showed increased tracer uptake at the site of the GBM, with highest activity toward the central portion of the tumor. At the ETA time point, a new distribution of tracer uptake was observed compared to baseline. Normalized pixel-by-pixel subtraction of baseline from ETA was used to quantify change in tracer distribution between (18)F-ML-10 PET imaging time points. Results of this analysis showed reduction in (18)F-ML-10 uptake at the site of greatest baseline uptake, but increased uptake around the periphery of the tumor at the early-therapy time point. CONCLUSION: The changing patterns of (18)F-ML-10 uptake between baseline and ETA are suggestive for therapy-induced tumor cellular apoptosis.


Assuntos
Apoptose , Neoplasias Encefálicas , Glioblastoma , Ácido Metilmalônico/análogos & derivados , Tomografia por Emissão de Pósitrons/métodos , Idoso , Antineoplásicos Alquilantes/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Glioblastoma/diagnóstico por imagem , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Humanos , Masculino , Temozolomida , Resultado do Tratamento
14.
J Labelled Comp Radiopharm ; 56(5): 289-94, 2013 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24285373

RESUMO

Microfluidics technology has emerged as a powerful tool for the radiosynthesis of positron emission tomography (PET) and single-photon emission computed tomography radiolabeled compounds. In this work, we have exploited a continuous flow microfluidic system (Advion, Inc., USA) for the [(18) F]-fluorine radiolabeling of the malonic acid derivative, [(18) F] 2-(5-fluoro-pentyl)-2-methyl malonic acid ([(18) F]-FPMA), also known as [(18) F]-ML-10, a radiotracer proposed as a potential apoptosis PET imaging agent. The radiosynthesis was developed using a new tosylated precursor. Radiofluorination was initially optimized by manual synthesis and served as a basis to optimize reaction parameters for the microfluidic radiosynthesis. Under optimized conditions, radio-thin-layer chromatography analysis showed 79% [(18) F]-fluorine incorporation prior to hydrolysis and purification. Following hydrolysis, the [(18) F]-FPMA was purified by C18 Sep-Pak, and the final product was analyzed by radio-HPLC (high-performance liquid chromatography). This resulted in a decay-corrected 60% radiochemical yield and ≥98% radiochemical purity. Biodistribution data demonstrated rapid blood clearance with less than 2% of intact [(18) F]-FPMA radioactivity remaining in the circulation 60 min post-injection. Most organs showed low accumulation of the radiotracer, and radioactivity was predominately cleared through kidneys (95% in 1 h). Radio-HPLC analysis of plasma and urine samples showed a stable radiotracer at least up to 60 min post-injection.


Assuntos
Marcação por Isótopo/métodos , Ácido Metilmalônico/análogos & derivados , Microfluídica/métodos , Compostos Radiofarmacêuticos/síntese química , Animais , Radioisótopos de Flúor/química , Radioisótopos de Flúor/farmacocinética , Ácido Metilmalônico/síntese química , Ácido Metilmalônico/farmacocinética , Camundongos , Camundongos Nus , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual
15.
J Labelled Comp Radiopharm ; 56(6): 330-3, 2013 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-24285414

RESUMO

[(18)F]ML10 is a promising novel low molecular weight positron emission tomography probe for apoptosis. As part of the quality control to support clinical studies for cancer therapy monitoring in the GSK Clinical Imaging Centre, a simple and sensitive liquid chromatography mass spectrometry method has been developed and validated for the quantification of total ML10 and impurity content in the final product. Chromatographic separation of ML10 and its radiolabelling precursor and impurities was achieved. Mass curves were constructed from a concentration range of ML10 and known impurities and were linear. Quantification was achieved by comparison of the area under the curve for ML10 content (m/z = 205) and the mass curve. The method was validated over a concentration range of 0.1-1 µg/ml.


Assuntos
Radioisótopos de Flúor/normas , Cromatografia Gasosa-Espectrometria de Massas/métodos , Ácido Metilmalônico/análogos & derivados , Controle de Qualidade , Compostos Radiofarmacêuticos/normas , Radioisótopos de Flúor/química , Ácido Metilmalônico/síntese química , Ácido Metilmalônico/química , Compostos Radiofarmacêuticos/química
16.
Q J Nucl Med Mol Imaging ; 57(2): 187-200, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23389693

RESUMO

AIM: Recently, 18F-labeled 2-(5-fluoropentyl)-2-methylmalonic acid or ML10 has been proposed as a promising PET tracer for imaging of apoptosis. In this study we compared 18F-ML10, the 123I labeled 5-iodo derivative (123I-ML10) and a 68Ga-labeled Annexin A5 (AnxA5) and evaluated them as apoptosis tracers in several distinct models. METHODS: In vivo stability and biodistribution were studied in healthy mice. Apoptosis imaging was evaluated in anti-Fas treated mice and mice with muscular apoptosis. Furthermore, 18F-ML10 and 68Ga-Cys2-AnxA5 were evaluated in a rat model with reperfused liver infarct and a rat model with cerebral infarct as well as in Daudi tumor bearing mice, before and after treatment with cyclophosphamide and/or radiotherapy. RESULTS: 18F-ML10 and 68Ga-Cys2-AnxA5 were both stable, while 123I-ML10 metabolized very quickly in vivo. All tracers showed a 3-4 times higher uptake in apoptotic muscular tissue in comparison to that in healthy muscular tissue. Animals with anti-Fas induced hepatic apoptosis showed an increased liver uptake which was most pronounced for 18F-ML10. The uptake of both 18F-ML10 and 68Ga-Cys2-AnxA5 increased in the apoptotic region surrounding the cerebral infarction and the reperfused liver infarction. Tumor uptake of 68Ga-Cys2-AnxA5, but not of 18F-ML10, was statistically significantly higher after therapy as measured with PET/MRI. CONCLUSION: All radiotracers were able to detect apoptosis in vitro and in vivo in each of the studied animal models of apoptosis. 68Ga-Cys2-AnxA5, but not 18F-ML10, allowed to visualize the effect of tumor therapy in a statistically significant way.


Assuntos
Anexina A5 , Ácido Metilmalônico/análogos & derivados , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/radioterapia , Tomografia por Emissão de Pósitrons/métodos , Animais , Apoptose , Linhagem Celular Tumoral , Radioisótopos de Flúor , Radioisótopos de Gálio , Radioisótopos do Iodo , Marcação por Isótopo , Masculino , Camundongos , Neoplasias Experimentais/patologia , Compostos Radiofarmacêuticos , Ratos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Resultado do Tratamento
17.
Mol Imaging Biol ; 15(1): 12-8, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22752653

RESUMO

PURPOSE: [(18)F]ML-10 is the most advanced radiopharmaceutical for the clinical imaging of the apoptosis phenomenon by PET. The preparation of this radiopharmaceutical on a commercial radiosynthesis module and the requested quality controls for its release are presented herein. PROCEDURES: ML-10 as reference and its mesyloxy derivative as precursor for labelling with fluorine-18 were prepared. [(18)F]ML-10 was synthesized via a [(18)F]fluorine-de-mesyloxy aliphatic nucleophilic substitution via a GE TRACERLab® FX-FN module. Quality controls were performed. RESULTS: The labelling precursor was obtained in a four step synthesis in 28 % overall yield affording ML-10 in two steps (88 % yield). Pure [(18)F]ML-10 was obtained with a decay corrected yield of 39.8 % ± 8.4 % (n = 7) in 70 min and a specific activity of 235 ± 85 GBq/µmol at the end of synthesis. CONCLUSIONS: [(18)F]ML-10 was prepared on a widely available automated module and passed the quality control. A LC/MS method was developed to measure specific radioactivity.


Assuntos
Ácido Metilmalônico/análogos & derivados , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/síntese química , Apoptose/fisiologia , Cinética , Ácido Metilmalônico/síntese química , Ácido Metilmalônico/química , Imagem Molecular/métodos , Compostos Radiofarmacêuticos/química
18.
Eur J Nucl Med Mol Imaging ; 39(9): 1400-8, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22699524

RESUMO

PURPOSE: Early assessment of tumor response to therapy is vital for treatment optimization for the individual cancer patient. Induction of apoptosis is an early and nearly universal effect of anticancer therapies. The purpose of this study was to assess the performance of (18)F-ML-10, a novel PET radiotracer for apoptosis, as a tool for the early detection of response of brain metastases to whole-brain radiation therapy (WBRT). MATERIALS AND METHODS: Ten patients with brain metastases treated with WBRT at 30 Gy in ten daily fractions were enrolled in this trial. Each patient underwent two (18)F-ML-10 PET scans, one prior to the radiation therapy (baseline scan), and the second after nine or ten fractions of radiotherapy (follow-up scan). MRI was performed at 6-8 weeks following completion of the radiation therapy. Early treatment-induced changes in tumor (18)F-ML-10 uptake on the PET scan were measured by voxel-based analysis, and were then evaluated by correlation analysis as predictors of the extent of later changes in tumor anatomical dimensions as seen on MRI scans 6-8 weeks after completion of therapy. RESULTS: In all ten patients, all brain lesions were detected by both MRI and the (18)F-ML-10 PET scan. A highly significant correlation was found between early changes on the (18)F-ML-10 scan and later changes in tumor anatomical dimensions (r = 0.9). CONCLUSION: These results support the potential of (18)F-ML-10 PET as a novel tool for the early detection of response of brain metastases to WBRT.


Assuntos
Apoptose , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Ácido Metilmalônico/análogos & derivados , Tomografia por Emissão de Pósitrons/métodos , Adulto , Idoso , Transporte Biológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Ácido Metilmalônico/efeitos adversos , Ácido Metilmalônico/metabolismo , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/efeitos adversos , Traçadores Radioativos , Segurança , Razão Sinal-Ruído , Resultado do Tratamento
19.
J Nucl Med ; 52(5): 720-5, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21498526

RESUMO

UNLABELLED: Clinical PET of apoptosis may have substantial value in advancing patient care. We report here the first-in-humans study with (18)F-labeled 2-(5-fluoropentyl)-2-methyl malonic acid ((18)F-ML-10), a small-molecule PET tracer for apoptosis. Presented are the dosimetry, biodistribution, stability, and safety profiles of this PET tracer in healthy human volunteers. Also reported is tracer binding to targeted apoptotic cells in testicular tissue, where a relative abundance of apoptotic cells is normally observed. METHODS: (18)F-ML-10 (233 ± 90 MBq) was intravenously administered to 8 healthy subjects, followed by whole-body PET/CT for 220 min. Serial blood and urine samples were collected for radioactivity measurement, and plasma tracer stability was assessed by high-performance liquid chromatography. Dosimetry calculations were performed using OLINDA/EXM software. RESULTS: (18)F-ML-10 manifested high stability in vivo and rapid distribution followed by fast clearance, with an elimination half-life of 1.3 ± 0.1 and 1.1 ± 0.2 h from the blood and from all other organs, respectively, and excretion through the urine. Dosimetry showed an average effective whole-body dose of 15.4 ± 3.7 µSv/MBq, with the urinary bladder being the dose-limiting organ. Selective accumulation and retention of the tracer in the testes was observed in all male subjects, a finding also demonstrated in mice using both small-animal PET and histopathology, confirming binding to apoptotic cells. Administration of (18)F-ML-10 was safe, without adverse effects. CONCLUSION: (18)F-ML-10 administered to healthy humans demonstrated a favorable dosimetry, biodistribution, stability, and safety profile. Binding to apoptotic sites was also demonstrated. These data support further development of this small-molecule probe for clinical PET of apoptosis.


Assuntos
Apoptose , Ácido Metilmalônico/análogos & derivados , Tomografia por Emissão de Pósitrons/métodos , Adulto , Animais , Transporte Biológico , Estabilidade de Medicamentos , Feminino , Humanos , Masculino , Ácido Metilmalônico/efeitos adversos , Ácido Metilmalônico/metabolismo , Ácido Metilmalônico/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Traçadores Radioativos , Radiometria , Segurança , Espermatogênese , Testículo/citologia , Testículo/metabolismo , Adulto Jovem
20.
Anal Chem ; 81(24): 10246-53, 2009 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-19904966

RESUMO

A selective and sensitive molecular sensor for trivalent lanthanide (Ln(3+)) ions based upon a malonamide-functionalized gold nanoparticle was developed for colorimetric detection in water. A new synthetic approach permits nanoparticle synthesis, stabilization, and incorporation of a selective lanthanide binding site in a single, direct step. The design incorporates a specifically tailored dual function precursor ligand that bears a sodium thiosulfate (Bunte salt) group that links to the gold nanoparticle core and a tetramethylmalonamide (TMMA) group that serves as a selective Ln(3+) binding site. The sensor's colorimetric response to lanthanide ions is immediate, and it is sensitive down to approximately 50 nM for Eu(3+) and Sm(3+). This study demonstrates a general strategy for direct, convenient nanoparticle synthesis that enables the incorporation of analyte binding groups directly to the nanoparticle surface, allowing colorimetric sensors to be developed for widespread use. The one-step synthesis offers uniform surface ligand composition, reduces the volume of waste generated during nanoparticle synthesis and purification, produces functionalized gold nanoparticles that are stable in nonmodified aqueous environments, and offers colorimetric detection at ambient temperature.


Assuntos
Ouro/química , Elementos da Série dos Lantanídeos/análise , Nanopartículas Metálicas/química , Ácido Metilmalônico/análogos & derivados , Ácido Metilmalônico/química , Sítios de Ligação , Colorimetria , Íons/análise , Água/química
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