RESUMO
BACKGROUND: Direct detection of the notorious explosive triacetone triperoxide (TATP) is very difficult because it lacks facile ionization and UV absorbance or fluorescence. Besides, the current indirect methods are time-consuming and need a pre-step for TATP cleavage to hydrogen peroxide. Moreover, they commonly show significant false-positive results in the presence of some camouflage which limits their field applications. Herein, for the first time, a novel label-free field-applicable spectrofluorimetric nanobiosensor was developed for direct TATP detection using a novel activated-protein protected gold nanocluster (ABSA-AuNCs; QY = 28.3 %) synthesized by a combined protein-assisted-ultrasonication procedure. RESULTS: The ABSA-AuNCs revealed a fluorescence spectrum centered at 330.0 nm which was significantly quenched by TATP (binding constant = 154.06 M-1; ΔG = -12.5 kJ mol-1; E(%) = 88.5 %). This phenomenon was used as a basis for direct TATP quantification, providing a working range of 0.01-40.0 mg L-1 and a detection limit of 6.7 µg L-1 which is the lowest LOD provided for TATP detection up to now. A %RSD of 0.9 % and 1.56 % was obtained for repeatability and inter-day reproducibility, respectively. The selectivity was checked against a variety of camouflages, revealing ultra-selectivity. Several synthetic samples prepared by several camouflages and real samples (clay soil and real water media) were analyzed, revealing quantitative recoveries of TATP. SIGNIFICANCE: During the production of the notorious explosive TATP, it can be discharged into water and soil. This novel method eliminated the false-positive results of traditional methods and is applicable for direct quantitative detection of camouflaged TATP and its residues in real soil and water samples in a highly short response time (2 min). The camouflaged TATP analysis is important for tracking the terrorist attacks in field conditions and analysis of soil and water can provide a first indication of the location of the production site.
Assuntos
Substâncias Explosivas , Ouro , Compostos Heterocíclicos com 1 Anel , Nanopartículas Metálicas , Peróxidos , Espectrometria de Fluorescência , Espectrometria de Fluorescência/métodos , Substâncias Explosivas/análise , Compostos Heterocíclicos com 1 Anel/química , Nanopartículas Metálicas/química , Peróxidos/análise , Peróxidos/química , Ouro/química , Limite de Detecção , Técnicas Biossensoriais/métodosRESUMO
A 75-year-old man underwent a positron emission tomography/computed tomography (PET/CT) scan with fluorine-18-prostate specific membrane antigen ([¹8F]F-PSMA-1007) for initial staging of prostate adenocarcinoma. The scan showed lung infiltrates predominantly in both lower lobes with moderate uptake, in addition to a bilateral pulmonary hilar lymph node uptake. CT images revealed ground-glass opacities and a reticular pattern, suggesting COVID-19 pneumonia, which was confirmed by reverse transcription polymerase chain reaction (RT-PCR). Similar incidental findings have been reported in patients undergoing PET/CT scans with other radiotracers. In this case, the probable lung angiogenesis linked to COVID-19 infection can be potencially demonstrated by [¹8F]F-PSMA-1007, which helps ensure timely diagnosis and appropriate care for cancer patients.
Assuntos
COVID-19 , Achados Incidentais , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Masculino , Idoso , COVID-19/diagnóstico por imagem , Oligopeptídeos , Niacinamida/análogos & derivados , Radioisótopos de Flúor , Neoplasias da Próstata/diagnóstico por imagem , Compostos Heterocíclicos com 1 Anel , Ácido Edético/análogos & derivadosRESUMO
Background Lutetium 177 [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) is a prostate-specific membrane antigen (PSMA)-targeted radioligand therapy for metastatic castration-resistant prostate cancer (mCRPC). Quantitative PSMA PET/CT analysis could provide information on 177Lu-PSMA-617 treatment benefits. Purpose To explore the association between quantitative baseline gallium 68 [68Ga]Ga-PSMA-11 (68Ga-PSMA-11) PET/CT parameters and treatment response and outcomes in the VISION trial. Materials and Methods This was an exploratory secondary analysis of the VISION trial. Eligible participants were randomized (June 2018 to October 2019) in a 2:1 ratio to 177Lu-PSMA-617 therapy (7.4 GBq every 6 weeks for up to six cycles) plus standard of care (SOC) or to SOC only. Baseline 68Ga-PSMA-11 PET parameters, including the mean and maximum standardized uptake value (SUVmean and SUVmax), PSMA-positive tumor volume, and tumor load, were extracted from five anatomic regions and the whole body. Associations of quantitative PET parameters with radiographic progression-free survival (rPFS), overall survival (OS), objective response rate, and prostate-specific antigen response were investigated using univariable and multivariable analyses (with treatment as the only other covariate). Outcomes were assessed in subgroups based on SUVmean quartiles. Results Quantitative PET parameters were well balanced between study arms for the 826 participants included. The median whole-body tumor SUVmean was 7.6 (IQR, 5.8-9.9). Whole-body tumor SUVmean was the best predictor of 177Lu-PSMA-617 efficacy, with a hazard ratio (HR) range of 0.86-1.43 for all outcomes (all P < .001). A 1-unit whole-body tumor SUVmean increase was associated with a 12% and 10% decrease in risk of an rPFS event and death, respectively. 177Lu-PSMA-617 plus SOC prolonged rPFS and OS in all SUVmean quartiles versus SOC only, with no identifiable optimum among participants receiving 177Lu-PSMA-617. Higher baseline PSMA-positive tumor volume and tumor load were associated with worse rPFS (HR range, 1.44-1.53 [P < .05] and 1.02-1.03 [P < .001], respectively) and OS (HR range, 1.36-2.12 [P < .006] and 1.04 [P < .001], respectively). Conclusion Baseline 68Ga-PSMA-11 PET/CT whole-body tumor SUVmean was the best predictor of 177Lu-PSMA-617 efficacy in participants in the VISION trial. Improvements in rPFS and OS with 177Lu-PSMA-617 plus SOC were greater among participants with higher whole-body tumor SUVmean, with evidence for benefit at all SUVmean levels. ClinicalTrials.gov identifier: NCT03511664 Published under a CC BY 4.0 license. Supplemental material is available for this article.
Assuntos
Dipeptídeos , Isótopos de Gálio , Radioisótopos de Gálio , Compostos Heterocíclicos com 1 Anel , Lutécio , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias de Próstata Resistentes à Castração , Compostos Radiofarmacêuticos , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Lutécio/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Idoso , Dipeptídeos/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Pessoa de Meia-Idade , Resultado do Tratamento , Radioisótopos/uso terapêutico , Ácido Edético/análogos & derivados , Ácido Edético/uso terapêutico , Antígeno Prostático EspecíficoRESUMO
Prostate cancer is one of the most common cancers and leading cause of death due to cancer across the globe. This persuaded researchers to devise innovative treatment modalities that may prove effective, safe, and demonstrate better outcomes in terms of patient morbidity and survival. The advancement in theranostics such as lutetium-177 (177Lu)-PSMA-617 radioligand therapies can target prostate cancer cells causing negligible or no damage to most of the normal tissues in patients. It has been proven to effectively improve the quality of life and progression-free survival. In this study, stage IV metastatic castration-resistant prostate cancer patients were treated with 177Lu-PSMA-617, and the therapeutic response and safety of 177Lu-PSMA-617 radioligand therapy were evaluated six months after the treatment. Additionally, molecular docking studies were also conducted to find the possible mechanism at the molecular level that causes the effectiveness of 177Lu-PSMA-617 in prostate cancer.
Assuntos
Dipeptídeos , Compostos Heterocíclicos com 1 Anel , Lutécio , Neoplasias de Próstata Resistentes à Castração , Radioisótopos , Compostos Radiofarmacêuticos , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/patologia , Lutécio/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Dipeptídeos/uso terapêutico , Radioisótopos/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Idoso , Simulação de Acoplamento Molecular , Antígeno Prostático Específico , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Radiolabelled puromycin analogues will allow the quantification of protein synthesis through nuclear medicine-based imaging. A particularly useful application could be the non-invasive longitudinal visualisation of mycobacterial activity through direct quantification of puromycin binding. This study assesses the value of [68Ga]Ga-DOTA-puromycin in the visualisation of mycobacteria through positron emission tomography combined with magnetic resonance imaging (µPET/MRI). The radiopharmaceutical was produced by previously published and validated methods. [68Ga]Ga-DOTA-Puromycin imaging was performed on severe immunodeficient mice infected with Bacille Calmette-Guérin-derived M. Bovis (BCG). Acute and chronic infection stages were examined by µPET/MRI. A follow-up group of animals acted as controls (animals bearing S. aureus-derived infection and sterile inflammation) to assess tracer selectivity. [68Ga]Ga-DOTA-puromycin-µPET/MRI images revealed the acute, widespread infection within the right upper shoulder and armpit. Also, [68Ga]Ga-DOTA-puromycin signal sensitivity measured after a 12-week period was lower than that of [18F]FDG-PET in the same animals. A suitable correlation between normalised uptake values (NUV) and gold standard histopathological analysis confirms accurate tracer accumulation in viable bacteria. The radiopharmaceutical showed infection selectivity over inflammation but accumulated in both M. Bovis and S. Aureus, lacking pathogen specificity. Overall, [68Ga]Ga-DOTA-puromycin exhibits potential as a tool for non-invasive protein synthesis visualization, albeit without pathogen selectivity.
Assuntos
Radioisótopos de Gálio , Imageamento por Ressonância Magnética , Mycobacterium bovis , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Animais , Imageamento por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons/métodos , Camundongos , Compostos Radiofarmacêuticos/química , Compostos Organometálicos , Compostos Heterocíclicos com 1 Anel/química , Camundongos SCID , Feminino , Tuberculose/diagnóstico por imagem , Tuberculose/microbiologia , Tuberculose/metabolismo , Infecções por Mycobacterium/diagnóstico por imagem , Infecções por Mycobacterium/microbiologiaRESUMO
ABSTRACT: Metastatic insulinomas can cause recurrent hypoglycemia requiring continuous IV glucose infusion. Various medical and chemotherapeutic treatment options are used to reduce the patient's risk of death due to hypoglycemia. Treatment-resistant hepatic metastatic insulinomas may benefit clinically from 90Y transarterial radioembolization therapy. In this case, we present a case of liver metastatic insulinoma that achieved clinical improvement after 2 cycles of 90Y microspheres transarterial radioembolization, and the presence of active metastases was demonstrated with 68Ga-NODAGA-exendin-4 PET/CT imaging.
Assuntos
Embolização Terapêutica , Exenatida , Radioisótopos de Gálio , Hipoglicemia , Insulinoma , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Radioisótopos de Ítrio , Humanos , Insulinoma/diagnóstico por imagem , Radioisótopos de Ítrio/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Acetatos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/radioterapia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/radioterapia , Masculino , Metástase Neoplásica , Pessoa de Meia-IdadeRESUMO
Tetrazine-derived fluorogenic labels are extensively studied for their potential in biological and medical imaging. Nonetheless, the fluorescence quenching mechanism in numerous precursors continues to be debated, particularly as the wavelengths extend into the red and near-infrared (NIR) regions. This challenge poses obstacles to systematically optimizing their fluorogenicity, i.e., achieving red-shifted wavelengths and improved fluorescence turn-on signals through click reactions. This paper highlights the significance of photoinduced charge centralization (PCC), a quenching mechanism observed in tetrazine-fused fluorogenic labels with integrated π-conjugations. PCC is primarily responsible for the quenching effects observed in such labels emitting in the red-to-NIR spectrum. Drawing from structure-property relationships, this study proposes two molecular design strategies that incorporate the PCC mechanism and constitutional isomerization to develop high-performance tetrazine-based labels. These strategies facilitate multiplex fluorescence imaging following click reactions, promising significant advancements in bio-orthogonal imaging techniques.
Assuntos
Corantes Fluorescentes , Corantes Fluorescentes/química , Compostos Heterocíclicos com 1 Anel/química , Fluorescência , Química Click , Imagem Óptica/métodos , Processos FotoquímicosRESUMO
Introduction: Prostate Specific Membrane Antigen Positron Emission Tomography (PSMA-PET) is routinely used for the staging of patients with prostate cancer, but data on response assessment are sparse and primarily stem from metastatic castration-resistant prostate cancer (mCRPC) patients treated with PSMA radioligand therapy. Still, follow-up PSMA-PET is employed in earlier disease stages in case of clinical suspicion of disease persistence, recurrence or progression to decide if localized or systemic treatment is indicated. Therefore, the prognostic value of PSMA-PET derived tumor volumes in earlier disease stages (i.e., hormone-sensitive prostate cancer (HSPC) and non-[177Lu]Lu-PSMA-617 (LuPSMA) therapy castration resistant prostate cancer (CRPC)) are evaluated in this manuscript. Methods: A total number of 73 patients (6 primary staging, 42 HSPC, 25 CRPC) underwent two (i.e., baseline and follow-up, median interval: 379 days) whole-body [68Ga]Ga-PSMA-11 PET/CT scans between Nov 2014 and Dec 2018. Analysis was restricted to non-LuPSMA therapy patients. PSMA-PETs were retrospectively analyzed and primary tumor, lymph node-, visceral-, and bone metastases were segmented. Body weight-adjusted organ-specific and total tumor volumes (PSMAvol: sum of PET volumes of all lesions) were measured for baseline and follow-up. PSMAvol response was calculated as the absolute difference of whole-body tumor volumes. High metastatic burden (>5 metastases), RECIP 1.0 and PSMA-PET Progression Criteria (PPP) were determined. Survival data were sourced from the cancer registry. Results: The average number of tumor lesions per patient on the initial PET examination was 10.3 (SD 28.4). At baseline, PSMAvol was strongly associated with OS (HR 3.92, p <0.001; n = 73). Likewise, response in PSMAvol was significantly associated with OS (HR 10.48, p < 0.005; n = 73). PPP achieved significance as well (HR 2.19, p <0.05, n = 73). Patients with hormone sensitive disease and poor PSMAvol response (upper quartile of PSMAvol change) in follow-up had shorter outcome (p < 0.05; n = 42). PSMAvol in bones was the most relevant parameter for OS prognostication at baseline and for response assessment (HR 31.11 p < 0.001; HR 32.27, p < 0.001; n = 73). Conclusion: PPP and response in PSMAvol were significantly associated with OS in the present heterogeneous cohort. Bone tumor volume was the relevant miTNM region for OS prognostication. Future prospective evaluation of the performance of organ specific PSMAvol in more homogeneous cohorts seems warranted.
Assuntos
Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Idoso , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/patologia , Pessoa de Meia-Idade , Seguimentos , Radioisótopos de Gálio , Estudos Retrospectivos , Idoso de 80 Anos ou mais , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Glutamato Carboxipeptidase II/metabolismo , Compostos Radiofarmacêuticos , Antígenos de Superfície/metabolismo , Isótopos de Gálio , Prognóstico , Lutécio/uso terapêutico , Tomografia por Emissão de Pósitrons/métodos , Carga Tumoral , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Dipeptídeos/uso terapêuticoRESUMO
BACKGROUND: FAP radiopharmaceuticals show promise for cancer diagnosis; however, their limited tumor residency hinders treatment. This study compared two FAPi derivatives, DOTA.SA.FAPi and DOTAGA.(SA.FAPi)2, labeled with gallium-68 and lutetium-177, aiming to determine an optimum combination for creating theranostic pairs. METHODS: The radiotracers were studied for lipophilicity, binding to human serum proteins, and binding to human cancer-associated fibroblasts (CAFs) in vitro, including saturation and internalization/externalization studies. PET/SPECT/CT and biodistribution studies were conducted in PC3 and U87MG xenografts for [68Ga]Ga-DOTA.SA.FAPi and [68Ga]Ga-DOTAGA.(SA.FAPi)2. [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2, were evaluated in PC3 xenografts. Biodistribution studies of [68Ga]Ga-DOTA.SA.FAPi were performed in healthy male and female mice. RESULTS: All radiotracers exhibited strong binding to FAP. Their internalization rate was fast while only [177Lu]Lu-DOTAGA.(SA.FAPi)2 was retained longer in CAFs. [68Ga]Ga-DOTAGA.(SA.FAPi)2 and [177Lu]Lu-DOTAGA.(SA.FAPi)2 displayed elevated lipophilicity and affinity for human serum proteins compared to [68Ga]Ga-DOTA.SA.FAPi and [177Lu]Lu-DOTA.SA.FAPi. In vivo studies revealed slower washout of [68Ga]Ga-DOTAGA.(SA.FAPi)2 within 3 h compared to [68Ga]Ga-DOTA.SA.FAPi. The tumor-to-tissue ratios of [68Ga]Ga-DOTAGA.(SA.FAPi)2 versus [68Ga]Ga-DOTA.SA.FAPi did not exhibit any significant differences. [177Lu]Lu-DOTAGA.(SA.FAPi)2 maintained a significant tumor uptake even after 96 h p.i. compared to [177Lu]Lu-DOTA.SA.FAPi. CONCLUSIONS: Dimeric compounds hold promise for therapy, while monomers are better suited for diagnostics. Finding the right combination is essential for effective disease management.
Assuntos
Endopeptidases , Radioisótopos de Gálio , Lutécio , Radioisótopos , Compostos Radiofarmacêuticos , Lutécio/química , Humanos , Animais , Camundongos , Distribuição Tecidual , Radioisótopos/química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/farmacologia , Radioisótopos de Gálio/química , Linhagem Celular Tumoral , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Gelatinases/antagonistas & inibidores , Gelatinases/metabolismo , Compostos Heterocíclicos com 1 Anel/química , Feminino , Masculino , Nanomedicina TeranósticaAssuntos
Neoplasias das Glândulas Suprarrenais , Lutécio , Compostos Radiofarmacêuticos , Idoso , Humanos , Masculino , Neoplasias das Glândulas Suprarrenais/secundário , Neoplasias das Glândulas Suprarrenais/radioterapia , Dipeptídeos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Lutécio/uso terapêutico , Antígeno Prostático Específico , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/patologia , Radioisótopos/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêuticoRESUMO
Recently, the folate receptor (FR) has become an exciting target for the diagnosis of FR-positive malignancies. Nevertheless, suboptimal in vivo pharmacokinetic properties, particularly high uptake in the renal and hepatobiliary systems, are important limiting factors for the clinical translation of most FR-based radiotracers. In this study, we developed a novel 18F-labeled FR-targeted positron emission tomography (PET) tracer [18F]AlF-NOTA-Asp2-PEG2-Folate modified with a hydrophilic linker (-Asp2-PEG2) to optimize its pharmacokinetic properties and conducted a comprehensive preclinical assessment. The [18F]AlF-NOTA-Asp2-PEG2-Folate was manually synthesized within 30 min with a non-decay-corrected radiochemical yield of 16.3 ± 2.0% (n = 5). Among KB cells, [18F]AlF-NOTA-Asp2-PEG2-Folate exhibited high specificity and affinity for FR. PET/CT imaging and biodistribution experiments in KB tumor-bearing mice showed decent tumor uptake (1.7 ± 0.3% ID/g) and significantly decreased uptake in kidneys and liver (22.2 ± 2.1 and 0.3 ± 0.1% ID/g at 60 min p.i., respectively) of [18F]AlF-NOTA-Asp2-PEG2-Folate, compared to the known tracer [18F]AlF-NOTA-Folate (78.6 ± 5.1 and 5.3 ± 0.5 % ID/g at 90 min p.i., respectively). The favorable properties of [18F]AlF-NOTA-Asp2-PEG2-Folate, including its efficient synthesis, decent tumor uptake, relatively low renal uptake, and rapid clearance from most normal organs, portray it as a promising PET tracer for FR-positive tumors.
Assuntos
Radioisótopos de Flúor , Ácido Fólico , Tomografia por Emissão de Pósitrons , Animais , Tomografia por Emissão de Pósitrons/métodos , Camundongos , Humanos , Distribuição Tecidual , Radioisótopos de Flúor/química , Ácido Fólico/química , Ácido Fólico/farmacocinética , Células KB , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/química , Técnicas de Química Sintética , Receptores de Folato com Âncoras de GPI/metabolismo , Compostos Heterocíclicos com 1 AnelRESUMO
The overexpression of HER2 is pivotal in the initiation and progression of breast cancer. Developing HER2-targeted radiotracers is crucial for noninvasive assessment of HER2 expression, patient selection for HER2-targeted therapy, monitoring treatment response, and identifying resistance. Here, we reported a nonsite-specific coupled radiotracer, 68Ga-NOTA-SNA004-His6, and a site-specific coupled radiotracer, 68Ga-NODAGA-SNA004-GSC, based on a novel HER2 nanobody, SNA004. Both radiotracers exhibited high affinity, specific targeting, and rapid clearance in vitro and in vivo. Additionally, these tracers and trastuzumab showed noncompetitive binding to HER2. Compared to 68Ga-NOTA-SNA004-His6, 68Ga-NODAGA-SNA004-GSC demonstrated significantly reduced renal and liver uptake. PET/CT imaging with 68Ga-NODAGA-SNA004-GSC sensitively detected the responsiveness of various tumor models to trastuzumab and its antibody-drug conjugates (ADCs). Overall, the site-specific coupled radiotracer 68Ga-NODAGA-SNA004-GSC offered significant advantages in biodistribution and signal-to-noise ratio, making it a valuable tool for monitoring HER2 expression levels before, during, and after trastuzumab and ADC treatment.
Assuntos
Radioisótopos de Gálio , Compostos Heterocíclicos com 1 Anel , Imunoconjugados , Receptor ErbB-2 , Anticorpos de Domínio Único , Receptor ErbB-2/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Humanos , Imunoconjugados/química , Imunoconjugados/farmacocinética , Imunoconjugados/farmacologia , Animais , Radioisótopos de Gálio/química , Feminino , Compostos Heterocíclicos com 1 Anel/química , Anticorpos de Domínio Único/química , Camundongos , Distribuição Tecidual , Linhagem Celular Tumoral , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Acetatos/química , Acetatos/farmacologia , Compostos Radiofarmacêuticos/química , Camundongos Nus , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodosRESUMO
Purpose: Somatostatin receptor imaging with 18F-AlF-NOTA-octreotide (18F-AlF-OC) has shown promising performance in neuroendocrine neoplasms (NENs). In this study, we aim to investigate the diagnostic performance and clinical impact of 18F-AlF-OC in a large prospective cohort of patients with NEN. Methods: Between January 2023 and November 2023, a total of 219 patients with confirmed or suspected NEN were enrolled prospectively and underwent 18F-AlF-OC PET/CT at 2 h post-injection. The primary endpoint was the diagnostic performance, including sensitivity, specificity, and accuracy. An additional primary endpoint was the impact of 18F-AlF-OC on clinical management. The reference standard was based on the results of histopathology or radiological follow-up. Results: 205 patients were included in the final analysis. The patient-level sensitivity, specificity, and accuracy of 18F-AlF-OC PET/CT compared with contrast-enhanced CT/MRI were 90.5% vs. 81.8%, 93.1% vs. 71.1%, and 91.2% vs. 79.4%, respectively. 26 patients had tiny gastrointestinal NENs (smaller than 1 cm in diameter). The patient-based sensitivity of 18F-AlF-OC PET/CT and contrast-enhanced CT/MRI were 61.5% (16/26) and 37.5% (9/24), respectively. The smallest diameter of gastrointestinal NEN detected by 18F-AlF-OC PET/CT was 0.6 cm in the rectum, 0.3 cm in the stomach, and 0.5 cm in the duodenum. 18F-AlF-OC PET/CT results led to changes in clinical management in 19.5% of patients (40/205), owing mainly to new or unexpected findings compared to contrast-enhanced CT/MRI. Conclusion: 18F-AlF-OC PET/CT demonstrated great diagnostic performance in patients with NEN, particularly for detecting tiny gastrointestinal NEN. Furthermore, 18F-AlF-OC PET/CT impacted the therapeutic management in 19.5% of patients. Our results further validate the role of 18F-AlF-OC as a somatostatin receptor imaging tracer in clinical practice.
Assuntos
Tumores Neuroendócrinos , Octreotida , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Prospectivos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Octreotida/análogos & derivados , Idoso , Adulto , Sensibilidade e Especificidade , Compostos Radiofarmacêuticos , Compostos Heterocíclicos com 1 Anel , Receptores de Somatostatina/metabolismo , Radioisótopos de Flúor , Imageamento por Ressonância Magnética/métodos , Idoso de 80 Anos ou mais , Compostos HeterocíclicosRESUMO
Introduction: This study explores tumor-induced osteomalacia (TIO) through a case series and literature review, assessing the diagnostic potential of 18F-AlF-NOTA-octreotide (18F-OC) positron emission tomography/computed tomography (PET/CT). Methods: We analyzed TIO patients who underwent 18F-OC PET/CT. Parameters such as tumor dimension, the maximum standardized uptake value (SUVmax), the mean standardized uptake value (SUVmean) and metabolic tumor volume (MTV) were meticulously assessed. Clinical features and imaging characteristics pertinent to TIO were reviewed. Results: 6 patients with clinical suspicion of TIO exhibited hypophosphatemia (0.25 to 0.64 mmol/L), elevated alkaline phosphatase (ALP) levels (142 to 506 U/L), and increased parathyroid hormone (PTH) levels (92.9 to 281.7 pg/mL). Of these patients, two underwent FGF-23 testing, with results of 3185.00 pg/ml and 17.56 pg/ml, respectively. Conventional imaging modalities depicted widespread osteoporosis, with several cases demonstrating fractures indicative of osteomalacic and associated pathological fractures. Subsequent 18F-OC PET/CT facilitated the accurate localization of causative tumors, with histopathological examination confirming the diagnosis of phosphaturic mesenchymal tumor (PMT). The interval from initial clinical presentation to definitive TIO diagnosis spanned approximately 2.5 years (range: 1 - 4 years), with tumors varying in size (maximum diameter: 7.8 to 40.0 mm), SUVmax (5.47 to 25.69), SUVmean (3.43 to 7.26), and MTV (1.27 to 18.59 cm3). Conclusion: The implementation of whole-body 18F-OC PET/CT imaging emerges as a critical tool in the identification of occult tumors causing TIO. Future investigations incorporating a broader cohort are imperative to further delineate the diagnostic and therapeutic implications of 18F-OC PET/CT in managing TIO.
Assuntos
Osteomalacia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Fator de Crescimento de Fibroblastos 23 , Radioisótopos de Flúor , Compostos Heterocíclicos , Compostos Heterocíclicos com 1 Anel , Neoplasias de Tecido Conjuntivo/diagnóstico por imagem , Octreotida/análogos & derivados , Osteomalacia/diagnóstico por imagem , Osteomalacia/etiologia , Síndromes Paraneoplásicas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Compostos RadiofarmacêuticosRESUMO
Scandium (Sc) isotopes have recently attracted significant attention in the search for new radionuclides with potential uses in personalized medicine, especially in the treatment of specific cancer patient categories. In particular, Sc-43 and Sc-44, as positron emitters with a satisfactory half-life (3.9 and 4.0 h, respectively), are ideal for cancer diagnosis via Positron Emission Tomography (PET). On the other hand, Sc-47, as an emitter of beta particles and low gamma radiation, may be used as a therapeutic radionuclide, which also allows Single-Photon Emission Computed Tomography (SPECT) imaging. As these scandium isotopes follow the same biological pathway and chemical reactivity, they appear to fit perfectly into the "theranostic pair" concept. A step-by-step description, initiating from the moment of scandium isotope production and leading up to their preclinical and clinical trial applications, is presented. Recent developments related to the nuclear reactions selected and employed to produce the radionuclides Sc-43, Sc-44, and Sc-47, the chemical processing of these isotopes and the main target recovery methods are also included. Furthermore, the radiolabeling of the leading chelator, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and its structural analogues with scandium is also discussed and the advantages and disadvantages of scandium complexation are evaluated. Finally, a review of the preclinical studies and clinical trials involving scandium, as well as future challenges for its clinical uses and applications, are presented.
Assuntos
Quelantes , Compostos Heterocíclicos com 1 Anel , Medicina Nuclear , Radioisótopos , Compostos Radiofarmacêuticos , Escândio , Escândio/química , Humanos , Radioisótopos/química , Radioisótopos/uso terapêutico , Quelantes/química , Quelantes/uso terapêutico , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/química , Medicina Nuclear/métodos , Animais , Tomografia por Emissão de Pósitrons/métodos , Neoplasias/diagnóstico por imagem , Neoplasias/radioterapia , Tomografia Computadorizada de Emissão de Fóton Único/métodosRESUMO
Bioorthogonal reactions have revolutionized chemical biology by enabling selective chemical transformations within living organisms and cells. This review comprehensively explores bioorthogonal chemistry, emphasizing inverse-electron-demand Diels-Alder (IEDDA) reactions between tetrazines and strained dienophiles and their crucial role in chemical biology and various applications within the human body. This highly reactive and selective reaction finds diverse applications, including cleaving antibody-drug conjugates, prodrugs, proteins, peptide antigens, and enzyme substrates. The versatility extends to hydrogel chemistry, which is crucial for biomedical applications, yet it faces challenges in achieving precise cellularization. In situ activation of cytotoxic compounds from injectable biopolymer belongs to the click-activated protodrugs against cancer (CAPAC) platform, an innovative approach to tumor-targeted prodrug delivery and activation. The CAPAC platform, relying on click chemistry between trans-cyclooctene (TCO) and tetrazine-modified biopolymers, exhibits modularity across diverse tumor characteristics, presenting a promising approach in anticancer therapeutics. The review highlights the importance of bioorthogonal reactions in developing radiopharmaceuticals for positron emission tomography (PET) imaging and theranostics, offering a promising avenue for diverse therapeutic applications.
Assuntos
Reação de Cicloadição , Ciclo-Octanos , Humanos , Ciclo-Octanos/química , Ciclo-Octanos/síntese química , Química Click , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Neoplasias/tratamento farmacológico , Neoplasias/diagnóstico por imagem , Estrutura MolecularRESUMO
Doxorubicin (DOX) is a common and highly effective chemotherapeutic. However, its use is limited by cardiotoxic effects and the lack of methods to detect these at early time points. In the present study, we evaluated if [64Cu]Cu-NODAGA-E[(cRGDyK)]2 positron emission tomography-computed tomography ([64Cu]Cu-RGD PET/CT) could detect cardiotoxicity in a rat model of DOX-induced heart failure. Male Lewis rats were divided into two groups and treated with either a cumulative dose of 15 mg/kg of DOX or left untreated. Cardiac anatomy and function were assessed using magnetic resonance imaging at baseline and in week 8. [64Cu]Cu-RGD PET/CT scans were performed in week 4. DOX treatment led to a decline in pump function as well as an increase in cardiac and thymic uptake of [64Cu]Cu-RGD. In addition, DOX altered cardiac gene expression, led to infiltration of immune cells, reduced endothelial content, and increased interstitial fibrosis. Furthermore, concentrations of inflammatory plasma proteins were increased in the DOX group. In conclusion, DOX treatment resulted in the development of cardiotoxicity and heart failure, which could be detected using [64Cu]Cu-RGD PET/CT at early time points. [64Cu]Cu-RGD uptake in the myocardial septum and thymus predicted a low left ventricular ejection fraction in week 8.
Assuntos
Radioisótopos de Cobre , Modelos Animais de Doenças , Doxorrubicina , Insuficiência Cardíaca , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Ratos Endogâmicos Lew , Animais , Doxorrubicina/efeitos adversos , Doxorrubicina/toxicidade , Ratos , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/diagnóstico por imagem , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Compostos Heterocíclicos com 1 Anel , Cardiotoxicidade/etiologia , Acetatos/química , Imageamento por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons/métodos , Coração/efeitos dos fármacos , Coração/diagnóstico por imagem , Compostos RadiofarmacêuticosRESUMO
Internal dosimetry supports safe and effective patient management during radionuclide therapy. Yet, it is associated with high clinical workload, costs, and patient burden, as patient scans at multiple time points (MTPs) must be acquired. Dosimetry based on imaging at a single time point (STP) has continuously gained popularity. However, MTP protocols, used as a reference to judge the validity of STP dosimetry, differ depending on local requirements and deviate from the unknown patient-specific ground truth pharmacokinetics. The aim of this study was to compare the error and optimum time point for different STP approaches using different reference MTP protocols. Methods: Whole-body SPECT/CT scans of 7 patients (7.4-8.9 GBq of [177Lu]Lu-PSMA-I&T) were scheduled at 24, 48, 72, and 168 h after injection. Sixty lesions, 14 kidneys, and 10 submandibular glands were delineated in the SPECT/CT data. Two curve models, that is, a mono- and a biexponential model, were fitted to the MTP data, in accordance with goodness-of-fit analysis (coefficients of variation, sum of squared errors). Three population-based STP approaches were compared: one method published by Hänscheid et al., one by Jackson et al., and one using population-based effective half-lives in the mono- or biexponential curve models. Percentage differences between STP and MTP dosimetry were evaluated. Results: Goodness-of-fit parameters show that a monoexponential function and a biexponential function with shared population-based parameters and physical tail are reasonable reference models. When comparing both reference models, we observed maximum differences of -44%, -19%, and -28% in the estimated absorbed doses for lesions, kidneys, and salivary glands, respectively. STP dosimetry with an average deviation of less than 10% from MTP dosimetry may be feasible; however, this deviation and the optimum imaging time point showed a dependence on the chosen reference protocol. Conclusion: STP dosimetry for [177Lu]Lu-PSMA therapy is promising to boost the integration of dosimetry into clinical routine. According to our patient cohort, 48 h after injection may be regarded as a compromise for STP dosimetry for lesions and at-risk organs. The results from this analysis show that a common gold standard for dosimetry is desirable to allow for reliable and comparable STP dosimetry.
Assuntos
Lutécio , Radiometria , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Humanos , Fatores de Tempo , Dipeptídeos/uso terapêutico , Reprodutibilidade dos Testes , Masculino , Radioisótopos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Compostos Radiofarmacêuticos/farmacocinética , Feminino , Antígeno Prostático EspecíficoRESUMO
Fibrinogen-like protein 1 (FGL1) is a potential novel immune checkpoint target for malignant tumor diagnosis and therapy. Accurate detection of FGL1 levels in tumors via noninvasive PET imaging might be beneficial for managing the disease. To achieve this, multiple FGL1-targeting peptides (FGLP) were designed, and a promising candidate, 68Ga-NOTA-FGLP2, was identified through a high-throughput screening approach using microPET imaging of 68Ga-labeled peptides. Subsequent in vitro cell experiments showed that uptake values of 68Ga-NOTA-FGLP2 in FGL1 positive Huh7 tumor cells were significantly higher than those in FGL1 negative U87 MG tumor cells. Further microPET imaging showed that the Huh7 xenografts were clearly visualized with a favorable contrast. ROI analysis showed that the uptake values of the tracer in Huh7 xenografts were 2.63 ± 0.07% ID/g at 30 min p.i.. After treatment with an excess of unlabeled FGLP2, the tumor uptake significantly decreased to 0.54 ± 0.05% ID/g at 30 min p.i.. Moreover, the uptake in U87 MG xenografts was 0.44 ± 0.06% ID/g at the same time point. The tracer was excreted mainly through the renal system. 18F-FDG PET imaging was also performed in mice bearing Huh7 and U87 MG xenografts, respectively. However, there was no significant difference in the uptake between the tumors with different FGL1 expressions. Preclinical data indicated that 68Ga-NOTA-FGLP2 might be a suitable radiotracer for in vivo noninvasive visualization of tumors with abundant expression of FGL1. Further investigation of 68Ga-NOTA-FGLP2 for tumor diagnosis and therapy is undergoing.
Assuntos
Radioisótopos de Gálio , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Animais , Humanos , Camundongos , Tomografia por Emissão de Pósitrons/métodos , Linhagem Celular Tumoral , Compostos Radiofarmacêuticos/farmacocinética , Camundongos Nus , Distribuição Tecidual , Peptídeos/química , Camundongos Endogâmicos BALB C , Feminino , Compostos Heterocíclicos com 1 Anel/químicaRESUMO
While most FDA-approved peptide drugs are cyclic, robust cyclization chemistry of peptides and the deconvolution of the cyclic peptide sequences using tandem mass spectrometry render cyclic peptide drug discovery difficult. In this chapter, the protocol for the successful synthesis of tetrazine-linked cyclic peptide library in solid phase, which shows both robust cyclization and easy sequence deconvolution, is described. The protocol for the linearization and cleavage of cyclic peptides from the solid phase by simple UV light irradiation, followed by accurate sequencing using tandem mass spectrometry, is described. We describe the troubleshooting for this dithiol bis-arylation reaction and for the successful cleavage of the aryl cyclic peptide into linear form. This method for efficient solid-phase macrocyclization can be used for the rapid production of loop-based peptides and screening for inhibition of protein-protein interactions, by using the covalent inverse electron-demand Diels Alder reaction to supplement the non-covalent interaction between a protein and its peptide binder, isolating highly selective peptides in the process.