Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 26
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mol Pharm ; 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38831541

RESUMO

Carbonic anhydrase IX (CAIX), a zinc metal transmembrane protein, is highly expressed in 95% of clear cell renal cell carcinomas (ccRCCs). A positron emission tomography (PET) probe designed to target CAIX in nuclear medicine imaging technology can achieve precise positioning, is noninvasive, and can be used to monitor CAIX expression in lesions in real time. In this study, we constructed a novel acetazolamide dual-targeted small-molecule probe [68Ga]Ga-LF-4, which targets CAIX by binding to a specific amino acid sequence. After attenuation correction, the radiolabeling yield reached 66.95 ± 0.57% (n = 5) after 15 min of reaction and the radiochemical purity reached 99% (n = 5). [68Ga]Ga-LF-4 has good in vitro and in vivo stability, and in vivo safety and high affinity for CAIX, with a Kd value of 6.62 nM. Moreover, [68Ga]Ga-LF-4 could be quickly cleared from the blood in vivo. The biodistribution study revealed that the [68Ga]Ga-LF-4 signal was concentrated in the heart, lung, and kidney after administration, which was the same as that observed in the micro-PET/CT study. In a ccRCC patient-derived xenograft (PDX) model, the signal significantly accumulated in the tumor after administration, where it was retained for up to 4 h. After competitive blockade with LF-4, uptake at the tumor site was significantly reduced. The SUVmax of the probe [68Ga]Ga-LF-4 at the ccRCC tumor site was three times greater than that in the PC3 group with low CAIX expression at 30 min (ccRCC vs PC3:1.86 ± 0.03 vs 0.62 ± 0.01, t = 48.2, P < 0.0001). These results indicate that [68Ga]Ga-LF-4 is a novel small-molecule probe that targets CAIX and can be used to image localized and metastatic ccRCC lesions.

2.
Front Oncol ; 14: 1281645, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38887231

RESUMO

Background: The use of immune checkpoint inhibitors (ICIs) has become the standard of care for non-small cell lung cancer. The purpose of this study was to systematically review the literature to determine whether the occurrence of immune-related adverse events (irAEs) following the use of ICIs predicts different clinical outcomes in non-small cell lung cancer (NSCLC). Methods: Relevant studies from the time of database creation to July 20, 2023, were systematically searched to explore the differences in clinical outcomes in patients with advanced NSCLC with or without irAEs. The outcome indicators included the occurrence of irAEs, progression-free survival (PFS), and overall survival (OS). Results: 25 studies met the inclusion criteria. Of these studies, 22 reported the effect on OS, and 19 reported the effect on PFS. The results showed that for patients with NSCLC, the occurrence of irAEs after receiving immunotherapy showed a statistically significant benefit over the absence of irAEs for OS (HR=0.55,95% CI=0.46-0.65) and PFS (HR=0.55 95% CI=0.48-0.64), but severe irAEs (grades 3-5) were associated with worse OS (HR=1.05, 95% CI=0.87-1.27). Compared with gastrointestinal, lung, and hepatitis, irAEs of the skin and endocrine system tend to predict better OS and PFS. Conclusion: The occurrence of irAEs, especially mild and early irAEs, indicates better OS and PFS in patients with NSCLC treated with ICIs, irrespective of patient characteristics, type of ICIs, and irAEs. However, Grade 3 or higher toxicities resulted in worse OS. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023409444.

3.
Biotechnol Biofuels Bioprod ; 17(1): 68, 2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38802837

RESUMO

BACKGROUND: Bacterial nanocellulose (BNC), a natural polymer material, gained significant popularity among researchers and industry. It has great potential in areas, such as textile manufacturing, fiber-based paper, and packaging products, food industry, biomedical materials, and advanced functional bionanocomposites. The main current fermentation methods for BNC involved static culture, as the agitated culture methods had lower raw material conversion rates and resulted in non-uniform product formation. Currently, studies have shown that the production of BNC can be enhanced by incorporating specific additives into the culture medium. These additives included organic acids or polysaccharides. γ-Polyglutamic acid (γ-PGA), known for its high polymerization, excellent biodegradability, and environmental friendliness, has found extensive application in various industries including daily chemicals, medicine, food, and agriculture. RESULTS: In this particular study, 0.15 g/L of γ-PGA was incorporated as a medium additive to cultivate BNC under agitated culture conditions of 120 rpm and 30 â„ƒ. The BNC production increased remarkably by 209% in the medium with 0.15 g/L γ-PGA and initial pH of 5.0 compared to that in the standard medium, and BNC production increased by 7.3% in the medium with 0.06 g/L γ-PGA. The addition of γ-PGA as a medium additive resulted in significant improvements in BNC production. Similarly, at initial pH levels of 4.0 and 6.0, the BNC production also increased by 39.3% and 102.3%, respectively. To assess the characteristics of the BNC products, scanning electron microscopy, Fourier transform infrared spectroscopy, and thermogravimetric analysis were used. The average diameter of BNC fibers, which was prepared from the medium adding 0.15 g/L γ-PGA, was twice thicker than that of BNC fibers prepared from the control culture medium. That might be because that polyglutamic acid relieved the BNC synthesis from the shear stress from the agitation. CONCLUSIONS: This experiment held great significance as it explored the use of a novel medium additive, γ-PGA, to improve the production and the glucose conversion rate in BNC fermentation. And the BNC fibers became thicker, with better thermal stability, higher crystallinity, and higher degree of polymerization (DPv). These findings lay a solid foundation for future large-scale fermentation production of BNC using bioreactors.

4.
Mol Pharm ; 21(4): 2034-2042, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38456403

RESUMO

Pancreatic ductal adenocarcinoma (PDAC), which has a poor prognosis and nonspecific symptoms and progresses rapidly, is the most common pancreatic cancer type. Inhibitors targeting KRAS G12D and G12C mutations have been pivotal in PDAC treatment. Cancer cells with different KRAS mutations exhibit various degrees of glutamine dependency; in particular, cells with KRAS G12D mutations exhibit increased glutamine uptake. (2S,4R)-4-[18F]FGln has recently been developed for clinical cancer diagnosis and tumor cell metabolism analysis. Thus, we verified the heterogeneity of glutamine dependency in PDAC models with different KRAS mutations by a visual and noninvasive method with (2S,4R)-4-[18F]FGln. Two tumor-bearing mouse models (bearing the KRAS G12D or G12C mutation) were injected with (2S,4R)-4-[18F]FGln, and positron emission tomography (PET) imaging features and biodistribution were observed and analyzed. The SUVmax in the regions of interest (ROI) was significantly higher in PANC-1 (G12D) tumors than in MIA PaCa-2 (G12C) tumors. Biodistribution analysis revealed higher tumor accumulation of (2S,4R)-4-[18F]FGln and other metrics, such as T/M and T/B, in the PANC-1 mouse models compared to those in the MIAPaCa-2 mouse models. In conclusion, PDAC cells with the KRAS G12D and G12C mutations exhibit various degrees of (2S,4R)-4-[18F]FGln uptake, indicating that (2S,4R)-4-[18F]FGln might be applied to detect KRAS G12C and G12D mutations and provide treatment guidance.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animais , Camundongos , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/genética , Glutamina/metabolismo , Glutamina/farmacologia , Mutação , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Distribuição Tecidual , Radioisótopos de Flúor/química , Radioisótopos de Flúor/farmacologia
5.
Biochem Pharmacol ; 222: 116077, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38395264

RESUMO

Compound G-4 is a derivate of cyclin-dependent kinase inhibitor Rocovitine and showed strong sensitivity to triple negative breast cancer (TNBC) cells. In this study, the antitumor activity, mechanism and possible targets of G-4 in TNBC were investigated. Flow cytometry and immunoblotting showed that G-4 not only arrested the S phase of the cell cycle, but also induced apoptosis in TNBC cells via the mitochondrial pathway through inhibiting epidermal growth factor receptor (EGFR), AKT and MAPK pathways. In addition, G-4 induced the iron-mutagenesis process in TNBC cells and down-regulated differentially expressed gene lipid carrier protein 2 (LCN2) by RNA-seq. Moreover, G-4 elevated levels of cytosolic reactive oxygen species (ROS), lipid ROS, Fe and malondialdehyde (MDA), but decreased levels of superoxide dismutase (SOD) and glutathione (GSH), consistent with the effects of iron-mutagenic agonists Erastin and RSL3, which were inhibited by the iron inhibitor ferrostatin-1 (Fer-1). Furthermore, a LCN2 knockdown cell model was established by siRNA transfection, the IC50 of G-4 was increased nearly 100-fold, accompanied by a trend of no ferroptosis characteristic index. The results indicated that G-4 suppressed the malignant phenotype of TNBC, induced apoptosis by inhibiting EGFR pathway and promoted LCN2-dependent ferroptosis.


Assuntos
Ferroptose , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Proteínas de Transporte/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Apoptose , Receptores ErbB/metabolismo , Ferro/metabolismo , Lipídeos/farmacologia , Lipocalina-2
6.
Eur J Nucl Med Mol Imaging ; 50(12): 3735-3749, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37382662

RESUMO

PURPOSE: An accurate diagnosis of colorectal carcinoma (CRC) can assist physicians in developing reasonable therapeutic regimens, thereby significantly improving the patient's prognosis. Carcinoembryonic antigen (CEA)-targeted PET imaging shows great potential for this purpose. Despite showing remarkable abilities to detect primary and metastatic CRC, previously reported CEA-specific antibody radiotracers or pretargeted imaging are not suitable for clinical use due to poor pharmacokinetics and complicated imaging procedures. In contrast, radiolabeled nanobodies exhibit ideal characteristics for PET imaging, for instance, rapid clearance rates and excellent distribution profiles, allowing same-day imaging with sufficient contrast. In this study, we developed a novel CEA-targeted nanobody radiotracer, [68 Ga]Ga-HNI01, and assessed its tumor imaging ability and biodistribution profile in preclinical xenografts and patients with primary and metastatic CRC. METHODS: The novel nanobody HNI01 was acquired by immunizing the llama with CEA proteins. [68 Ga]Ga-HNI01 was synthesized by site-specifically conjugating [68 Ga]Ga with tris(hydroxypyridinone) (THP). Small-animal PET imaging and biodistribution studies were performed in CEA-overexpressed LS174T and CEA-low-expressed HT-29 tumor models. Following successful preclinical assessment, a phase I study was conducted on 9 patients with primary and metastatic CRC. Study participants received 151.21 ± 25.25 MBq of intravenous [68 Ga]Ga-HNI01 and underwent PET/CT scans at 1 h and 2 h post injection. Patients 01-03 also underwent whole-body dynamic PET imaging within 0-40 min p.i. All patients underwent [18F]F-FDG PET/CT imaging within 1 week after [68 Ga]Ga-HNI01 imaging. Tracer distribution, pharmacokinetics, and radiation dosimetry were calculated. RESULTS: [68 Ga]Ga-HNI01 was successfully synthesized within 10 min under mild conditions, and the radiochemical purity was more than 98% without purification. Micro-PET imaging with [68 Ga]Ga-HNI01 revealed clear visualization of LS174T tumors, while signals from HT-29 tumors were significantly lower. Biodistribution studies indicated that uptake of [68 Ga]Ga-HNI01 in LS174T and HT-29 was 8.83 ± 3.02%ID/g and 1.81 ± 0.87%ID/g, respectively, at 2 h p.i. No adverse events occurred in all clinical participants after the injection of [68 Ga]Ga-HNI01. A fast blood clearance and low background uptake were observed, and CRC lesions could be visualized with high contrast as early as 30 min after injection. [68 Ga]Ga-HNI01 PET could clearly detect metastatic lesions in the liver, lung, and pancreas and showed superior ability in detecting small metastases. A significant accumulation of radioactivity was observed in the kidney, and normal tissues physiologically expressing CEA receptors showed slight uptakes of [68 Ga]Ga-HNI01. An interesting finding was that strong uptake of [68 Ga]Ga-HNI01 was found in non-malignant colorectal tissues adjacent to the primary tumor in some patients, suggesting abnormal CEA expression in these healthy tissues. CONCLUSION: [68 Ga]Ga-HNI01 is a novel CEA-targeted PET imaging radiotracer with excellent pharmacokinetics and favorable dosimetry profiles. [68 Ga]Ga-HNI01 PET is an effective and convenient imaging tool for detecting CRC lesions, particularly for identifying small metastases. Furthermore, its high specificity for CEA in vivo makes it an ideal tool for selecting patients for anti-CEA therapy.


Assuntos
Neoplasias Colorretais , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Animais , Humanos , Anticorpos Monoclonais/metabolismo , Antígeno Carcinoembrionário , Neoplasias Colorretais/diagnóstico por imagem , Radioisótopos de Gálio , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia por Emissão de Pósitrons/métodos , Distribuição Tecidual , Anticorpos de Domínio Único/química , Anticorpos de Domínio Único/farmacologia
7.
Eur J Nucl Med Mol Imaging ; 50(9): 2775-2786, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37093312

RESUMO

PURPOSE: A novel HER2 affibody-based molecular probe, [18F]AlF-RESCA-HER2-BCH, was developed for reducing renal uptake, evaluated, and compared with [18F]AlF-NOTA-HER2-BCH. METHODS: In preclinical studies, micro-PET/CT was performed using HER2-positive gastric cancer patient-derived xenografts (PDX) model at 0.5-1 (dynamic), 2, 4, and 6 h post-injection. For blocking experiment, 0.5 mg cold affibody was co-injected with probes. Biodistribution were performed on HER2-positive PDX models at 2 h post-injection. For clinical study, PET/CT images were acquired at 2 h and 4 h after injection of 231.29 ± 17.77 MBq [18F]AlF-NOTA-HER2-BCH or [18F]AlF-RESCA-HER2-BCH in five breast cancer patients (4 HER2-positive and 1 HER2-low). Standardized uptake values (SUVs) were measured in tumors and source-organs for semi-quantitative analysis. The OLINDA/EXM software (version 1.2) was used to calculate the radiation doses. RESULTS: [18F]AlF-NOTA-HER2-BCH and [18F]AlF-RESCA-HER2-BCH were stably labeled with [18F]F, with high binding specificity and affinity to HER2. Micro-PET/CT of both tracers could clearly visualize HER2-positive PDX tumors with high uptake of 16.24 ± 1.74% ID/g and 14.39 ± 2.45% ID/g at 2 h post-injection. The renal accumulation of [18F]AlF-RESCA-HER2-BCH was significantly lower than that of [18F]AlF-NOTA-HER2-BCH (5.16 ± 0.22% ID/g vs. 158.73 ± 5.44% ID/g at 2 h, p < 0.0001). In the clinical study, both [18F]AlF-NOTA-HER2-BCH and [18F]AlF-RESCA-HER2-BCH demonstrated favorable tumor targeting and image contrast. [18F]AlF-RESCA-HER2-BCH showed a higher SUVmax in both primary tumor and metastases, and a significantly higher target-to-nontarget ratio in metastases than [18F]AlF-NOTA-HER2-BCH. Moreover, [18F]AlF-RESCA-HER2-BCH had lower renal accumulation (43.56 ± 7.88 vs. 79.81 ± 3.81 at 2 h, p < 0.0001; 33.23 ± 6.89 vs. 78.63 ± 4.00 at 4 h, p < 0.0001) as well as a significantly lower renal absorbed dose than [18F]AlF-NOTA-HER2-BCH (0.4450 ± 0.1117 mGy/MBq vs. 0.8030 ± 0.1604 mGy/MBq, p < 0.01). CONCLUSIONS: [18F]AlF-RESCA-HER2-BCH tended to provide better image contrast than [18F]AlF-NOTA-HER2-BCH with a higher target-to-nontarget ratio in detection of metastases. Notably, [18F]AlF-RESCA-HER2-BCH had lower renal accumulation than [18F]AlF-NOTA-HER2-BCH.


Assuntos
Neoplasias da Mama , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Camundongos , Humanos , Animais , Feminino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Distribuição Tecidual , Linhagem Celular Tumoral , Radioisótopos de Flúor/química , Compostos Heterocíclicos com 1 Anel/química , Neoplasias da Mama/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos
8.
Front Immunol ; 14: 1108213, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37033991

RESUMO

Background: The neoadjuvant use of immune checkpoint inhibitor combined with chemotherapy (nICT) or chemoradiotherapy (nICRT) in locally advanced esophageal cancer (EC) is currently an area of active ongoing research. Therefore, we carried out a comprehensive meta-analysis to compare the efficacy and safety of the new strategy with routine neoadjuvant strategy, which included neoadjuvant chemotherapy (nCT) and neoadjuvant chemoradiotherapy (nCRT). Patients and methods: MEDLINE (via PubMed), Embase (via OVID), ISI Web of Science database and Cochrane Library were included. And, all of them were searched for eligible studies between January, 2000 and February, 2023. The pathological complete response (pCR) and major pathological response (MPR) were primary outcome of our study. The second outcome of interest was R0 resection rate. Odds ratio (OR) and associated 95% CI were used as the effect indicators comparing the safety and efficiency of the neoadjuvant immunotherapy with the routine neoadjuvant therapy. Fixed-effect model (Inverse Variance) or random-effect model (Mantel-Haenszel method) was performed depending on the statistically heterogeneity. Results: There were eight trials with 652 patients were included in our meta-analysis. The estimated pCR rate was higher in the neoadjuvant immunotherapy group (OR =1.86; 95% CI, 1.25-2.75; I2 = 32.8%, P=0.166). The different results were found in the esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) subgroups, the estimated OR was 2.35 (95%CI, 1.00-2.72; I2 = 30.9%, P=0.215) in the EAC subgroup, and 2.35 (95% CI, 1.20-4.54; I2 = 45.3%, P=0.161) in the ESCC subgroup, respectively. The neoadjuvant immunotherapy also showed the advantage in the MPR rates (OR =2.66; 95% CI, 1.69-4.19; I2 = 24.3%, P=0.252). There was no obvious difference between the neoadjuvant immunotherapy and routine neoadjuvant therapy with respect to surgical resection rate, R0 resection rate, surgical delay rate; while more treatment-related adverse events were observed for the neoadjuvant immunotherapy for pneumonitis/pneumonia (OR=3.46, 95% CI, 1.31-9.16; I2 = 67.3%, P=0.005) and thyroid dysfunction (OR=4.69, 95% CI, 1.53-14.36; I2 = 56.5%, P=0.032). Conclusion: The pooled correlations indicated that the neoadjuvant immunotherapy (both nICT and nICRT) could significantly increase the rates of pCR and MPR, compared with routine neoadjuvant therapy (both nCT and nCRT) in the treatment of locally advanced EC. The neoadjuvant immunotherapy and routine neoadjuvant therapy were with acceptable toxicity. However, randomized studies with larger groups of patients need to performed to confirm these results. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42020155802.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patologia , Terapia Neoadjuvante/métodos , Carcinoma de Células Escamosas do Esôfago/terapia , Imunoterapia/efeitos adversos
9.
Mol Pharm ; 20(2): 1415-1425, 2023 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-36697367

RESUMO

Prostate-specific membrane antigen (PSMA) is a prostate cancer target that plays a crucial role in prostate cancer diagnosis and therapy. Herein, a novel dual-targeted imaging probe, [68Ga]Ga-FAPI-PSMA, was prepared by radiolabeling conjugated DOTA-FAPI-PSMA with the short half-life radionuclide gallium-68 (68Ga), which is dedicated to prostate cancer diagnostic imaging. In vitro, [68Ga]Ga-FAPI-PSMA had higher affinity for the PSMA and FAP high-expressing cell lines 22Rv1 and U87 MG with IC50 values of 4.73 and 2.10 nM, respectively, than in the corresponding negative expression cell lines PC3 and A549, and significant differences in cell uptake were also observed. In vivo, [68Ga]Ga-FAPI-PSMA was rapidly cleared from the body, and the estimated radiation dose was relatively low compared with several other FAPI probes. In 22Rv1 and U87 MG tumor xenografts, [68Ga]Ga-FAPI-PSMA rapidly accumulated in tumors after administration, and the best images can be obtained at 1 h postinjection. In conclusion, the dual-targeted probe [68Ga]Ga-FAPI-PSMA was successfully prepared for in vivo prostate cancer PET/CT imaging.


Assuntos
Radioisótopos de Gálio , Neoplasias da Próstata , Masculino , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Fibroblastos/metabolismo
11.
Mol Pharm ; 19(7): 2629-2637, 2022 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-35704773

RESUMO

Activated T cells played critical roles in immunotherapy and adoptive T cell therapy, and a non-invasive imaging strategy can provide us useful information concerning the transportation, accumulation, and homing of T cells in vivo. In this paper, by utilizing the long half-life radionuclide iodine-124 (124I) and CD25 specific monoclonal antibody Basiliximab, we have fabricated a novel probe, namely, 124I-Basiliximab, which was highly promising in the immuno-PET imaging of T cells. In vitro, 124I-Basiliximab had superior affinity to CD25 protein (Kd = 5.31 nM) and exhibited much higher accumulation in CD25 high-expression lymphoma cell line Karpas299 than that in CD25-negative cell line Daudi. In vivo, 124I-Basiliximab was excreted slowly from the body of mice, rendering it a relatively high effective dose (0.393 mSv/MBq) when applied in the immuno-PET imaging. In Karpas299 tumor xenograft, 124I-Basiliximab probe was observed to accumulate in the tumor quickly after tracer administration, with the optimal image acquired at 24 h post-injection. More importantly, PHA-activated hPBMC had much higher uptake of 124I-Basiliximab, indicating the potential utility of 124I-Basiliximab to discriminate activated hPBMC from its non-activated status. In summary, 124I-Basiliximab was fabricated for the first time, which can be applied in CD25-targeted immuno-PET imaging of activated T cells in vivo.


Assuntos
Neoplasias , Linfócitos T , Animais , Basiliximab , Humanos , Radioisótopos do Iodo , Camundongos , Tomografia por Emissão de Pósitrons , Proteínas Recombinantes de Fusão
12.
Eur J Nucl Med Mol Imaging ; 49(3): 1030-1040, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34453203

RESUMO

PURPOSE: Prostate-specific membrane antigen (PSMA) is a promising target for prostate cancer imaging and therapy. The most commonly used scaffold incorporates a glutamate-urea (Glu-Urea) function. We recently developed oxalyldiaminopropionic acid-urea (ODAP-Urea) PSMA ligands in an attempt to improve upon the pharmacokinetic properties of existing agents. Here, we report the synthesis of an optimized 68Ga-labeled ODAP-Urea-based ligand, [68Ga]Ga-P137, and first-in-human results. METHODS: Twelve ODAP-Urea-based ligands were synthesized and radiolabeled with 68Ga in high radiochemical yield and purity. Their PSMA inhibitory capacities were determined using the NAALADase assay. Radioligands were evaluated in mice-bearing 22Rv1 prostate tumors by microPET. Lead compound [68Ga]Ga-P137 was evaluated for stability, cell uptake, and biodistribution. PET imaging of [68Ga]Ga-P137 was performed in three patients head-to-head compared to [68Ga]Ga-PSMA-617. RESULTS: Ligands were synthesized in 11.1-44.4% yield and > 95% purity. They have high affinity to PSMA (Ki of 0.13 to 5.47 nM). [68Ga]Ga-P137 was stable and hydrophilic. [68Ga]Ga-P137 showed higher uptake than [68Ga]Ga-PSMA-617 in tumor-bearing mice at 6.43 ± 0.98%IA/g vs 3.41 ± 1.31%IA/g at 60-min post-injection. In human studies, the normal organ biodistribution of [68Ga]Ga-P137 was grossly equivalent to that of [68Ga]Ga-PSMA-617 except for within the urinary tract, in which [68Ga]Ga-P137 demonstrated lower uptake. CONCLUSION: The optimized ODAP-Urea-based ligand [68Ga]Ga-P137 can image PSMA in xenograft models and humans, with lower bladder accumulation to the Glu-Urea-based agent, [68Ga]Ga-PSMA-617, in a preliminary, first-in-human study. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04560725, Registered 23 September 2020. https://clinicaltrials.gov/ct2/show/NCT04560725.


Assuntos
Glutamato Carboxipeptidase II , Neoplasias da Próstata , Diamino Aminoácidos , Animais , Antígenos de Superfície/metabolismo , Linhagem Celular Tumoral , Radioisótopos de Gálio , Glutamato Carboxipeptidase II/metabolismo , Humanos , Masculino , Camundongos , Tomografia por Emissão de Pósitrons/métodos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Distribuição Tecidual , Ureia
13.
Bioorg Med Chem Lett ; 40: 127901, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33705912

RESUMO

As an indicative biomarker for immunotherapy, PD-L1 plays an important role in the clinical decision-making of the immune checkpoint blockade therapy. PET imaging through radiotracer can real-timely, quantitatively, and non-invasively assess the expression of PD-L1 in tumors. Here, we reported a copper-64 radiolabeled NOTA-WL12, 64Cu-NOTA-WL12, and preliminarily evaluated its application in non-invasively detecting the PD-L1 expression.64Cu-NOTA-WL12 was produced with high radiochemical yield (>90%), radiochemical purity (>98%), and specific activity (20 MBq/nmol). 64Cu-NOTA-WL12 showed high in vitro stability and high binding affinity to the PD-L1 (KD ≈ 3.012 nM). The micro-positron emission tomography/computerized tomography (micro-PET/CT) imaging indicated that 64Cu-NOTA-WL12 was specifically accumulated in the tumor with PD-L1 expression. All results demonstrated that 64Cu-NOTA-WL12 holds great potential for noninvasive evaluation of PD-L1 expression levels.


Assuntos
Antígeno B7-H1/análise , Antígeno B7-H1/genética , Radioisótopos de Cobre/economia , Peptídeos/química , Compostos Radiofarmacêuticos/química , Animais , Células CHO , Cricetulus , Expressão Gênica , Humanos , Neoplasias Experimentais , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Ligação Proteica , Coloração e Rotulagem , Relação Estrutura-Atividade
14.
Bioorg Med Chem Lett ; 30(14): 127253, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32527554

RESUMO

To facilitate the discovery of FAP inhibitors, a convenient cell-based fluorescent assay was developed by using a commonly available U87MG cell line and a FAP-specific substrate Suc-Gly-Pro-AMC. The assay enabled the fast determination of multiple IC50s by simply incubating a solution of phosphate-buffered saline in a 96-well plate within 30 min. The substrate specificity, cross-reaction and other related conditions were systematically optimized. This method was successfully applied to determine the IC50s of seven known inhibitors. The results are in consistence with the trend reported, which indicating that this practical assay is a valuable method to accelerate the discovery of FAP inhibitor.


Assuntos
Descoberta de Drogas , Corantes Fluorescentes/farmacologia , Gelatinases/antagonistas & inibidores , Proteínas de Membrana/antagonistas & inibidores , Imagem Óptica , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Endopeptidases , Corantes Fluorescentes/química , Gelatinases/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Microscopia Confocal , Estrutura Molecular , Serina Endopeptidases/metabolismo , Relação Estrutura-Atividade
15.
J Med Chem ; 63(7): 3563-3576, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32207938

RESUMO

In an effort to seek novel agents targeting prostate-specific membrane antigen (PSMA), 16 ligands (L1-L16) with structural modifications in S1' binding pocket were synthesized and evaluated for PSMA inhibition. (S)-3-(Carboxyformamido)-2-(3-(carboxymethyl)ureido)propanoic acids proved to be potent PSMA ligands with Ki values ranging from 0.08 nM to 8.98 nM, which are in the range of or are higher in potency compared to previously published urea-based ligands. Computational docking was performed to study the binding mode of the two most potent ligands discovered. FITC-conjugated L14 could selectively stain PSMA+ LNCaP cells over PSMA- PC3 cells. IRDye800CW conjugated L16 can effectively image tumors in a murine xenograft model of prostate cancer.


Assuntos
Corantes Fluorescentes/farmacologia , Neoplasias da Próstata/diagnóstico por imagem , Ureia/análogos & derivados , Ureia/farmacologia , Animais , Antígenos de Superfície/metabolismo , Linhagem Celular Tumoral , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/metabolismo , Glutamato Carboxipeptidase II/metabolismo , Humanos , Masculino , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Imagem Óptica/métodos , Estudo de Prova de Conceito , Ligação Proteica , Ureia/metabolismo
16.
J Labelled Comp Radiopharm ; 63(3): 108-118, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31697847

RESUMO

Amyvid (florbetapir f18, [18 F]AV-45, [18 F]5) was the first FDA-approved positron emission tomography imaging agent targeting ß-amyloid (Aß) plaques for assisting the diagnosis of Alzheimer disease. This work aimed to improve the [18 F]AV-45 ([18 F]5) preparation by using solid-phase extraction (SPE) purification. [18 F]AV-45 ([18 F]5) was synthesized by direct nucleophilic radiofluorination of O-tosylated precursor (1 mg) at 120°C in anhydrous dimethyl sulfoxide (DMSO), followed by acid hydrolysis of the N-Boc protecting group. Purification was accomplished by loading the crude reaction mixture to a cartridge (Oasis HLB 3 cc) and eluting with different combinations of solvents. This method removed the chemical impurity while leaving [18 F]AV-45 ([18 F]5) on the cartridge. The final dose was eluted by ethanol. [18 F]AV-45 ([18 F]5) was produced within 51 minutes (radiochemical yield 42.7 ± 5.9%, decay corrected, n = 3), and the radiochemical purity was greater than 95%. Total chemical impurity per batch (24.1 ± 2.7 µg per batch) was below the limit described in the package insert of Amyvid, florbetapir f18 (chemical mass: less than 50 µg/dose). In summary, [18 F]AV-45 ([18 F]5) was produced efficiently and reproducibly using a cartridge-based SPE purification. This method brings the process closer for routine preparation, similar to the commercially used [18 F]FDG.


Assuntos
Compostos de Anilina/química , Compostos de Anilina/isolamento & purificação , Etilenoglicóis/química , Etilenoglicóis/isolamento & purificação , Extração em Fase Sólida , Tomografia por Emissão de Pósitrons , Radioquímica
17.
Nucl Med Biol ; 72-73: 26-35, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31330409

RESUMO

OBJECTIVES: Recently, a deuterated tracer, D6-[18F]FP-(+)-DTBZ, 9-O-hexadeutero-3-[18F]fluoropropoxyl-(+)-dihydrotetrabenazine ([18F]9), targeting vesicular monoamine transporter 2 (VMAT2) in the central nervous system, was reported as a useful imaging agent for the diagnosis of Parkinson's disease (PD). The production of [18F]9 was optimized and simplified by using solid-phase extraction (SPE) purification. METHODS: Three major nonradioactive impurities were synthesized and characterized. The preparation of [18F]9 was optimized by using different labeling conditions, and an SPE purification method was evaluated. The influence of chemical impurities in the final dose of [18F]9 was assessed by an in vitro binding assay, an assay of the in vivo biodistribution in mice, and ex vivo and in vitro autoradiography of brain sections. RESULTS: Optimized fluorination conditions for [18F]9 were found - heating at 130 °C for 10 min in DMSO, and a high radiochemical yield and three major chemical impurities were observed. An SPE method involving a Sep-Pak® tC18 Plus Light cartridge with a two-step elution process was successfully implemented. This process gave a good radiochemical yield (38.7 ±â€¯10.5%, decay corrected; radiochemical purity >99%) and low chemical impurities. An in vivo biodistribution study and autoradiography of brain sections showed that there was no significant difference between HPLC-purified and SPE-purified [18F]9. CONCLUSION: A VMAT2 targeting imaging agent, D6-[18F]FP-(+)-DTBZ, [18F]9, was prepared by optimized labeling conditions and an easy SPE purification. This method offers a short preparation time and operational simplicity. In conjunction with PET imaging, this new VMAT2 agent might be a useful clinical tool for diagnosing PD.


Assuntos
Encéfalo/metabolismo , Radioisótopos de Flúor/metabolismo , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/metabolismo , Extração em Fase Sólida/métodos , Tetrabenazina/análogos & derivados , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Radioisótopos de Flúor/química , Radioisótopos de Flúor/isolamento & purificação , Halogenação , Masculino , Camundongos , Tomografia por Emissão de Pósitrons , Radioquímica , Compostos Radiofarmacêuticos/isolamento & purificação , Tetrabenazina/química
18.
Nucl Med Biol ; 71: 54-64, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31152974

RESUMO

INTRODUCTION: Alzheimer's disease is a common neurodegenerative disease that is characterized by the presence of Aß plaques in the brain. The FDA has approved the use of Amyvid (florbetapir f18, AV-45) as a PET imaging agent for detecting Aß plaques in the living human brain. In an attempt to reduce N-demethylation in vivo by taking advantage of more stable C-D bonds, an analog of AV-45, [18F]D3FSP ([18F]7), was synthesized to improve image contrast for detecting and monitoring the Aß plaques. A convenient and improved preparation of [18F]D3FSP ([18F]7) is needed for widespread clinical application. We report herein the optimization of the radiosynthesis and solid-phase extraction (SPE) procedure. METHODS: Radiosyntheses of [18F]D3FSP ([18F]7) under different fluorination conditions were evaluated, and the intermediate, containing an N-Boc protecting group, was deprotected using different acids. One of the major objectives was to simplify the final purification step via SPE to avoid the commonly employed HPLC purification and maximize the radiochemical yields of [18F]D3FSP ([18F]7) while simultaneously removing several chemical impurities (pseudocarriers). Washing various solid-phase cartridges with different combinations of ethanol/water and acetonitrile/water was explored to optimize the purification step. To evaluate the potential interference in Aß plaques imaging from the presence of pseudocarriers, each chemical was identified and quantified by LC/MS and HPLC. An in vitro binding assay was employed to evaluate the binding affinities of [18F]D3FSP ([18F]7) and the pseudocarriers to Aß plaques using postmortem AD brain tissue. RESULTS: Using the optimized radiosynthesis method and SPE purification, the final dose of [18F]D3FSP ([18F]7) was obtained in 50 min with a very low content of pseudocarriers (21.7 ±â€¯5.5 µg). The radiochemical yield was 44.4 ±â€¯5.7% (decay corrected), and the radiochemical purity was >95%. SPE-purified doses of [18F]D3FSP ([18F]7) displayed excellent binding affinity and specificity for Aß plaques as measured in an in vitro binding assay using AD brain homogenates, and the OH-pseudocarrier, 8 (Ki = 19.5 ±â€¯0.5 nM), and the Cl-pseudocarrier, 10 (Ki = 18.6 ±â€¯3.9 nM), showed lower binding affinities for Aß plaques than those of AV-45 (Ki = 8.6 ±â€¯0.5 nM) and D3FSP, 7 (Ki = 9.8 ±â€¯0.5 nM). CONCLUSIONS: An optimized radiosynthesis and fast SPE purification method suitable for the preparation of clinical doses of [18F]D3FSP ([18F]7) was accomplished. The results of quality control tests and binding studies suggested that the SPE-purified doses of [18F]D3FSP ([18F]7) are appropriate for imaging Aß plaques in the human brain.


Assuntos
Placa Amiloide/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Piridinas/isolamento & purificação , Radioisótopos/química , Extração em Fase Sólida/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Humanos , Piridinas/química , Radioquímica
19.
Nucl Med Biol ; 66: 1-9, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30096380

RESUMO

OBJECTIVES: Serotonin transporters (SERT) play an important role in controlling serotonin concentration in the synaptic cleft and in managing postsynaptic signal transduction. Inhibitors of SERT binding are well known as selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, sertraline, paroxetine, and escitalopram, that are commonly prescribed antidepressants. Positron emission tomography (PET) and single photon emission tomography (SPECT) imaging agents targeting SERT may be useful for studying its function and providing a tool for monitoring drug treatment. METHODS: A series of novel 18F-labeled diphenyl sulfide derivatives were prepared and tested for their binding affinity. Among them, 2-((2-((dimethylamino)-methyl)-4-(2-(2-fluoroethoxy)ethoxy)phenyl)thio)aniline, 1, which showed excellent binding toward serotonin transporter (SERT) in the brain (Ki = 0.09 nM), was selected for further evaluation. An active OTs intermediate, 7, was treated with [18F]F-/K222 to provide [18F]1 in one step and in high radiochemical yields. This new SERT targeting agent was evaluated in rats by biodistribution studies and animal PET imaging studies. RESULTS: The radiolabeling reaction led to the desired [18F]1. After HPLC purification no-carrier-added [18F]1 was obtained (radiochemical yield, 23-47% (n = 10,); radiochemical purity >99%; molar activity, 15-28 GBq/µmol). Biodistribution studies with [18F]1 showed good brain uptake (1.04% dose/g at 2 min post-injection), high uptake into the hypothalamus (1.55% dose/g at 30 min), and a high target-to-non-target (hypothalamus to cerebellum) ratio of 6.1 at 120 min post-injection. A PET imaging study in normal rats showed excellent uptake in the midbrain and thalamus regions known to be rich in SERT binding sites at 60 min after iv injection. Chasing experiment with escitalopram (iv, 2 mg/kg) in a rat at 60 min after iv injection caused a noticeable reduction in the regional radioactivity and the target-to-non-target ratio, suggesting binding by [18F]1 was highly specific and reversible for SERT binding sites in the brain. CONCLUSIONS: A novel diphenyl sulfide derivative, [18F]1 for SERT imaging was successfully prepared and evaluated. Results suggest that this new chemical entity is targeting SERT binding sites in the brain, and it is a suitable candidate for future commercial development.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Radioisótopos de Flúor , Tomografia por Emissão de Pósitrons/métodos , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Sulfetos/química , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Animais , Marcação por Isótopo , Radioquímica , Ratos , Sulfetos/farmacocinética , Distribuição Tecidual
20.
J Labelled Comp Radiopharm ; 61(8): 576-585, 2018 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-29644713

RESUMO

Positron emission tomography imaging of serotonin transporter (SERT) is useful for studying brain diseases with altered serotonergic function. A deuterated imaging agent, ([18 F]2-((2-((bis(methyl-d3 )amino)methyl)-4-(3-fluoropropoxy-1,1,2,2,3,3-d6 )phenyl)thio)aniline, [18 F]D12FPBM, [18 F]1), was prepared as a new chemical entity. The deuterated agent, 1, showed excellent binding affinity to SERT; Ki was 0.086 nM, comparable with the undeuterated FPBM. In vivo biodistribution studies in rats with [18 F]1 showed good brain uptake (1.09% dose/g at 2 min post injection) and high specific uptake into the hypothalamus (HY) as compared with cerebellum (CB) (HY/CB = 7.55 at 120 min), suggesting a specific localization to SERT binding sites. Regional brain distribution in rats provided clear indication that [18 F]1 concentrated in the hypothalamus, hippocampus, and striatum, areas with a high SERT density. Results indicate that very little D to H substitution effect was found; [18 F]FPBM and [18 F]1 showed very similar SERT binding. [18 F]1 might be an excellent candidate for SERT imaging.


Assuntos
Aminas/química , Deutério/química , Tomografia por Emissão de Pósitrons/métodos , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Aminas/metabolismo , Aminas/farmacocinética , Animais , Linhagem Celular , Marcação por Isótopo , Radioquímica , Ratos , Distribuição Tecidual
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...