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1.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803361

RESUMO

Radionuclide imaging of HER2 expression in tumours may enable stratification of patients with breast, ovarian, and gastroesophageal cancers for HER2-targeting therapies. A first-generation HER2-binding affibody molecule [99mTc]Tc-ZHER2:V2 demonstrated favorable imaging properties in preclinical studies. Thereafter, the affibody scaffold has been extensively modified, which increased its melting point, improved storage stability, and increased hydrophilicity of the surface. In this study, a second-generation affibody molecule (designated ZHER2:41071) with a new improved scaffold has been prepared and characterized. HER2-binding, biodistribution, and tumour-targeting properties of [99mTc]Tc-labelled ZHER2:41071 were investigated. These properties were compared with properties of the first-generation affibody molecules, [99mTc]Tc-ZHER2:V2 and [99mTc]Tc-ZHER2:2395. [99mTc]Tc-ZHER2:41071 bound specifically to HER2 expressing cells with an affinity of 58 ± 2 pM. The renal uptake for [99mTc]Tc-ZHER2:41071 and [99mTc]Tc-ZHER2:V2 was 25-30 fold lower when compared with [99mTc]Tc-ZHER2:2395. The uptake in tumour and kidney for [99mTc]Tc-ZHER2:41071 and [99mTc]Tc-ZHER2:V2 in SKOV-3 xenografts was similar. In conclusion, an extensive re-engineering of the scaffold did not compromise imaging properties of the affibody molecule labelled with 99mTc using a GGGC chelator. The new probe, [99mTc]Tc-ZHER2:41071 provided the best tumour-to-blood ratio compared to HER2-imaging probes for single photon emission computed tomography (SPECT) described in the literature so far. [99mTc]Tc-ZHER2:41071 is a promising candidate for further clinical translation studies.


Assuntos
Antineoplásicos Imunológicos , Rim , Neoplasias Experimentais , Compostos Radiofarmacêuticos , Receptor ErbB-2/metabolismo , Tecnécio , Tomografia Computadorizada de Emissão de Fóton Único , Animais , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacocinética , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Rim/diagnóstico por imagem , Rim/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/farmacologia , Tecnécio/química , Tecnécio/farmacocinética , Tecnécio/farmacologia , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
2.
AJR Am J Roentgenol ; 216(6): 1634-1640, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33852335

RESUMO

OBJECTIVE. Knowledge of normal testicular 18F-FDG PET/CT (FDG PET/CT) SUVs is crucial for accurate examination interpretation. The objective of this study was to establish normal testicular SUV ranges among adult men receiving health care in North America. MATERIALS AND METHODS. A retrospective review of an institutional electronic database identified adult men undergoing pretreatment clinical FDG PET/CT examinations from March 15, 2013, through March 15, 2018. An FDG PET/CT image review of 700 testicles in 350 male patients was performed. Data collected included testicular SUVmax, SUVmean, and visual PET pattern of uptake. RESULTS. Testicular SUVmean and SUVmax values (mean ± SD) by age group were as follows: 3.1 ± 0.7 and 3.8 ± 0.9 for the age group of 18-30 years; 3.2 ± 0.6 and 4.0 ± 0.8, 31-40 years; 3.1 ± 0.4 and 3.8 ± 0.5, 41-50 years; 3.0 ± 0.5 and 3.7 ± 0.7, 51-60 years; 2.9 ± 0.5 and 3.5 ± 0.7, 61-70 years; 2.8 ± 0.5 and 3.5 ± 0.7, 71-80 years; and 2.6 ± 0.5 and 3.3 ± 0.6, more than 80 years. A statistically significant difference exists between age groups for testicular SUVmean (p ≤ .001) and SUVmax (p < .001), with SUVs peaking in the 4th decade of life and subsequently declining with age. A small but significant negative correlation exists between blood glucose level and testicular SUVmean (r = -0.12). CONCLUSION. This study reports the largest currently known cohort of SUVs in normal testicles and may guide clinical interpretation of testicular FDG activity. Discrepancies in normal SUVs may exist because of differences in patient demographics and PET technology.


Assuntos
Fluordesoxiglucose F18/farmacocinética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Compostos Radiofarmacêuticos/farmacocinética , Testículo/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Estudos Retrospectivos , Testículo/diagnóstico por imagem , Testículo/fisiologia , Adulto Jovem
3.
AAPS PharmSciTech ; 22(3): 115, 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33763814

RESUMO

Nanomedicine is a highly demanded discipline. Liposomes have seen an increased attention due to their physicochemical properties that allow them to act as nanocarriers of drugs and also of radioisotopes that can be used to diagnose and treat cancer. In order to obtain a novel permeability cancer imaging agent based on 99mTc-labeled liposomes, we describe microwave-assisted synthesis of stearyl 6-(benzylidenehydrazinyl) nicotinamide lipid, which was included in two formulations: nanometric hydrazinonicotinic acid (HYNIC) liposome and its PEGylated coated analogue, HYNIC-PEG liposome. Radiolabeling with 99mTc via stearyl 6-(benzylidenehydrazinyl) nicotinamide was found to be easy, reproducible, and stable, revealing high radiochemical purity (94 ± 1.7%) for both liposomal formulations. Biodistribution at 4 h and 24 h and scintigraphic images at 4 h were performed in normal and melanoma-bearing C57BL/6 mice. Biodistribution studies at 4 h showed tumor uptake of 99mTc-HYNIC liposome and 99mTc-HYNIC-PEG liposome (1.1 ± 0.6 and 2.5 ± 0.4, respectively) and also at 24 h p.i. (1.8 ± 0.5 and 3.0 ± 1.1, respectively). Scintigraphic images showed appreciable tumor uptake in melanoma tumor-bearing mice with both liposomal formulations. Our results show that 99mTc stearyl 6-(benzylidenehydrazinyl) nicotinamide liposomes can be used as diagnostic noninvasive in vivo tumor-targeting agents capable of evaluating tumor permeability and development who can be used in personalized chemotherapy planning.


Assuntos
Melanoma Experimental/metabolismo , Niacinamida/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Tecnécio/farmacocinética , Animais , Linhagem Celular Tumoral , Lipossomos , Melanoma Experimental/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Niacinamida/administração & dosagem , Niacinamida/química , Permeabilidade/efeitos dos fármacos , Cintilografia/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/química , Tecnécio/administração & dosagem , Tecnécio/química , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/fisiologia
4.
Int J Nanomedicine ; 16: 1943-1960, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33727808

RESUMO

Introduction: The overexpression of Human Epidermal Growth Factor Receptor 2 (HER2) is usually associated with aggressive and infiltrating breast cancer (BC) phenotype, and metastases. Functionalized silica-based nanocarriers (SiNPs) can be labeled for in vivo imaging applications and loaded with chemotherapy drugs, making possible the simultaneous noninvasive diagnosis and treatment (theranostic) for HER2-positive BC. Methods: Firstly, FITC-filled SiNPs, were engineered with two different amounts of Hc-TZ (trastuzumab half-chain) per single nanoparticle (1:2 and 1:8, SiNPs to Hc-TZ ratio), which was 99mTc-radiolabeled at histidine residues for ex vivo and in vivo biodistribution evaluations. Secondly, nanoparticles were loaded with DOX and their in vitro and ex vivo/in vivo delivery was assessed, in comparison with liposomal Doxorubicin (Caelyx). Finally, the treatment efficacy of DOX-SiNPs-TZ (1:8 Hc-TZ) was evaluated in vivo by PET and supported by MS-based proteomics profiling of tumors. Results: SiNPs-TZ (1:8 Hc-TZ) tumor uptake was significantly greater than that of SiNPs-TZ (1:2 Hc-TZ) at 6 hours post-injection (p.i.) in ex vivo biodistribution experiment. At 24 h p.i., radioactivity values remained steady. Fluorescence microscopy, confirmed the presence of radiolabeled SiNPs-TZ (1:8 Hc-TZ) within tumor even at later times. SiNPs-TZ (1:8 Hc-TZ) nanoparticles loaded with Doxorubicin (DOX-SiNPs-TZ) showed a similar DOX delivery capability than Caelyx (at 6 h p.i.), in in vitro and ex vivo assays. Nevertheless, at the end of treatment, tumor volume was significantly reduced by DOX-SiNPs-TZ (1:8 Hc-TZ), compared to Caelyx and DOX-SiNPs treatment. Proteomics study identified 88 high stringent differentially expressed proteins comparing the three treatment groups with controls. Conclusion: These findings demonstrated a promising detection specificity and treatment efficacy for our system (SiNPs-TZ, 1:8 Hc-TZ), encouraging its potential use as a new theranostic agent for HER2-positive BC lesions. In addition, proteomic profile confirmed that a set of proteins, related to tumor aggressiveness, were positively affected by targeted nanoparticles.


Assuntos
Neoplasias da Mama/diagnóstico , Portadores de Fármacos/química , Nanopartículas/química , Compostos Radiofarmacêuticos/química , Receptor ErbB-2/metabolismo , Dióxido de Silício/química , Tecnécio/química , Animais , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Doxorrubicina/análogos & derivados , Doxorrubicina/química , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Endocitose , Feminino , Fluoresceína-5-Isotiocianato/química , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Polietilenoglicóis/uso terapêutico , Proteoma/metabolismo , Proteômica , Compostos Radiofarmacêuticos/farmacocinética , Tecnécio/farmacocinética , Distribuição Tecidual/efeitos dos fármacos , Tomografia Computadorizada de Emissão de Fóton Único , Resultado do Tratamento
5.
J Int Soc Sports Nutr ; 18(1): 21, 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33676541

RESUMO

BACKGROUND: Electromyography (EMG) has been used for evaluating skeletal muscle activity during pitching. However, it is difficult to observe the influence of movement on skeletal muscle activity in deep-lying regions of the trunk and extremities using EMG. An alternative method that may be used is the measurement of glucose metabolism of skeletal muscle using positron emission tomography-computed tomography (PET-CT). This technique is a reliable measure of muscle metabolism, demonstrating a high correlation with the intensity of muscle activity. This study aimed to evaluate whole-body skeletal muscle metabolism during pitching using PET-CT. METHODS: Ten uninjured, skilled, adult pitchers, who were active at college or professional level, threw 40 baseballs at maximal effort before an intravenous injection of 37 MBq of 18F-fluorodeoxyglucose (FDG). Subsequently, additional 40 balls were pitched. PET-CT images were obtained 50 min after FDG injection, and regions of interest were defined within 72 muscles. The standardized uptake value (SUV) of FDG by muscle tissue per unit volume was calculated, and the mean SUV of the pitchers was compared with that of a healthy adult control group who did not exercise before the measurements. Statistical analysis was performed using a t-test, and P < 0.05 was considered statistically significant. RESULTS: Whole-body PET images showed a significant increase in glucose metabolism in the muscle groups of the fingers and toes in both the throwing and non-throwing sides. Additionally, asymmetric increases in glucose metabolism were observed in the muscles of the thigh. CONCLUSIONS: This is the first study to evaluate whole-body muscle metabolism during pitching using PET-CT. Our findings would be useful in determining the training required for pitchers, and can be further applied to other sporting activities that involve throwing.


Assuntos
Beisebol/fisiologia , Músculo Esquelético/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Imagem Corporal Total/métodos , Estudos de Casos e Controles , Dedos/diagnóstico por imagem , Fluordesoxiglucose F18/administração & dosagem , Fluordesoxiglucose F18/farmacocinética , Glucose/metabolismo , Humanos , Masculino , Músculo Esquelético/diagnóstico por imagem , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/farmacocinética , Coxa da Perna/diagnóstico por imagem , Fatores de Tempo , Dedos do Pé/diagnóstico por imagem , Adulto Jovem
6.
Biomed Res Int ; 2021: 6642973, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33778075

RESUMO

Introduction: The aminopeptidase N (APN/CD13) receptor plays an important role in the neoangiogenic process and metastatic tumor cell invasion. Clinical and preclinical studies reported that bestatin and actinonin are cytotoxic to APN/CD13-positive tumors and metastases due to their APN/CD13-specific inhibitor properties. Our previous studies have already shown that 68Ga-labeled NGR peptides bind specifically to APN/CD13 expressing tumor cells. The APN/CD13 specificity of 68Ga-NGR radiopharmaceuticals enables the following of the efficacy of antiangiogenic therapy with APN/CD13-specific inhibitors using positron emission tomography (PET). The aim of this in vivo study was to assess the antitumor effect of bestatin and actinonin treatment in subcutaneous transplanted HT1080 and B16-F10 tumor-bearing animal models using 68Ga-NODAGA-c(NGR). Materials and Methods: Three days after the inoculation of HT1080 and B16-F10 cells, mice were treated with intraperitoneal injection of bestatin (15 mg/kg) or actinonin (5 mg/kg) for 7 days. On the 5th and 10th day, in vivo PET scans and ex vivo biodistribution studies were performed 90 min after intravenous injection of 5.5 ± 0.2 MBq68Ga-NODAGA-c(NGR). Results: Control-untreated HT1080 and B16-F10 tumors were clearly visualized by the APN/CD13-specific 68Ga-NODAGA-c(NGR) radiopharmaceutical. The western blot analysis also confirmed the strong APN/CD13 positivity in the investigated tumors. We found significantly (p ≤ 0.05) lower radiopharmaceutical uptake after bestatin treatment and higher radiotracer accumulation in the actinonin-treated HT1080 tumors. In contrast, significantly lower (p ≤ 0.01) 68Ga-NODAGA-c(NGR) accumulation was observed in both bestatin- and actinonin-treated B16-F10 melanoma tumors compared to the untreated-control tumors. Bestatin inhibited tumor growth and 68Ga-NODAGA-c(NGR) uptake in both tumor models. Conclusion: The bestatin treatment is suitable for suppressing the neoangiogenic process and APN/CD13 expression of experimental HT1080 and B16-F10 tumors; furthermore, 68Ga-NODAGA-c(NGR) is an applicable radiotracer for the in vivo monitoring of the efficacy of the APN/CD13 inhibition-based anticancer therapies.


Assuntos
Acetatos , Antígenos CD13 , Radioisótopos de Gálio , Compostos Heterocíclicos com 1 Anel , Melanoma Experimental , Imagem Molecular , Proteínas de Neoplasias , Oligopeptídeos , Compostos Radiofarmacêuticos , Acetatos/farmacocinética , Acetatos/farmacologia , Animais , Antígenos CD13/antagonistas & inibidores , Antígenos CD13/metabolismo , Radioisótopos de Gálio/farmacocinética , Radioisótopos de Gálio/farmacologia , Compostos Heterocíclicos com 1 Anel/farmacocinética , Compostos Heterocíclicos com 1 Anel/farmacologia , Humanos , Masculino , Melanoma Experimental/diagnóstico por imagem , Melanoma Experimental/enzimologia , Camundongos , Camundongos SCID , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Oligopeptídeos/farmacocinética , Oligopeptídeos/farmacologia , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/farmacologia
7.
J Med Chem ; 64(4): 2151-2166, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33534560

RESUMO

In this study, we describe the development of heterobivalent [DUPA-6-Ahx-([111In]In-DO3A)-8-Aoc-BBN ANT] and [DUPA-6-Ahx-([177Lu]Lu-DO3A)-8-Aoc-BBN ANT] radiotracers that display very high selectivity/specificity for gastrin-releasing peptide receptor (GRPR)-/prostate-specific membrane antigen (PSMA)-expressing cells. These studies include metallation, purification, characterization, and in vitro and in vivo evaluation of the new small-molecule-/peptide-based radiopharmaceuticals having utility for imaging and potentially therapy. Competitive displacement binding assays using PC-3 cells and LNCaP cell membranes showed high binding affinity for the GRPR or the PSMA. Biodistribution studies showed favorable excretion pharmacokinetics with high tumor uptake in PC-3 or PC-3 prostatic inhibin peptide (PIP) tumor-bearing mice. For example, tumor accumulation at the 1 h time point ranged from (4.74 ± 0.90) to (7.51 ± 2.61)%ID/g. Micro-single-photon emission computed tomography (microSPECT) molecular imaging investigations showed very high uptake in tumors with minimal accumulation of tracers in the surrounding collateral tissues in xenografted mice at 4 h postintravenous injection. In conclusion, [DUPA-6-Ahx-([111In]In-DO3A)-8-Aoc-BBN ANT] and [DUPA-6-Ahx-([177Lu]Lu-DO3A)-8-Aoc-BBN ANT] tracers displayed favorable pharmacokinetic and excretion profiles with high uptake and retention in tumors.


Assuntos
Complexos de Coordenação/farmacologia , Corantes Fluorescentes/farmacologia , Glutamato Carboxipeptidase II/metabolismo , Glicoproteínas de Membrana/metabolismo , Compostos Radiofarmacêuticos/farmacologia , Receptores da Bombesina/metabolismo , Animais , Antígenos de Superfície/metabolismo , Linhagem Celular Tumoral , Complexos de Coordenação/farmacocinética , Corantes Fluorescentes/farmacocinética , Humanos , Radioisótopos de Índio/química , Lutécio/química , Masculino , Camundongos , Oligopeptídeos/farmacocinética , Oligopeptídeos/farmacologia , Medicina de Precisão/métodos , Radioisótopos/química , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único
8.
Molecules ; 26(4)2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33572353

RESUMO

The cholecystokinin-2 receptor (CCK-2R) is overexpressed in several human cancers but displays limited expression in normal tissues. For this reason, it is a suitable target for developing specific radiotracers. In this study, a nastorazepide-based ligand functionalized with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator (IP-001) was synthesized and labelled with indium-111. The radiolabeling process yielded >95% with a molar activity of 10 MBq/nmol and a radiochemical purity of >98%. Stability studies have shown a remarkable resistance to degradation (>93%) within 120 h of incubation in human blood. The in vitro uptake of [111In]In-IP-001 was assessed for up to 24 h on a high CCK-2R-expressing tumor cell line (A549) showing maximal accumulation after 4 h of incubation. Biodistribution and single photon emission tomography (SPECT)/CT imaging were evaluated on BALB/c nude mice bearing A549 xenograft tumors. Implanted tumors could be clearly visualized after only 4 h post injection (2.36 ± 0.26% ID/cc), although a high amount of radiotracer was also found in the liver, kidneys, and spleen (8.25 ± 2.21%, 6.99 ± 0.97%, and 3.88 ± 0.36% ID/cc, respectively). Clearance was slow by both hepatobiliary and renal excretion. Tumor retention persisted for up to 24 h, with the tumor to organs ratio increasing over-time and ending with a tumor uptake (1.52 ± 0.71% ID/cc) comparable to liver and kidneys.


Assuntos
Benzodiazepinas/química , Radioisótopos de Índio/farmacocinética , Neoplasias Pulmonares/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Receptor de Colecistocinina B/antagonistas & inibidores , Animais , Apoptose , Proliferação de Células , Feminino , Humanos , Radioisótopos de Índio/administração & dosagem , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Compostos Radiofarmacêuticos/administração & dosagem , Receptor de Colecistocinina B/metabolismo , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
AJR Am J Roentgenol ; 216(3): 769-775, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33405948

RESUMO

OBJECTIVE. Pulmonary intravascular metastasis is a special type of pulmonary metastasis of malignancies; however, few relevant studies have been performed. This study aimed to determine the characteristics of pulmonary intravascular metastasis and improve understanding of the disease by retrospective analysis of FDG PET/CT and thin-layer high-resolution CT (HRCT) imaging of the chest in patients with tumors. MATERIALS AND METHODS. We identified all patients who underwent FDG PET/CT at two hospitals between January 2016 and February 2019 and conducted a comparative analysis of HRCT and PET/CT images. In total, 84 patients (38 women and 46 men) ranging in age from 35 to 82 years old (mean age, 54.7 ± 14.5 [SD] years) participated in the study. Patient characteristics were summarized, and diagnosis was confirmed by chest CT or PET/CT follow-up. RESULTS. A total of 260 pulmonary intravascular metastases were found, which were classified as type I (no significant abnormality, n = 5), type II (abrupt and uneven thickening of the pulmonary vessel, n = 118), type III (simultaneous invasion of adjacent pulmonary vessel, n = 121), and type IV (large strip-shaped high-density mass, n = 16). The majority were located in peripheral pulmonary vessels (94.2% [245/260]). FDG up-take was increased in 252 lesions, and the mean SUVmax was 4.6 ± 2.5. CONCLUSION. The combination of PET/CT and chest HRCT is an effective approach for detecting pulmonary intravascular metastasis. The linear pattern of FDG uptake, abnormal pulmonary blood vessel morphology, and location (below the lung segment) are specific indicators for the diagnosis of pulmonary intravascular metastasis and should be recognized by clinicians and radiologists.


Assuntos
Fluordesoxiglucose F18 , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/secundário , Tomografia Computadorizada Multidetectores/métodos , Células Neoplásicas Circulantes , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Compostos Radiofarmacêuticos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Fluordesoxiglucose F18/farmacocinética , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Pulmão/irrigação sanguínea , Pulmão/diagnóstico por imagem , Pulmão/metabolismo , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/metabolismo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/metabolismo , Radiografia Torácica/métodos , Compostos Radiofarmacêuticos/farmacocinética , Estudos Retrospectivos
10.
AJR Am J Roentgenol ; 216(3): 759-768, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33474983

RESUMO

OBJECTIVE. The purpose of this article is to summarize the role of molecular imaging of the brain by use of SPECT, FDG PET, and non-FDG PET radiotracers in epilepsy. CONCLUSION. Quantitative image analysis with PET and SPECT has increased the diagnostic utility of these modalities in localizing epileptogenic onset zones. A multi-modal platform approach integrating the functional imaging of PET and SPECT with the morphologic information from MRI in presurgical evaluation of epilepsy can greatly improve outcomes.


Assuntos
Encéfalo/diagnóstico por imagem , Epilepsia/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada de Emissão de Fóton Único , Adolescente , Adulto , Criança , Pré-Escolar , Cisteína/análogos & derivados , Cisteína/farmacocinética , Feminino , Fluordesoxiglucose F18/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Organotecnécio/farmacocinética , Oximas/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética
11.
Life Sci ; 269: 119086, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33476634

RESUMO

AIM: To evaluate the diagnostic performance of combining 18F-2-fluoro-2-D-deoxyglucose-positron emission tomography (18F-FDG PET) and gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) for liver fibrosis staging. MATERIALS AND METHODS: Male New Zealand white rabbits (n = 48) were treated with carbon tetrachloride (CCl4) to induce liver fibrosis, while control group rabbits (n = 8) received normal saline. The liver tissues of rabbits were histopathologically examined (classified according to the METAVIR classification system) for liver fibrosis staging and real-time polymerase chain reaction (RT-PCR) was used to ensure diagnostic accuracy. Integrated PET/MRI was performed. The mean standardised uptake value (SUVmean) and relative enhancement (RE) were evaluated for different liver fibrosis stages using a Mann-Whitney U test. The performance of PET/MRI was evaluated by using the receiver operating characteristic curve (ROC) and the area under the ROC curve (AUC). KEY FINDINGS: In total, 10, 16, and 8 rabbits classified into no fibrosis (F0), mild fibrosis (F1-2), and severe fibrosis (F3-4) categories, respectively. There were significant differences in SUVmean and RE between F0 and F3-4 and between F1-2 and F3-4 (p < 0.01), but no significance between F0 and F1-2 (p > 0.5). Combined SUVmean and RE performed well in staging liver fibrosis, with AUC of 0.8 for F0 or greater, 0.744 for F0 or F1-2, 0.945 for F1-2 or F3-4, and 0.962 for F3-4. SIGNIFICANCE: Combining SUVmean and RE provides high accuracy for grading liver fibrosis, especially in the differentiation between F1-2 and F3-4. 18F-FDG and Gd-EOB-DTPA-enhanced PET/MRI could be a non-invasive diagnostic method to guide the selection of clinical treatment options.


Assuntos
Fluordesoxiglucose F18/farmacocinética , Gadolínio DTPA/farmacocinética , Cirrose Hepática/patologia , Imageamento por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Animais , Tetracloreto de Carbono/toxicidade , Meios de Contraste , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/metabolismo , Masculino , Coelhos , Distribuição Tecidual
13.
Arterioscler Thromb Vasc Biol ; 41(2): 822-836, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33327748

RESUMO

OBJECTIVE: vMIP-II (viral macrophage inflammatory protein 2)/vCCL2 (viral chemotactic cytokine ligand 2) binds to multiple chemokine receptors, and vMIP-II-based positron emission tomography tracer (64Cu-DOTA-vMIP-II: vMIP-II tracer) accumulates at atherosclerotic lesions in mice. Given that it would be expected to react with multiple chemokine receptors on monocytes and macrophages, we wondered if its accumulation in atherosclerosis lesion-bearing mice might correlate with overall macrophage burden or, alternatively, the pace of monocyte recruitment. Approach and Results: We employed a mouse model of atherosclerosis regression involving adenoassociated virus 8 vector encoding murine Apoe (AAV-mApoE) treatment of Apoe-/- mice where the pace of monocyte recruitment slows before macrophage burden subsequently declines. Accumulation of 64Cu-DOTA-vMIP-II at Apoe-/- plaque sites was strong but declined with AAV-mApoE-induced decline in monocyte recruitment, before macrophage burden reduced. Monocyte depletion indicated that monocytes and macrophages themselves were not the only target of the 64Cu-DOTA-vMIP-II tracer. Using fluorescence-tagged vMIP-II tracer, competitive receptor blocking with CXCR4 antagonists, endothelial-specific Cre-mediated deletion of CXCR4, CXCR4-specific tracer 64Cu-DOTA-FC131, and CXCR4 staining during disease progression and regression, we show endothelial cell expression of CXCR4 is a key target of 64Cu-DOTA-vMIP-II imaging. Expression of CXCR4 was low in nonplaque areas but strongly detected on endothelium of progressing plaques, especially on proliferating endothelium, where vascular permeability was increased and monocyte recruitment was the strongest. CONCLUSIONS: Endothelial injury status of plaques is marked by CXCR4 expression and this injury correlates with the tendency of such plaques to recruit monocytes. Furthermore, our findings suggest positron emission tomography tracers that mark CXCR4 can be used translationally to monitor the state of plaque injury and monocyte recruitment.


Assuntos
Aorta Torácica/diagnóstico por imagem , Aterosclerose/diagnóstico por imagem , Quimiocinas/administração & dosagem , Endotélio Vascular/diagnóstico por imagem , Imagem Molecular , Monócitos/metabolismo , Compostos Organometálicos/administração & dosagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/administração & dosagem , Receptores CXCR4/metabolismo , Animais , Aorta Torácica/imunologia , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Aterosclerose/imunologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Biomarcadores/metabolismo , Linhagem Celular , Quimiocinas/farmacocinética , Modelos Animais de Doenças , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Injeções Intravenosas , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Knockout para ApoE , Monócitos/imunologia , Monócitos/patologia , Compostos Organometálicos/farmacocinética , Placa Aterosclerótica , Valor Preditivo dos Testes , Compostos Radiofarmacêuticos/farmacocinética , Receptores CXCR4/genética
14.
J Nucl Med ; 62(1): 6-14, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33334911

RESUMO

The Society of Nuclear Medicine and Molecular Imaging created the Value Initiative in 2017 as a major component of its strategic plan to further demonstrate the value of molecular imaging and molecularly targeted radiopharmaceutical therapy to patients, physicians, payers, and funding agencies. The research and discovery domain, 1 of 5 under the Value Initiative, has a goal of advancing the research and development of diagnostic and therapeutic nuclear medicine. Research and discovery efforts and achievements are essential to ensure a bright future for NM and to translate science to practice. Given the remarkable progress in the field, leaders from the research and discovery domain and society councils identified 5 broad areas of opportunity with potential for substantive growth and clinical impact. This article discusses these 5 growth areas, identifying specific areas of particularly high importance for future study and development. As there was an understanding that goals should be both visionary yet achievable, this effort was called the Mars shot for nuclear medicine.


Assuntos
Imagem Molecular , Terapia de Alvo Molecular , Medicina Nuclear , Compostos Radiofarmacêuticos/uso terapêutico , Humanos , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/farmacologia
16.
PLoS One ; 15(10): e0238704, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33035214

RESUMO

The aim of this work was to use TOPAS Monte Carlo simulations to model the effect of magnetic fields on dose distributions in brachytherapy lung treatments, under ideal and clinical conditions. Idealistic studies were modeled consisting of either a monoenergetic electron source of 432 keV, or a polyenergetic electron source using the spectrum of secondary electrons produced by 192Ir gamma-ray irradiation. The electron source was positioned in the center of a homogeneous, lung tissue phantom (ρ = 0.26 g/cm3). Conversely, the clinical study was simulated using the VariSource VS2000 192Ir source in a patient with a lung tumor. Three contoured volumes were considered: the tumor, the planning tumor volume (PTV), and the lung. In all studies, dose distributions were calculated in the presence or absence of a constant magnetic field of 3T. Also, TG-43 parameters were calculated for the VariSource and compared with published data from EGS-brachy (EGSnrc) and PENELOPE. The magnetic field affected the dose distributions in the idealistic studies. For the monoenergetic and poly-energetic studies, the radial distance of the 10% iso-dose line was reduced in the presence of the magnetic field by 64.9% and 24.6%, respectively. For the clinical study, the magnetic field caused differences of 10% on average in the patient dose distributions. Nevertheless, differences in dose-volume histograms were below 2%. Finally, for TG-43 parameters, the dose-rate constant from TOPAS differed by 0.09% ± 0.33% and 0.18% ± 0.33% with respect to EGS-brachy and PENELOPE, respectively. The geometry and anisotropy functions differed within 1.2% ± 1.1%, and within 0.0% ± 0.3%, respectively. The Lorentz forces inside a 3T magnetic resonance machine during 192Ir brachytherapy treatment of the lung are not large enough to affect the tumor dose distributions significantly, as expected. Nevertheless, large local differences were found in the lung tissue. Applications of this effect are therefore limited by the fact that meaningful differences appeared only in regions containing air, which is not abundant inside the human.


Assuntos
Braquiterapia/métodos , Neoplasias Pulmonares/radioterapia , Pulmão/efeitos da radiação , Campos Magnéticos , Braquiterapia/estatística & dados numéricos , Simulação por Computador , Relação Dose-Resposta à Radiação , Elétrons , Humanos , Radioisótopos de Irídio/administração & dosagem , Radioisótopos de Irídio/farmacocinética , Radioisótopos de Irídio/uso terapêutico , Imageamento por Ressonância Magnética , Método de Monte Carlo , Imagens de Fantasmas , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/uso terapêutico , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Distribuição Tecidual
17.
Mol Pharmacol ; 98(2): 109-119, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32487736

RESUMO

Radiolabeled meta-iodobenzylguanidine (mIBG) is an important radiopharmaceutical used in the diagnosis and treatment of neuroendocrine cancers. mIBG is known to enter tumor cells through the norepinephrine transporter. Whole-body scintigraphy has shown rapid mIBG elimination through the kidney and high accumulation in several normal tissues, but the underlying molecular mechanisms are unclear. Using transporter-expressing cell lines, we show that mIBG is an excellent substrate for human organic cation transporters 1-3 (hOCT1-3) and the multidrug and toxin extrusion proteins 1 and 2-K (hMATE1/2-K), but not for the renal organic anion transporter 1 and 3 (hOAT1/3). Kinetic analysis revealed that hOCT1, hOCT2, hOCT3, hMATE1, and hMATE2-K transport mIBG with similar apparent affinities (K m of 19.5 ± 6.9, 17.2 ± 2.8, 14.5 ± 7.1, 17.7 ± 10.9, 12.6 ± 5.6 µM, respectively). Transwell studies in hOCT2/hMATE1 double-transfected Madin-Darby canine kidney cells showed that mIBG transport in the basal (B)-to-apical (A) direction is much greater than in the A-to-B direction. Compared with control cells, the B-to-A permeability of mIBG increased by 20-fold in hOCT2/hMATE1 double-transfected cells. Screening of 23 drugs used in the treatment of neuroblastoma identified several drugs with the potential to inhibit hOCT- or hMATE-mediated mIBG uptake. Interestingly, irinotecan selectively inhibited hOCT1, whereas crizotinib potently inhibited hOCT3-mediated mIBG uptake. Our results suggest that mIBG undergoes renal tubular secretion mediated by hOCT2 and hMATE1/2-K, and hOCT1 and hOCT3 may play important roles in mIBG uptake into normal tissues. SIGNIFICANCE STATEMENT: mIBG is eliminated by the kidney and extensively accumulates in several tissues known to express hOCT1 and hOCT3. Our results suggest that hOCT2 and human multidrug and toxin extrusion proteins 1 and 2-K are involved in mIBG renal elimination, whereas hOCT1 and hOCT3 may play important roles in mIBG uptake into normal tissues. These findings may help to predict and prevent adverse drug interaction with therapeutic [131I]mIBG and develop clinical strategies to reduce [131I]mIBG accumulation and toxicity in normal tissues and organs.


Assuntos
3-Iodobenzilguanidina/farmacocinética , Proteínas de Ciclo Celular/metabolismo , Fatores de Transcrição de Octâmero/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Fatores de Transcrição/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Crizotinibe/farmacologia , Cães , Células HEK293 , Humanos , Irinotecano/farmacologia , Células Madin Darby de Rim Canino
18.
J Cancer Res Clin Oncol ; 146(10): 2595-2605, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32494919

RESUMO

PURPOSE: The combined small-cell lung cancer (c-SCLC) is rare and has unique clinicopathological futures. The aim of this study is to investigate 18F-FDG PET/CT parameters and clinicopathological factors that influence the prognosis of c-SCLC. METHODS: Between November 2005 and October 2014, surgical-resected tumor samples from c-SCLC patients who received preoperative 18F-FDG PET/CT examination were retrospectively reviewed. The maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were used to evaluate metabolic parameters in primary tumors. The survivals were evaluated with the Kaplan-Meier method. Univariate and multivariate analyses were used to evaluate potential prognostic factors. RESULTS: Thirty-one patients were enrolled, with a median age of 62 (range: 35 - 79) years. The most common mixed component was squamous cell carcinoma (SCC, n = 12), followed by large-cell carcinoma (LCC, n = 7), adenocarcinoma (AC, n = 6), spindle cell carcinoma (n = 4), adenosquamous carcinoma (n = 1) and atypical carcinoid (n = 1). The median follow-up period was 53.0 (11.0-142.0) months; the 5-year overall survival (OS) and progression-free survival(PFS) rate were 48.4% and 35.5%, respectively. Univariate survival analysis showed that gender, smoking history, tumor location were associated with PFS (P = 0.036, P = 0.043, P = 0.048), SUVmax and TNM stage were closely related to PFS in both Mixed SCC and non-SCC component groups (P = 0.007, P = 0.048). SUVmax, smoking history, tumor size and mixed SCC component were influencing factors of OS in patients (P = 0.040, P = 0.041, P = 0.046, P = 0.029). Multivariate survival analysis confirmed that TNM stage (HR = 2.885, 95%CI: 1.323-6.289, P = 0.008) was the most significantly influential factor for PFS. High SUVmax value (HR = 9.338, 95%CI: 2.426-35.938, P = 0.001) and mixed SCC component (HR = 0.155, 95%CI: 0.045-0.530, P = 0.003) were poor predictors for OS. CONCLUSION: Surgical-resected c-SCLCs have a relatively good prognosis. TNM stage is the most significant factor influencing disease progression in surgical-resected c-SCLCs. SUVmax and mixed NSCLC components within c-SCLCs had a considerable influence on the survival. Both high SUVmax and mixed SCC component are poor predictors for patients with c-SCLCs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Fluordesoxiglucose F18/farmacocinética , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/metabolismo , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Quimioterapia Adjuvante , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Prognóstico , Compostos Radiofarmacêuticos/farmacocinética , Análise de Sobrevida
19.
PLoS One ; 15(5): e0232480, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32365074

RESUMO

A five-compartmental biokinetic model of I-131 radioiodine based on in-vivo gamma camera scanning results was developed and successfully applied to nine thyroid cancer patients who were administered 1,110 MBq I-131 in capsules for the residual thyroid gland ablation. The I-131 solution activity among internal organs was analyzed via the revised biokinetic model of iodine recommended by the ICRP-30 and -56 reports. Accordingly, a five-compartmental (stomach, body fluid, thyroid, whole body, and excretion) model was established to simulate the metabolic mechanism of I-131 in thyroid cancer patients, whereas the respective four simultaneous differential equations were solved via a self-developed program run in MATLAB. This made it possible to provide a close correlation between MATLAB simulation results and empirical data. The latter data were collected through in-vivo gamma camera scans of nine patients obtained after 1, 4, 24, 48, 72, and 168 hours after radioactive I-131 administration. The average biological half-life values for the stomach, body fluid, thyroid, and whole body of thyroid cancer patients under study were 0.54±0.32, 12.6±1.8, 42.8±5.1, and 12.6±1.8 h, respectively. The corresponding branching ratios I12, I23, I25, I34, I42, and I45 as denoted in the biokinetic model of iodine were 1.0, 0.21±0.14, 0.79±0.14, 1.0, 0.1, and 0.9, respectively. The average values of the AT dimensionless index used to verify the agreement between empirical and numerical simulation results were 0.056±0.017, 0.017±0.014, 0.044±0.023, and 0.045±0.009 for the stomach, thyroid, body fluid + whole body, and total, respectively. The results obtained were considered quite instrumental in the elucidation of metabolic mechanisms in the human body, particularly in thyroid cancer patients.


Assuntos
Radioisótopos do Iodo/farmacocinética , Modelos Biológicos , Compostos Radiofarmacêuticos/farmacocinética , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/metabolismo , Adulto , Idoso , Simulação por Computador , Feminino , Câmaras gama , Meia-Vida , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Distribuição Tecidual
20.
Br J Radiol ; 93(1110): 20200095, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32401541

RESUMO

Currently, Nuclear Medicine has a clearly defined role in clinical practice due to its usefulness in many medical disciplines. It provides relevant diagnostic and therapeutic options leading to patients' healthcare and quality of life improvement. During the first two decades of the 21stt century, the number of Nuclear Medicine procedures increased considerably.Clinical and research advances in Nuclear Medicine and Molecular Imaging have been based on developments in radiopharmaceuticals and equipment, namely, the introduction of multimodality imaging. In addition, new therapeutic applications of radiopharmaceuticals, mainly in oncology, are underway.This review will focus on radiopharmaceuticals for positron emission tomography (PET), in particular, those labeled with Fluorine-18 and Gallium-68. Multimodality as a key player in clinical practice led to the development of new detector technology and combined efforts to improve resolution. The concept of dual probe (a single molecule labeled with a radionuclide for single photon emission computed tomography)/positron emission tomography and a light emitter for optical imaging) is gaining increasing acceptance, especially in minimally invasive radioguided surgery. The expansion of theranostics, using the same molecule for diagnosis (γ or positron emitter) and therapy (ß minus or α emitter) is reshaping personalized medicine.Upcoming research and development efforts will lead to an even wider array of indications for Nuclear Medicine both in diagnosis and treatment.


Assuntos
Imagem Molecular/tendências , Medicina Nuclear/tendências , Tomografia por Emissão de Pósitrons/tendências , Compostos Radiofarmacêuticos , Humanos , Medicina Nuclear/instrumentação , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética
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