RESUMO
Recent advances in intratracheal delivery strategies have sparked considerable biomedical interest in developing this promising approach for lung cancer diagnosis and treatment. However, there are very few relevant studies on the behavior and mechanism of imaging nanoparticles (NPs) after intratracheal delivery. Here, we found that nanosized perfluoro-15-crown-5-ether (PFCE NPs, â¼200 nm) exhibite significant 19F-MRI signal-to-noise ratio (SNR) enhancement than perfluorooctyl bromide (PFOB NPs) up to day 7 after intratracheal delivery. Alveolar macrophages (AMs) engulf PFCE NPs, become PFCE NPs-laden AMs, and then migrate into the tumor margin, resulting in increased tumor PFCE concentration and 19F-MRI signals. AMs-mediated translocation of PFCE NPs to lung draning lymph nodes (dLNs) decreases the background PFCE concentration. Our results shed light on the dynamic AMs-mediated translocation of intratracheally delivered PFC NPs for effective lung tumor visualization and reveal a pathway to develop and promote the clinical translation of an intratracheal delivery-based imaging strategy.
Assuntos
Fluorocarbonos , Neoplasias Pulmonares , Nanopartículas , Humanos , Macrófagos Alveolares , Imageamento por Ressonância Magnética/métodos , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
Inefficient tumor accumulation and penetration remain as the main challenges to therapy efficacy of lung cancer. Local delivery of smart nanoclusters can increase drug penetration and provide superior antitumor effects than systemic routes. Here, we report self-assembled pH-sensitive superparamagnetic iron oxide nanoclusters (SPIONCs) that enhance in situ ferroptosis and apoptosis with radiotherapy and chemodynamic therapy. After pulmonary delivery in orthotopic lung cancer, SPIONCs disintegrate into smaller nanoparticles and release more iron ions in an acidic microenvironment. Under single-dose X-ray irradiation, endogenous superoxide dismutase converts superoxide radicals produced by mitochondria to hydrogen peroxide, which in turn generates hydroxyl radicals by the Fenton reaction from iron ions accumulated inside the tumor. Finally, irradiation and iron ions enhance tumor lipid peroxidation and induce cell apoptosis and ferroptosis. Thus, rationally designed pulmonary delivered nanoclusters provide a promising strategy for noninvasive imaging of lung cancer and synergistic therapy.
Assuntos
Ferroptose , Neoplasias Pulmonares , Nanopartículas , Neoplasias , Linhagem Celular Tumoral , Humanos , Peróxido de Hidrogênio/farmacologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Medicina de Precisão , Microambiente TumoralRESUMO
BACKGROUND: Non-small cell lung cancer (NSCLC) patients with primary tumors and liver metastases have substantially reduced survival. Since mesenchymal-epithelial transition factor (MET) plays a significant role in the molecular mechanisms of advanced NSCLC, small molecule MET inhibitor capmatinib (INC280) hold promise for clinically NSCLC treatment. However, the major obstacles of MET-targeted therapy are poor drug solubility and off-tumor effects, even oral high-dosing regimens cannot significantly increase the therapeutic drug concentration in primary and metastatic NSCLC. METHODS: We developed a multirooted delivery system INC280-PFCE nanoparticles (NPs) by loading INC280 into perfluoro-15-crown-5-ether for improving MET-targeted therapy. Biodistribution and anti-MET/antimetastatic effects of NPs were validated in orthotopic NSCLC and NSCLC liver metastasis models in a single low-dose. The efficacy of INC280-PFCE NPs was also explored in human NSCLC specimens. RESULTS: INC280-PFCE NPs exhibited excellent antitumor ability in vitro. In orthotopic NSCLC models, sustained release and prolonged retention behaviors of INC280-PFCE NPs within tumors could be visualized in real-time by 19F magnetic resonance imaging (19F-MRI), and single pulmonary administration of NPs showed more significant tumor growth inhibition than oral administration of free INC280 at a tenfold higher dose. Furthermore, a single low-dose INC280-PFCE NPs administered intravenously suppressed widespread dissemination of liver metastasis without systemic toxicity. Finally, we verified the clinical translation potential of INC280-PFCE NPs in human NSCLC specimens. CONCLUSIONS: These results demonstrated high anti-MET/antimetastatic efficacies, real-time MRI visualization and high biocompatibility of NPs after a single low-dose.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Hepáticas , Neoplasias Pulmonares , Nanopartículas , Humanos , Medicina de Precisão , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Distribuição Tecidual , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológicoRESUMO
BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a two-stage strategy that may increase hepatic tumour resectability and reduce postoperative liver failure rate by inducing rapid hypertrophy of the future liver remnant (FLR). Pathophysiological mechanisms after the first stage of ALPPS are poorly understood. METHODS: An ALPPS model was established in rabbits with liver VX2 tumour. The pathophysiological mechanisms after the first stage of ALPPS in the FLR and tumour were assessed by multiplexed positron emission tomography (PET) tracers, dynamic contrast-enhanced MRI (DCE-MRI) and histopathology. RESULTS: Tumour volume in the ALPPS model differed from post-stage 1 ALPPS at day 14 compared to control animals. 18F-FDG uptake of tumour increased from day 7 onwards in the ALPPS model. Valid volumetric function measured by 18F-methylcholine PET showed good values in accurately monitoring dynamics and time window for functional liver regeneration (days 3 to 7). DCE-MRI revealed changes in the vascular hyperpermeability function, with a peak on day 7 for tumour and FLR. CONCLUSION: Molecular and functional imaging are promising non-invasive methods to investigate the pathophysiological mechanisms of ALPPS with potential for clinical application.
Assuntos
Hepatectomia , Neoplasias Hepáticas , Animais , Hepatectomia/métodos , Humanos , Ligadura/métodos , Fígado/irrigação sanguínea , Fígado/diagnóstico por imagem , Fígado/cirurgia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Regeneração Hepática/fisiologia , Modelos Teóricos , Veia Porta/diagnóstico por imagem , Veia Porta/cirurgia , CoelhosRESUMO
BACKGROUND: To assess the potential of apparent diffusion coefficient (ADC) map in predicting aggressiveness of papillary thyroid carcinoma (PTC) based on whole-tumor histogram-based analysis. METHODS: A total of 88 patients with PTC confirmed by pathology, who underwent neck magnetic resonance imaging, were enrolled in this retrospective study. Whole-lesion histogram features were extracted from ADC maps and compared between the aggressive and non-aggressive groups. Multivariable logistic regression analysis was performed for identifying independent predictive factors. Receiver operating characteristic curve analysis was used to evaluate the performances of significant factors, and an optimal predictive model for aggressiveness of PTC was developed. RESULTS: The aggressive and non-aggressive groups comprised 67 (mean age, 44.03 ± 13.99 years) and 21 (mean age, 43.86 ± 12.16 years) patients, respectively. Five histogram features were included into the final predictive model. ADC_firstorder_TotalEnergy had the best performance (area under the curve [AUC] = 0.77). The final combined model showed an optimal performance, with AUC and accuracy of 0.88 and 0.75, respectively. CONCLUSIONS: Whole-lesion histogram analysis based on ADC maps could be utilized for evaluating aggressiveness in PTC.
Assuntos
Imagem de Difusão por Ressonância Magnética , Neoplasias da Glândula Tireoide , Humanos , Adulto , Pessoa de Meia-Idade , Câncer Papilífero da Tireoide/diagnóstico por imagem , Câncer Papilífero da Tireoide/patologia , Estudos Retrospectivos , Sensibilidade e Especificidade , Imagem de Difusão por Ressonância Magnética/métodos , Curva ROC , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/patologiaRESUMO
OBJECTIVE: To investigate the ability of a multimodality MRI-based radiomics model in predicting the aggressiveness of papillary thyroid carcinoma (PTC). METHODS: This study included consecutive patients who underwent neck magnetic resonance (MR) scans and subsequent thyroidectomy during the study period. The pathological diagnosis of thyroidectomy specimens was the gold standard to determine the aggressiveness. Thyroid nodules were manually segmented on three modal MR images, and then radiomics features were extracted. A machine learning model was established to evaluate the prediction of PTC aggressiveness. RESULTS: The study cohort included 107 patients with PTC confirmed by pathology (cross-validation cohort: n = 71; test cohort: n = 36). A total of 1584 features were extracted from contrast-enhanced T1-weighted (CE-T1 WI), T2-weighted (T2 WI) and diffusion weighted (DWI) images of each patient. Sparse representation method is used for radiation feature selection and classification model establishment. The accuracy of the independent test set that using only one modality, like CE-T1WI, T2WI or DWI was not particularly satisfactory. In contrast, the result of these three modalities combined achieved 0.917. CONCLUSION: Our study shows that multimodality MR image based on radiomics model can accurately distinguish aggressiveness in PTC from non-aggressiveness PTC before operation. This method may be helpful to inform the treatment strategy and prognosis of patients with aggressiveness PTC.
Assuntos
Imageamento por Ressonância Magnética , Neoplasias da Glândula Tireoide , Humanos , Imageamento por Ressonância Magnética/métodos , Pescoço , Estudos Retrospectivos , Câncer Papilífero da Tireoide/diagnóstico por imagem , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgiaRESUMO
The influx of sodium (Na+ ) ions into a resting cell is regulated by Na+ channels and by Na+ /H+ and Na+ /Ca2+ exchangers, whereas Na+ ion efflux is mediated by the activity of Na+ /K+ -ATPase to maintain a high transmembrane Na+ ion gradient. Dysfunction of this system leads to changes in the intracellular sodium concentration that promotes cancer metastasis by mediating invasion and migration. In addition, the accumulation of extracellular Na+ ions in cancer due to inflammation contributes to tumor immunogenicity. Thus, alterations in the Na+ ion concentration may potentially be used as a biomarker for malignant tumor diagnosis and prognosis. However, current limitations in detection technology and a complex tumor microenvironment present significant challenges for the in vivo assessment of Na+ concentration in tumor. 23 Na-magnetic resonance imaging (23 Na-MRI) offers a unique opportunity to study the effects of Na+ ion concentration changes in cancer. Although challenged by a low signal-to-noise ratio, the development of ultrahigh magnetic field scanners and specialized sodium acquisition sequences has significantly advanced 23 Na-MRI. 23 Na-MRI provides biochemical information that reflects cell viability, structural integrity, and energy metabolism, and has been shown to reveal rapid treatment response at the molecular level before morphological changes occur. Here we review the basis of 23 Na-MRI technology and discuss its potential as a direct noninvasive in vivo diagnostic and prognostic biomarker for cancer therapy, particularly in cancer immunotherapy. We propose that 23 Na-MRI is a promising method with a wide range of applications in the tumor immuno-microenvironment research field and in cancer immunotherapy monitoring. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.
Assuntos
Neoplasias , Sódio , Biomarcadores , Humanos , Íons , Imageamento por Ressonância Magnética , Neoplasias/diagnóstico por imagem , Prognóstico , Microambiente TumoralRESUMO
BACKGROUND: To determine the predictive capability of MRI-based radiomics for extrathyroidal extension detection in papillary thyroid cancer (PTC) pre-surgically. METHODS: The present retrospective trial assessed individuals with thyroid nodules examined by multiparametric MRI and subsequently administered thyroid surgery. Diagnosis and extrathyroidal extension (ETE) feature of PTC were based on pathological assessment. The thyroid tumors underwent manual segmentation, for radiomic feature extraction. Participants were randomized to the training and testing cohorts, at a ratio of 7:3. The mRMR (maximum correlation minimum redundancy) algorithm and the least absolute shrinkage and selection operator were utilized for radiomics feature selection. Then, a radiomics predictive model was generated via a linear combination of the features. The model's performance in distinguishing the ETE feature of PTC was assessed by analyzing the receiver operating characteristic curve. RESULTS: Totally 132 patients were assessed in this study, including 92 and 40 in the training and test cohorts, respectively). Next, the 16 top-performing features, including 4, 7 and 5 from diffusion weighted (DWI), T2-weighted (T2 WI), and contrast-enhanced T1-weighted (CE-T1WI) images, respectively, were finally retained to construct the radiomics signature. There were 8 RLM, 5 CM, 2 shape, and 1 SZM features. The radiomics prediction model achieved AUCs of 0.96 and 0.87 in the training and testing sets, respectively. CONCLUSIONS: Our study indicated that MRI radiomics approach had the potential to stratify patients based on ETE in PTCs preoperatively.
Assuntos
Interpretação de Imagem Assistida por Computador , Imageamento por Ressonância Magnética Multiparamétrica/métodos , Câncer Papilífero da Tireoide/diagnóstico por imagem , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/patologia , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Período Pré-Operatório , Curva ROC , Estudos Retrospectivos , Adulto JovemRESUMO
20(s)-ginsenoside Rg3 is a red ginseng-derived compound with the formula C42H72O13 that has been increasingly used by humans, leading to safety concerns regarding this use. In the current study, we conducted a 26-week study during which 20(S)-ginsenoside Rg3 (0, 7, 20, or 60â¯mg/kg) was continuously administered orally to Beagle dogs in order to explore its toxicity in these animals, with control dogs receiving a vehicle capsule. In total, 10 dogs received each dose of this compound (nâ¯=â¯5 male, nâ¯=â¯5 female per dose). Animals were continuously monitored for a 26-week administration period and a subsequent 4-week follow-up recovery period. At the end of study, we observed no evidence of 20(S)-ginsenoside Rg3 toxicity in clinical indications, body weight, food intake, ophthalmoscopy, electrocardiogram, urinalysis, hematology, serum biochemistry, gross and histopathology findings. However, the kidney relative weight of animals receiving 60â¯mg/kg of compound was significantly elevated relative to control animals (5.15⯱â¯0.88 vs. 4.11⯱â¯0.59. Pâ¯<â¯0.05), and this effect was reversed after 4-week recovery period. Based on these results, the NOAEL value for orally administered 20(S)-ginsenoside Rg3 in dogs is 20â¯mg/kg.
Assuntos
Antineoplásicos Fitogênicos/toxicidade , Ginsenosídeos/toxicidade , Administração Oral , Animais , Cães , Feminino , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Nível de Efeito Adverso não Observado , Tamanho do Órgão/efeitos dos fármacos , Testes de Toxicidade SubcrônicaRESUMO
Epidermal growth factor receptor (EGFR)-targeted cancer therapy requires an accurate estimation of EGFR expression in tumors to identify responsive patients, monitor therapeutic effect, and estimate prognosis. The EGFR molecular imaging is an optimal method for evaluating EGFR expression in vivo accurately and noninvasively. In this review, we discuss the recent advances in EGFR-targeted molecular imaging in cancer, with a special focus on the development of imaging agents, including epidermal growth factor (EGF) ligand, monoclonal antibodies, antibody fragments, Affibody, and small molecules. Each substrate or probe, whether it is an endogenous ligand, antibody, peptide, or small molecule labeled with fluorochrome or radionuclide, has unique advantages and limitations. Antibody-based probes have high affinity but a long metabolic cycle and therefore offer poor imaging quality. Affibody molecules promise to surpass antibody-based probes due to their small size, stable chemical properties, and high affinity to the target. Small-molecule probes are safe, have favorable pharmacokinetics, and show high affinity and specificity, in addition to having an ideal size, but are inadequate for delayed imaging after injection due to their fast clearance.
Assuntos
Imagem Molecular/métodos , Neoplasias/diagnóstico por imagem , Animais , Anticorpos Monoclonais/administração & dosagem , Fator de Crescimento Epidérmico/administração & dosagem , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Fragmentos de Imunoglobulinas/administração & dosagem , Neoplasias/metabolismo , Bibliotecas de Moléculas Pequenas/administração & dosagemRESUMO
The assessment of vascular permeability of malignant tumor plays an important role in the diagnosis and treatment of cancer. Dynamic contrast-enhanced magnetic resonance image (DCE-MRI) using Gd-encapsulated carbonaceous dots and Gd-DTPA-BMA as contrast agents was performed in 4T1 mouse breast cancer and HCC827 human non-small-cell lung cancer (NSNLC) xenograft models. Histopathological parameters of tumor vascularity microvessel density (MVD), microvessel area (MVA), endothelial area (EA) and α-SMA CD31 Co-expression (α-SMA/CD31%) were compared with the DCE-MRI parameters. Results demonstrated that DCE-MRI with the new nanoparticle Gd@C-dots can noninvasively evaluate vascular permeability. Ktrans measured by DCE-MRI with Gd@C-dots is an accurate parameter for the characterization of tumor permeability. EA is a reliable microvessel parameter to evaluate vessel permeability.
Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Meios de Contraste , Endotélio Vascular/diagnóstico por imagem , Gadolínio , Neoplasias Pulmonares/diagnóstico por imagem , Imageamento por Ressonância Magnética , Neoplasias Mamárias Animais/diagnóstico por imagem , Nanopartículas/química , Neovascularização Patológica/diagnóstico por imagem , Animais , Carcinoma Pulmonar de Células não Pequenas/irrigação sanguínea , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Meios de Contraste/química , Meios de Contraste/farmacocinética , Meios de Contraste/farmacologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Gadolínio/química , Gadolínio/farmacocinética , Gadolínio/farmacologia , Xenoenxertos , Humanos , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Mamárias Animais/irrigação sanguínea , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/patologia , Camundongos , Transplante de Neoplasias , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Transplante IsogênicoRESUMO
BACKGROUND: Folate receptors (FRs) hold great potential as important diagnostic and prognostic biological marker for cancer. PURPOSE: To assess the targeted capability of the FR-targeted perfluorocarbon (PFC) nanoparticles and to assess in vivo the relationship between FR expression and tumor proliferation with fluorine-19 (19 F) MR molecular imaging. STUDY TYPE: Prospective animal cancer model. ANIMAL MODEL: H460 (n = 14) and A549 (n = 14) nude mice subcutaneous tumor models. FIELD STRENGTH: 9.4T, 1 H and 19 F RARE sequences. ASSESSMENT: Intracellular uptake of the PFC nanoparticles was tested in H460 and A549 cell lines. 19 F MRI of H460 and A549 subcutaneous tumors was performed following intravenous injection of PFC nanoparticles. The concentration of PFC in tumors were compared. 3'-Deoxy-3'-18 F-fluorothymidine (18 F-FLT) positron emission tomography / computed tomography (PET/CT) imaging, Ki-67, and proliferating cell nuclear antigen (PCNA) staining were performed to confirm tumor proliferation. STATISTICAL TESTS: One-way or two-way analysis of variance. P < 0.05 was considered a significant difference. RESULTS: The diameter of the FR-targeted nanoparticles was 108.8 ± 0.56 nm, and the zeta potential was -58.4 ± 10.8 mV. H460 cells incubated with FR-targeted nanoparticles showed â¼59.87 ± 3.91% nanoparticles-labeled, which is significantly higher than the other groups (P < 0.001). The PFC concentration in H460 tumors after injection with FR-targeted nanoparticles was 4.64 ± 1.21, 8.04 ± 1.38, and 9.16 ± 2.56 mmol/L at 8 hours, 24 hours, and 48 hours, respectively (P < 0.05 compared to others). The ratio of 18 F-FLT uptake for H460 and A549 tumors was 3.32 ± 0.17 and 1.48 ± 0.09 (P < 0.05), and there was more Ki-67 and PCNA in H460 tumor than A549. DATA CONCLUSION: 19 F MRI with FR-targeted PFC nanoparticles can be used in differentiating of FR-positive and FR-negative tumors, and further, in evaluation of the two cancer models proliferation. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1617-1625.
Assuntos
Radioisótopos de Flúor/química , Neoplasias Pulmonares/diagnóstico por imagem , Imageamento por Ressonância Magnética , Imagem Molecular , Nanopartículas/química , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Animais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Fluorocarbonos/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia de Fluorescência , Transplante de Neoplasias , Prognóstico , Compostos RadiofarmacêuticosRESUMO
The important role of insulin-like growth factor 1 receptor (IGF-1R) in malignant tumors has been well established. Increased IGF-1R activity promotes cancer cell proliferation, migration, and invasion and is associated with tumor metastasis, treatment resistance, poor prognosis, and shortened survival in patients with cancer. However, while IGF-1R has become a promising target for cancer therapy, IGF-1R-targeted therapy is ineffective in unselected patients. It is therefore essential to evaluate IGF-1R expression before treatment in order to identify responsive patients, monitor therapy efficacy, and estimate prognosis. Insulin-like growth factor 1 receptor molecular imaging is an optimal method for assessing the expression of IGF-1R in vivo accurately and noninvasively. In this review, we will summarize the current status of IGF-1R molecular imaging in cancer, in which 5 major classes of ligands that have been developed for noninvasive IGF-1R molecular imaging will be discussed: natural ligands, monoclonal antibodies, antibody fragments, affibodies, and small molecules. For decades, IGF-1R molecular imaging is studied in full swing and more effort is needed in the future.
Assuntos
Imagem Molecular/métodos , Neoplasias/diagnóstico por imagem , Receptores de Somatomedina/metabolismo , Animais , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Regulação Neoplásica da Expressão Gênica , Humanos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Medicina de Precisão , Prognóstico , Receptor IGF Tipo 1 , Resultado do TratamentoRESUMO
EGFR (epidermal growth factor receptor) targeted therapy has shown great success in clinical comparing with chemotherapy in EGFR mutation NSCLCs. Such as, gefitinib, first generation EGFR TKI, has obviously prolonged the FPS (progression free survival) of the subgroup of patients, but to those who did not get a certain mutation in EGFR kinase domain, the outcome is poor. In view of this situation, scientists have synthesized many radiotracers for selecting the right people by PET/CT imaging to NSCLC TKI therapy. In this study, we developed a novel PET radiotracer 18F-IRS in one-step with a radio yield 20% (non-corrected), radiochemistry>98.5%, specific activity>105GBq/µmol, the pharmacokinetics and capacity of the tracer binding to mutant EGFR were evaluated both in vitro and in vivo.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Receptores ErbB/genética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Quinazolinas/farmacocinética , Animais , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Receptores ErbB/metabolismo , Humanos , Camundongos , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Traçadores Radioativos , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
Mutated epidermal growth factor receptor (EGFR) is an important biomarker for cancer diagnosis and molecular target for many anticancer drugs. Localizing EGFR and evaluating EGFR mutational status can help to identify patients who are potentially the most suitable ones for targeted treatments. Hence, we developed a novel EGFR tyrosine kinase inhibitor labeled with (99m)Tc ((99m)Tc-HYNIC-MPG) and evaluated its EGFR binding capacity in vitro and in vivo. This molecular probe was synthesized by one-step method that is simple and highly efficient. Importantly, the uptake rate for (99m)Tc-HYNIC-MPG in the liver was as low as 28.44 ± 0.15% (mean ± SD, n=3). This finding presents for the first time that (99m)Tc-HYNIC-MPG can bind to mutated EGFR efficiently and thus provides a novel molecular tool to detect mutated EGFR and suppress tumorigenesis.
Assuntos
Receptores ErbB/antagonistas & inibidores , Sondas Moleculares/farmacologia , Compostos de Organotecnécio/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Tomografia Computadorizada de Emissão de Fóton Único , Animais , Linhagem Celular , Receptores ErbB/genética , Feminino , Humanos , Camundongos , Camundongos Endogâmicos , Imagem Molecular , Sondas Moleculares/síntese química , Sondas Moleculares/química , Mutação , Compostos de Organotecnécio/síntese química , Compostos de Organotecnécio/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinas/síntese química , Quinazolinas/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Breast cancer is the most common malignancy and the leading cause of cancer death in women worldwide; however, early diagnosis has been difficult due to its complex pathological structure. This study evaluated the value of morphological examination in conjunction with dynamic contrast-enhanced MRI (DCE-MRI) for more precise diagnosis of breast cancer, as well as their correlation with angiogenesis and proliferation biomarkers. MATERIAL/METHODS: DCE-MRI parameters (including Ktrans: volume transfer coefficient reflecting vascular permeability, Kep: flux rate constant, Ve: extracellular volume ratio reflecting vascular permeability, and ADC: apparent diffusion coefficient) were obtained from 124 patients with breast cancer (124 lesions). Microvessel density (MVD) was evaluated by the immunohistochemical analysis of tumor vessels for CD31 and CD105 expression. The proliferation was assessed by analyzing Ki67. RESULTS: Ktrans values were in the order of: malignant lesions>benign lesions>normal glands. Similar results were observed for Kep. The opposite changes were seen with Ve. Ktrans and Kep values were significantly higher in invasive ductal carcinoma (IDC) and ductal carcinoma in situ (DCIS) than in mammary ductal dysplasia (MDD; ANOVA followed by Dunnett's test). In sharp contrast, ADC values were lower in IDC and DCIS than in MDD, and Ve was not significantly different among the three groups. The data from MIP (maximum intensity projection) showed that benign breast lesions had no or only one blood vessel, whereas malignant lesions had two or more blood vessels. In addition, expression of CD105 and Ki67, the commonly recognized markers for angiogenesis and proliferation, respectively, were closely correlated with MRI parameters as revealed by Pearson analysis. CONCLUSIONS: Determination of Ktrans, Kep and ADC values permits estimation of tumor angiogenesis and proliferation in breast cancer and DCE-MRI parameters can be used as imaging biomarkers to predict patient prognosis and the biologic aggressiveness of the tumor.
Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Meios de Contraste/química , Imageamento por Ressonância Magnética/métodos , Neovascularização Patológica/patologia , Adulto , Idoso , Antígenos CD/metabolismo , Biomarcadores/metabolismo , Neoplasias da Mama/metabolismo , Proliferação de Células , Endoglina , Feminino , Humanos , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Pessoa de Meia-Idade , Permeabilidade , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Prognóstico , Receptores de Superfície Celular/metabolismoRESUMO
The fungal immunomodulatory proteins (FIPs) are a new protein family identified from several edible and medical mushrooms and play an important role in antitumor, anti-allergy and immunomodulating activities. A gene encoding the FIP-vvo was cloned from the mycelia of Volvariella volvacea and recombinant expressed in the Pichia pastoris expression system. SDS-PAGE, amino acid composition and circular dichroism analyses of the recombinant FIP-vvo (reFIP-vvo) indicated that the gene was correctly and successfully expressed. In vitro assays of biological activities revealed that the reFIP-vvo exhibited similar immunomodulating capacities as native form. The reFIP-vvo significantly stimulated the proliferation of mouse spleen lymphocytes and apparently enhanced the expression level of IFN-γ released from the mouse splenocytes. Taken together, the FIP-vvo gene from V. volvacea has been integrated into the yeast genome and expressed effectively at a high level (about 410mg/L), it was capable of agglutinating sheep and rat red blood cells. The reFIP-vvo possessed very similar biological activities to native FIPs, suggesting its potential application as a food supplement or immunomodulating agent in pharmaceuticals and even medical studies.
Assuntos
Proteínas Fúngicas/biossíntese , Proteínas Fúngicas/genética , Imunomodulação/genética , Volvariella/genética , Sequência de Aminoácidos , Animais , Proliferação de Células/efeitos dos fármacos , Dicroísmo Circular , Proteínas Fúngicas/isolamento & purificação , Proteínas Fúngicas/farmacologia , Regulação Fúngica da Expressão Gênica , Imunomodulação/efeitos dos fármacos , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Camundongos , Pichia , Baço/citologia , Baço/efeitos dos fármacos , Volvariella/químicaRESUMO
Although our understanding of lung cancer has significantly improved in the past decade, it is still a disease with a high incidence and mortality rate. The key reason is that the efficacy of the therapeutic drugs is limited, mainly due to insufficient doses of drugs delivered to the lungs. To achieve precise lung cancer diagnosis and treatment, nano-particles (NPs) pulmonary delivery techniques have attracted much attention and facilitate the exploration of the potential of those in inhalable NPs targeting tumor lesions. Since the therapeutic research focusing on pulmonary delivery NPs has rapidly developed and evolved substantially, this review will mainly discuss the current developments of pulmonary delivery NPs for precision lung cancer diagnosis and therapy. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Respiratory Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.
Assuntos
Neoplasias Pulmonares , Nanopartículas , Humanos , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Pulmão , Preparações Farmacêuticas , Nanomedicina/métodos , Nanopartículas/uso terapêuticoRESUMO
INTRODUCTION: This study evaluates the role of quantitative characteristics of white matter hyperintensities (WMHs) in predicting the 1-year recurrence risk of ischemic stroke. METHODS: We conducted a retrospective analysis of 1061 patients with ischemic stroke from January 2018 to April 2021. WMHs were automatically segmented using a cluster-based method to quantify their volume and number of clusters (NoC). Additionally, two radiologists independently rated periventricular and deep WMHs using the Fazekas scale. The cohort was divided into a training set (70%) and a testing set (30%). We employed Cox proportional hazards models to develop predictors based on quantitative WMH characteristics, Fazekas scores, and clinical factors, and compared their performance using the concordance index (C-index). RESULTS: A total of 180 quantitative variables related to WMHs were extracted. A higher NoC in deep white matter and brainstem, advanced age (> 90 years old), specific stroke subtypes, and absence of discharge antiplatelets showed stronger associations with the risk of ischemic stroke recurrence within 1 year. The nomogram incorporating quantitative WMHs data showed superior discrimination compared to those based on the Fazekas scale or clinical factors alone, with C-index values of 0.709 versus 0.647 and 0.648, respectively, in the testing set. Notably, a combined model including both WMHs and clinical factors achieved the highest predictive accuracy, with a C-index of 0.735 in the testing set. CONCLUSION: Quantitative assessment of WMHs provides a valuable neuro-imaging tool for enhancing the prediction of ischemic stroke recurrence risk.
RESUMO
Although immunotherapy has revolutionized the entire cancer treatment landscape, small fractions of patients respond to immunotherapy. Early identification of responders may improve patient management during immunotherapy. In this study, we evaluated a PET approach for monitoring immunotherapy in lung cancer by imaging the upregulation of lymphocyte activation gene 3 (LAG-3)-expressing (LAG-3+) tumor-infiltrating lymphocytes (TILs). Methods: We synthesized a LAG-3-targeted molecular imaging probe, [68Ga]Ga-NOTA-C25 and performed a series of in vitro and in vivo assays to test its specificity. Next, [68Ga]Ga-NOTA-C25 PET was used to monitor immunotherapy in murine lung cancer-bearing mice and in humanized mouse models for assessing clinical translational potential, with confirmation by immunostaining and flow cytometry analysis. Results: [68Ga]Ga-NOTA-C25 PET could noninvasively detect intertumoral differences in LAG-3+ TIL levels in different tumor models. Importantly, in Lewis lung carcinoma tumor models treated with an agonist of a stimulator of interferon genes, [68Ga]Ga-NOTA-C25 PET also detected an immunophenotyping transition of the tumor from "cold" to "hot" before changes in tumor size. Meanwhile, animals carrying "hot" tumor showed more significant tumor inhibition and longer survival than those carrying "cold" tumor. [68Ga]Ga-NOTA-C25 PET also showed markedly higher tumor uptake in immune system-humanized mice carrying human non-small cell lung cancer than immunodeficient models. Conclusion: [68Ga]Ga-NOTA-C25 PET could be used to noninvasively monitor the early response to immunotherapy by imaging LAG-3+ TILs in lung cancer. [68Ga]Ga-NOTA-C25 PET also exhibited excellent translational potential, with great significance for the precise management of lung cancer patients receiving immunotherapy.