RESUMO
Chimeric antigen receptor (CAR) cell therapies utilize CARs to redirect immune cells towards cancer cells expressing specific antigens like human epidermal growth factor receptor 2 (HER2). Despite their potential, CAR T cell therapies exhibit variable response rates and adverse effects in some patients. Non-invasive molecular imaging can aid in predicting patient outcomes by tracking infused cells post-administration. CAR-T cells are typically autologous, increasing manufacturing complexity and costs. An alternative approach involves developing CAR natural killer (CAR-NK) cells as an off-the-shelf allogeneic product. In this study, we engineered HER2-targeted CAR-NK cells co-expressing the positron emission tomography (PET) reporter gene human sodium-iodide symporter (NIS) and assessed their therapeutic efficacy and PET imaging capability in a HER2 ovarian cancer mouse model.NK-92 cells were genetically modified to express a HER2-targeted CAR, the bioluminescence imaging reporter Antares, and NIS. HER2-expressing ovarian cancer cells were engineered to express the bioluminescence reporter Firefly luciferase (Fluc). Co-culture experiments demonstrated significantly enhanced cytotoxicity of CAR-NK cells compared to naive NK cells. In vivo studies involving mice with Fluc-expressing tumors revealed that those treated with CAR-NK cells exhibited reduced tumor burden and prolonged survival compared to controls. Longitudinal bioluminescence imaging demonstrated stable signals from CAR-NK cells over time. PET imaging using the NIS-targeted tracer 18F-tetrafluoroborate ([18F]TFB) showed significantly higher PET signals in mice treated with NIS-expressing CAR-NK cells.Overall, our study showcases the therapeutic potential of HER2-targeted CAR-NK cells in an aggressive ovarian cancer model and underscores the feasibility of using human-derived PET reporter gene imaging to monitor these cells non-invasively in patients.
RESUMO
This paper provides an in-depth overview of Deep Neural Networks and their application in the segmentation and analysis of lung Magnetic Resonance Imaging (MRI) scans, specifically focusing on hyperpolarized gas MRI and the quantification of lung ventilation defects. An in-depth understanding of Deep Neural Networks is presented, laying the groundwork for the exploration of their use in hyperpolarized gas MRI and the quantification of lung ventilation defects. Five distinct studies are examined, each leveraging unique deep learning architectures and data augmentation techniques to optimize model performance. These studies encompass a range of approaches, including the use of 3D Convolutional Neural Networks, cascaded U-Net models, Generative Adversarial Networks, and nnU-net for hyperpolarized gas MRI segmentation. The findings highlight the potential of deep learning methods in the segmentation and analysis of lung MRI scans, emphasizing the need for consensus on lung ventilation segmentation methods.
RESUMO
Stem cell-based therapies have demonstrated significant potential in clinical applications for many debilitating diseases. The ability to non-invasively and dynamically track the location and viability of stem cells post administration could provide important information on individual patient response and/or side effects. Multi-modal cell tracking provides complementary information that can offset the limitations of a single imaging modality to yield a more comprehensive picture of cell fate. In this study, mesenchymal stem cells (MSCs) were engineered to express human sodium iodide symporter (NIS), a clinically relevant positron emission tomography (PET) reporter gene, as well as labeled with superparamagnetic iron oxide nanoparticles (SPIOs) to allow for detection with magnetic particle imaging (MPI). MSCs were additionally engineered with a preclinical bioluminescence imaging (BLI) reporter gene for comparison of BLI cell viability data to both MPI and PET data over time. MSCs were implanted into the hind limbs of immunocompromised mice and imaging with MPI, BLI and PET was performed over a 30-day period. MPI showed sensitive detection that steadily declined over the 30-day period, while BLI showed initial decreases followed by later rapid increases in signal. The PET signal of MSCs was significantly higher than the background at later timepoints. Early-phase imaging (day 0-9 post MSC injections) showed correlation between MPI and BLI data (R2 = 0.671), while PET and BLI showed strong correlation for late-phase (day 10-30 post MSC injections) imaging timepoints (R2 = 0.9817). We report the first use of combined MPI and PET for cell tracking and show the complementary benefits of MPI for sensitive detection of MSCs early after implantation and PET for longer-term measurements of cell viability.
Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Camundongos , Animais , Humanos , Transplante de Células-Tronco Mesenquimais/métodos , Tomografia por Emissão de Pósitrons/métodos , Genes Reporter , Fenômenos MagnéticosRESUMO
The proteolytically-activated G protein-coupled receptor (GPCR) protease-activated receptor 2 (PAR2), is implicated in various cancers and inflammatory diseases. Synthetic ligands and in vitro imaging probes targeting this receptor have been developed with low nanomolar affinity, however, no in vivo imaging probes exist for PAR2. Here, we report the strategic design, synthesis, and biological evaluation of a series of novel 4-fluorobenzoylated PAR2-targeting peptides derived from 2f-LIGRLO-NH2 (2f-LI-) and Isox-Cha-Chg-Xaa-NH2 (Isox-) peptide families, where the 4-fluorobenzoyl moiety acts as the 19F-standard of an 18F-labeled probe for potential use in in vivo imaging. We found that several of the 4-fluorobenzoylated peptides from the 2f-LI-family exhibited PAR2 selectivity with moderate potency (EC50 = 151-252 nM), whereas several from the Isox-family exhibited PAR2 selectivity with high potency (EC50 = 13-42 nM). Our lead candidate, Isox-Cha-Chg-Ala-Arg-Dpr(4FB)-NH2 (EC50 = 13 nM), was successfully synthesized with fluorine-18 with a radiochemical yield of 37%, radiochemical purity of >98%, molar activity of 20 GBq/µmol, and an end of synthesis time of 125 min. Biodistribution studies and preliminary PET imaging of the tracer in mice showed predominantly renal clearance. This 18F-labeled tracer is the first reported PAR2 imaging agent with potential for use in vivo. Future work will explore the use of this tracer in cancer xenografts and inflammation models involving upregulation of PAR2 expression.
Assuntos
Neoplasias , Receptor PAR-2 , Camundongos , Humanos , Animais , Receptor PAR-2/metabolismo , Distribuição Tecidual , Peptídeos/farmacologia , Peptídeos/metabolismo , Radioisótopos de Flúor , Tomografia por Emissão de Pósitrons/métodosRESUMO
INTRODUCTION: The reliance on glycolytic metabolism is a hallmark of tumor metabolism. Excess acid and protons are produced, leading to an acidic tumor environment. Therefore, we explored the relationship between the tumor glycolytic metabolism and tissue pH by comparing 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and hyperpolarized [1-13C]pyruvate MR spectroscopy imaging (MRSI) to chemical exchange saturation transfer (CEST) MRI measurements of tumor pH. METHODS: 106 C6 glioma cells were implanted in the brains of male Wistar rats (N = 11) using stereotactic surgery. A 60-min PET acquisition after a bolus of FDG was performed at 11-13 days post implantation, and standardized uptake value (SUV) was calculated. CEST measurements were acquired the following day before and during constant infusion of glucose solution. Tumor intracellular pH (pHi) was evaluated using amine and amide concentration-independent detection (AACID) CEST MRI. The change of pHi (∆pHi) was calculated as the difference between pHi pre- and during glucose infusion. Rats were imaged immediately with hyperpolarized [1-13C]pyruvate MRSI. Regional maps of the ratio of Lac:Pyr were acquired. The correlations between SUV, Lac:Pyr ratio, and ∆pHi were evaluated using Pearson's correlation. RESULTS: A decrease of 0.14 in pHi was found after glucose infusion in tumor region. Significant correlations between tumor glycolysis measurements of Lac:Pyr and ∆pHi within the tumor (ρ = 0.83, P = 0.01) and peritumoral region (ρ = 0.76, P = 0.028) were observed. No significant correlations were found between tumor SUV and ∆pHi within the tumor (ρ = - 0.45, P = 0.17) and peritumor regions (ρ = - 0.6, P = 0.051). CONCLUSION: AACID detected the changes in pHi induced by glucose infusion. Significant correlations between tumor glycolytic measurement of Lac:Pyr and tumoral and peritumoral pHi and ∆pHi suggest the intrinsic relationship between tumor glycolytic metabolism and the tumor pH environment as well as the peritumor pH environment.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Ratos , Masculino , Animais , Glioblastoma/patologia , Neoplasias Encefálicas/patologia , Fluordesoxiglucose F18 , Glucose , Concentração de Íons de Hidrogênio , Ratos Wistar , Imageamento por Ressonância Magnética/métodos , Glicólise , PiruvatosRESUMO
Inhaled hyperpolarized 129Xe MRI is a non-invasive and radiation risk free lung imaging method, which can directly measure the business unit of the lung where gas exchange occurs: the alveoli and acinar ducts (lung function). Currently, three imaging approaches have been demonstrated to be useful for hyperpolarized 129Xe MR in lungs: Fast Gradient Recalled Echo (FGRE), Radial Projection Reconstruction (PR), and spiral/cones. Typically, non-Cartesian acquisitions such as PR and spiral/cones require specific data post-processing, such as interpolating, regridding, and density-weighting procedures for image reconstruction, which often leads to smoothing effects and resolution degradation. On the other hand, Cartesian methods such as FGRE are not short-echo time (TE) methods; they suffer from imaging gradient-induced diffusion-weighting of the k-space center, and employ a significant number of radio-frequency (RF) pulses. Due to the non-renewable magnetization of the hyperpolarized media, the use of a large number of RF pulses (FGRE/PR) required for full k-space coverage is a significant limitation, especially for low field (<0.5â¯T) hyperpolarized gas MRI. We demonstrate an ultra-fast, purely frequency-encoded, Cartesian pulse sequence called Frequency-Encoding Sectoral (FES), which takes advantage of the long T2* of hyperpolarized 129Xe gas at low field strength (0.074â¯T). In contrast to PR/FGRE, it uses a much smaller number of RF pulses, and consequently maximizes image Signal-to-Noise Ratio (SNR) while shortening acquisition time. Additionally, FES does not suffer from non-uniform T2* decay leading to image blurring; a common issue with interleaved spirals/cones. The Cartesian k-space coverage of the proposed FES method does not require specific k-space data post-processing, unlike PR/FGRE and spiral/cones methods. Proton scans were used to compare the FES sequence to both FGRE and Phase Encoding Sectoral, in terms of their SNR values and imaging efficiency estimates. Using FES, proton and hyperpolarized 129Xe images were acquired from a custom hollow acrylic phantom (0.04L) and two normal rats (129Xe only), utilizing both single-breath and multiple-breath schemes. For the 129Xe phantom images, the apparent diffusion coefficient, T1, and T2* relaxation maps were acquired and generated. Blurring due to the T2* decay and B0 field variation were simulated to estimate dependence of the image resolution on the duration of the data acquisition windows (i.e. sector length), and temperature-induced resonance frequency shift from the low field magnet hardware.
Assuntos
Prótons , Isótopos de Xenônio , Animais , Pulmão/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Ratos , Razão Sinal-RuídoRESUMO
PURPOSE: Chemical exchange saturation transfer MRI using an infusion of glucose (glucoCEST) is sensitive to the distribution of glucose in vivo; however, whether glucoCEST is more related to perfusion or glycolysis is still debatable. We compared glucoCEST to computed tomography perfusion (CTP), [18F] fluorodeoxyglucose positron emission tomography (FDG-PET), and hyperpolarized [1-13C] pyruvate magnetic resonance spectroscopy imaging (MRSI) in a C6 rat model of glioma to determine if glucoCEST is more strongly correlated with measurements of perfusion or glycolysis. METHODS: 106 C6 glioma cells were implanted in Wistar rat brains (n = 11). CTP (including blood volume, BV; blood flow, BF; and permeability surface area product, PS) and FDG-PET standardized uptake value (SUV) were acquired at 11 to 13 days post-surgery. GlucoCEST measurements (∆CEST) were acquired the following day on a 9.4 T MRI before and after an infusion of glucose solution. This was followed by MRSI on a 3.0 T MRI after the injection of hyperpolarized [1-13C] pyruvate to generate regional maps of the lactate:pyruvate ratio (Lac:Pyr). Pearson's correlations between glucoCEST, CTP, FDG-PET, and Lac:Pyr ratio were evaluated. RESULTS: Tumors had significantly higher SUV, BV, and PS than the contralateral brain. Tumor ∆CEST was most strongly correlated with CTP measurements of BV (ρ = 0.74, P = 0.01) and PS (ρ = 0.55, P = 0.04). No significant correlation was found between glycolysis measurements of SUV or Lac:Pyr with tumor ∆CEST. PS significantly correlated with SUV (ρ = 0.58, P = 0.005) and Lac:Pyr (ρ = 0.75, P = 0.005). BV significantly correlated with Lac:Pyr (ρ = 0.57, P = 0.02), and BF significantly correlated with SUV (ρ = 0.49, P = 0.02). CONCLUSION: This study determined that glucoCEST is more strongly correlated to measurements of perfusion than glycolysis. GlucoCEST measurements have additional confounds, such as sensitivity to changing pH, that merit additional investigation.
Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Glioma/diagnóstico por imagem , Glucose/metabolismo , Ácido Pirúvico/metabolismo , Animais , Apoptose/fisiologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proliferação de Células/fisiologia , Fluordesoxiglucose F18 , Glioma/metabolismo , Glioma/patologia , Glicólise , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Imagem Multimodal/métodos , Perfusão , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/metabolismo , Ratos , Ratos Wistar , Tomografia Computadorizada por Raios X/métodos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: Diffusion-weighted, hyperpolarized 129Xe MRI is useful for the characterization of microstructural changes in the lung. A stretched exponential model was proposed for morphometric extraction of the mean chord length (Lm) from diffusion-weighted data. The stretched exponential model enables accelerated mapping of Lm in a single-breathhold using compressed sensing. Our purpose was to compare Lm maps obtained from stretched-exponential model analysis of accelerated versus unaccelerated diffusion-weighted 129Xe MRI data obtained from healthy/injured rat lungs. MATERIAL AND METHODS: Lm maps were generated using a stretched-exponential model analysis of previously acquired fully sampled diffusion-weighted 129Xe rat data (b values = 0 110 s/cm2) and compared to Lm maps generated from retrospectively undersampled data simulating acceleration factors of 7/10. The data included four control rats and five rats receiving whole-lung irradiation to mimic radiation-induced lung injury. Mean Lm obtained from the accelerated/unaccelerated maps were compared to histological mean linear intercept. RESULTS: Accelerated Lm estimates were similar to unaccelerated Lm estimates in all rats, and similar to those previously reported (< 12% different). Lm was significantly reduced (p < 0.001) in the irradiated rat cohort (90 ± 20 µm/90 ± 20 µm) compared to the control rats (110 ± 20 µm/100 ± 15 µm) and agreed well with histological mean linear intercept. DISCUSSION: Accelerated mapping of Lm using a stretched-exponential model analysis is feasible, accurate and agrees with histological mean linear intercept. Acceleration reduces scan time, thus should be considered for the characterization of lung microstructural changes in humans where breath-hold duration is short.
Assuntos
Imagem de Difusão por Ressonância Magnética , Animais , Pulmão , Imageamento por Ressonância Magnética , Doença Pulmonar Obstrutiva Crônica , Ratos , Estudos Retrospectivos , Isótopos de XenônioRESUMO
BACKGROUND: Accurate and sensitive imaging biomarkers are required to study the progression of white matter (WM) inflammation in neurodegenerative diseases. Radioligands targeting the translocator protein (TSPO) are considered sensitive indicators of neuroinflammation, but it is not clear how well the expression of TSPO coincides with major histocompatibility complex class II (MHCII) molecules in WM. This study aimed to test the ability of TSPO to detect activated WM microglia that are immunohistochemically positive for MHCII in rat models of prodromal Alzheimer's disease and acute subcortical stroke. METHODS: Fischer 344 wild-type (n = 12) and TgAPP21 (n = 11) rats were imaged with [18F]FEPPA PET and MRI to investigate TSPO tracer uptake in the corpus callosum, a WM region known to have high levels of MHCII activated microglia in TgAPP21 rats. Wild-type rats subsequently received an endothelin-1 (ET1) subcortical stroke and were imaged at days 7 and 28 post-stroke before immunohistochemistry of TSPO, GFAP, iNOS, and the MHCII rat antigen, OX6. RESULTS: [18F]FEPPA PET was not significantly affected by genotype in WM and only detected increases near the ET1 infarct (P = 0.033, infarct/cerebellum uptake ratio: baseline = 0.94 ± 0.16; day 7 = 2.10 ± 0.78; day 28 = 1.77 ± 0.35). Immunohistochemistry confirmed that only the infarct (TSPO cells/mm2: day 7 = 555 ± 181; day 28 = 307 ± 153) and WM that is proximal to the infarct had TSPO expression (TSPO cells/mm2: day 7 = 113 ± 93; day 28 = 5 ± 7). TSPO and iNOS were not able to detect the chronic WM microglial activation that was detected with MHCII in the contralateral corpus callosum (day 28 OX6% area: saline = 0.62 ± 0.38; stroke = 4.30 ± 2.83; P = .029). CONCLUSION: TSPO was only expressed in the stroke-induced insult and proximal tissue and therefore was unable to detect remote and non-insult-related chronically activated microglia overexpressing MHCII in WM. This suggests that research in neuroinflammation, particularly in the WM, would benefit from MHCII-sensitive radiotracers.
RESUMO
Colorectal cancer is the third leading cause of cancer death worldwide. 5-Fluorouracil (5-FU) is one of the most commonly used chemotherapies for treatment of solid tumours, including colorectal cancer. The efficacy of treatment is dependent on tumour type and can only be determined six weeks after beginning chemotherapy, with only 40-50% of patients responding positively to the 5-FU therapy. In this paper, we demonstrate the potential of using Magnetic Resonance (MR) Chemical Shift Imaging (CSI) for in-vivo monitoring of 5-FU tumor-retention in two different colorectal tumour types (HT-29 & H-508). Time curves for 5-FU signals from the liver and bladder were also acquired. We observed significant differences (p < 0.01) in 5-FU signal time dependencies for the HT-29 and H-508 tumours. Retention of 5-FU occurred in the H-508 tumour, whereas the HT-29 tumour is not expected to retain 5FU due to the observation of the negative b time constant indicating a decline in 5FU within the tumour. This study successfully demonstrates that CSI may be a useful tool for early identification of 5-FU responsive tumours based on observed tumour retention of the 5-FU.
Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Neoplasias Colorretais/metabolismo , Fluoruracila/farmacologia , Imageamento por Ressonância Magnética/métodos , Animais , Apoptose , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Humanos , Masculino , Camundongos , Camundongos Nus , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Fluorine-19 (19 F) MRI using inhaled inert fluorinated gases is an emerging technique that can provide functional images of the lungs. Inert fluorinated gases are nontoxic, abundant, relatively inexpensive, and the technique can be performed on any MRI scanner with broadband multinuclear imaging capabilities. Pulmonary 19 F MRI has been performed in animals, healthy human volunteers, and in patients with lung disease. In this review, the technical requirements of 19 F MRI are discussed, along with various imaging approaches used to optimize the image quality. Lung imaging is typically performed in humans using a gas mixture containing 79% perfluoropropane (PFP) or sulphur hexafluoride (SF6 ) and 21% oxygen. In lung diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF), ventilation defects are apparent in regions that the inhaled gas cannot access. 19 F lung images are typically acquired in a single breath-hold, or in a time-resolved, multiple breath fashion. The former provides measurements of the ventilation defect percent (VDP), while the latter provides measurements of gas replacement (ie, fractional ventilation). Finally, preliminary comparisons with other functional lung imaging techniques are discussed, such as Fourier decomposition MRI and hyperpolarized gas MRI. Overall, functional 19 F lung MRI is expected to complement existing proton-based structural imaging techniques, and the combination of structural and functional lung MRI will provide useful outcome measures in the future management of pulmonary diseases in the clinic. Level of Evidence: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:343-354.
Assuntos
Imagem por Ressonância Magnética de Flúor-19 , Fluorocarbonos/administração & dosagem , Gases , Pulmão/diagnóstico por imagem , Hexafluoreto de Enxofre/administração & dosagem , Animais , Asma/diagnóstico por imagem , Calibragem , Fibrose Cística/diagnóstico por imagem , Voluntários Saudáveis , Humanos , Aumento da Imagem/métodos , Processamento de Imagem Assistida por Computador/métodos , Pneumopatias , Oxigênio , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Respiração , SoftwareRESUMO
A 19Fluorine (19F) perfluorocarbon cell labeling agent, when employed with an appropriate cellular MRI protocol, allows for in vivo cell tracking. 19F cellular MRI can be used to non-invasively assess the location and persistence of cell-based cancer vaccines and other cell-based therapies. This study was designed to determine the feasibility of labeling and tracking peripheral blood mononuclear cells (PBMC), a heterogeneous cell population. Under GMP-compliant conditions human PBMC were labeled with a 19F-based MRI cell-labeling agent in a manner safe for autologous re-injection. Greater than 99% of PBMC labeled with the 19F cell-labeling agent without affecting functionality or affecting viability. The 19F-labeled PBMC were detected in vivo in a mouse model at the injection site and in a draining lymph node. A clinical cellular MR protocol was optimized for the detection of PBMC injected both at the surface of a porcine shank and at a depth of 1.2 cm, equivalent to depth of a human lymph node, using a dual 1H/19F dual switchable surface radio frequency coil. This study demonstrates it is feasible to label and track 19F-labeled PBMC using clinical MRI protocols. Thus, 19F cellular MRI represents a non-invasive imaging technique suitable to assess the effectiveness of cell-based cancer vaccines.
Assuntos
Imagem por Ressonância Magnética de Flúor-19/métodos , Fluorocarbonos/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/transplante , Animais , Sobrevivência Celular , Rastreamento de Células/métodos , Estudos de Viabilidade , Humanos , Leucócitos Mononucleares/metabolismo , Linfonodos/diagnóstico por imagem , Linfonodos/metabolismo , Masculino , Camundongos , Coloração e Rotulagem , SuínosRESUMO
PURPOSE: Cellular MRI) was used to detect implanted human mesenchymal stem cells (hMSCs) and the resulting macrophage infiltration that occurs in response to xenotransplantation. METHODS: Human mesenchymal stem cells were prelabeled with a fluorine-19 (19 F) agent prior to implantation, allowing for their visualization and quantification over time. Following implantation of 1 × 10619 F-labeled hMSCs into the mouse hind limb, longitudinal imaging was performed to monitor the stem cell graft. Macrophages were labeled in situ by the intravenous administration of an ultrasmall superparamagentic iron oxide (USPIO), allowing for tracking of the inflammatory response. RESULTS: Quantification of 19 F MRI on day 0 agreed with the implanted number of cells, and 19 F signal decreased over time. By day 14, only 22% ± 11% of the original 19 F signal remained. In a second group, USPIO were administered intravenously after implantation of 19 F-labeled hMSCs. When imaged on day 2, a significant decrease in 19 F signal was observed compared to the first group alongside a large signal void region in the corresponding proton images. Immunohistochemistry confirmed the presence of iron-labeled macrophages in the stem cell tract. CONCLUSION: A dual-labeling technique was used to noninvasively track two distinct cell populations simultaneously. This information could be used to provide additional insight into the cause of graft failure. Magn Reson Med 78:713-720, 2017. © 2016 International Society for Magnetic Resonance in Medicine.
Assuntos
Rastreamento de Células/métodos , Flúor/química , Rejeição de Enxerto/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Nanopartículas de Magnetita/química , Transplante de Células-Tronco Mesenquimais/métodos , Animais , Flúor/análise , Flúor/metabolismo , Membro Posterior/metabolismo , Humanos , Nanopartículas de Magnetita/análise , Células-Tronco Mesenquimais/química , Células-Tronco Mesenquimais/citologia , CamundongosRESUMO
The purpose of this study was to extend established methods for fractional ventilation mapping using (19) F MRI of inert fluorinated gases to rat models of pulmonary inflammation and fibrosis. In this study, five rats were instilled with lipopolysaccharide (LPS) in the lungs two days prior to imaging, six rats were instilled with bleomycin in the lungs two weeks prior to imaging and an additional four rats were used as controls. (19) F MR lung imaging was performed at 3 T with rats continuously breathing a mixture of sulfur hexafluoride and O2 . Fractional ventilation maps were obtained using a wash-out approach, by switching the breathing mixture to pure O2 , and acquiring images following each successive wash-out breath. The mean fractional ventilation (r) was 0.29 ± 0.05 for control rats, 0.23 ± 0.10 for LPS-instilled rats and 0.19 ± 0.03 for bleomycin-instilled rats. Bleomycin-instilled rats had a significantly decreased mean r value compared with controls (P = 0.010). Although LPS-instilled rats had a slightly reduced mean r value, this trend was not statistically significant (P = 0.556). Fractional ventilation gradients were calculated in the anterior/posterior (A/P) direction, and the mean A/P gradient was -0.005 ± 0.008 cm(-1) for control rats, 0.013 ± 0.005 cm(-1) for LPS-instilled rats and 0.009 ± 0.018 cm(-1) for bleomycin-instilled rats. Fractional ventilation gradients were significantly different for control rats compared with LPS-instilled rats only (P = 0.016). The ventilation gradients calculated from control rats showed the expected gravitational relationship, while ventilation gradients calculated from LPS- and bleomycin-instilled rats showed the opposite trend. Histology confirmed that LPS-instilled rats had a significantly elevated alveolar wall thickness, while bleomycin-instilled rats showed signs of substantial fibrosis. Overall, (19)F MRI may be able to detect the effects of pulmonary inflammation and fibrosis using a simple and inexpensive imaging approach that can potentially be translated to humans.
Assuntos
Halogenação , Imageamento por Ressonância Magnética/métodos , Gases Nobres/química , Pneumonia/diagnóstico , Fibrose Pulmonar/diagnóstico , Ventilação Pulmonar , Animais , Bleomicina , Modelos Animais de Doenças , Pulmão/patologia , Masculino , Pneumonia/induzido quimicamente , Alvéolos Pulmonares/patologia , Ratos Sprague-DawleyRESUMO
Fluorine-19 ((19)F)-based contrast agents for magnetic resonance imaging stand to revolutionize imaging-based research and clinical trials in several fields of medical intervention. First, their use in characterizing in vivo cell behavior may help bring cellular therapy closer to clinical acceptance. Second, their use in lung imaging provides novel noninvasive interrogation of the ventilated airspaces without the need for complicated, hard-to-distribute hardware. This article reviews the current state of (19)F-based cell tracking and lung imaging using magnetic resonance imaging and describes the link between the methods across these fields and how they may mutually benefit from solutions to mutual problems encountered when imaging (19)F-containing compounds, as well as hardware and software advancements.
RESUMO
PURPOSE: Inert fluorinated gas lung MRI is a new and promising alternative to hyperpolarized gas lung MRI; it is less expensive and does not require expensive isotopes/polarizers. The thermally polarized nature of signal obtained from fluorinated gases makes it relatively easy to use for dynamic lung imaging and for obtaining lung ventilation maps. In this study, we propose that the sensitivity and resolution of fluorine-19 (19F) in vivo images can be improved using the x-centric pulse sequence, thereby achieving a short echo time/pulse repetition time. This study is a transitional step for converting to more sustainable gases for lung imaging. METHODS: A 19F-resolution phantom was used to validate the efficiency of performing the x-centric pulse sequence on a clinical scanner. Ventilation maps were obtained in the lungs of five normal rats with a washout approach (adapted from Xe-enhanced computed tomography [Xe-CT] regional ventilation mapping), using mixtures of either sulfur hexafluoride/oxygen or perfluoropropane/oxygen and a two-breath x-centric method. RESULTS: Fractional ventilation (r) values obtained in this study (0.35-0.46 interval) were in good agreement with previously published values for 3He/129Xe. Calculated r gradients agreed well with published gradients obtained in rats with Xe-CT measurements. CONCLUSIONS: These results suggest that fluorinated gases can be reliably used in vivo in dynamic lung studies as an alternative to 3He/129Xe.
Assuntos
Algoritmos , Imagem por Ressonância Magnética de Flúor-19/métodos , Interpretação de Imagem Assistida por Computador/métodos , Ventilação Pulmonar/fisiologia , Processamento de Sinais Assistido por Computador , Administração por Inalação , Animais , Gases/farmacocinética , Aumento da Imagem/métodos , Projetos Piloto , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Magnetic resonance imaging (MRI) is a potentially ideal imaging modality for noninvasive, nonionizing, and longitudinal assessment of disease. Hyperpolarized (HP) agents have been developed in the past 20 years for MR imaging, and they have the potential to vastly improve MRI sensitivity for the diagnosis and management of various diseases. The polarization of nuclear magnetic resonance (NMR)-sensitive nuclei other than (1)H (e.g., (3)He, (129)Xe) can be enhanced by a factor of up to 100,000 times above thermal equilibrium levels, which enables direct detection of the HP agent with no background signal. In this review, a number of HP media applications in MR imaging are discussed, including HP (3)He and (129)Xe lung imaging, HP (129)Xe brain imaging, and HP (129)Xe biosensors. Inert fluorinated gas MRI, which is a new lung imaging technique that does not require hyperpolarization, is also briefly discussed. This technique will likely be an important future direction for the HP gas lung imaging community.
Assuntos
Imageamento por Ressonância Magnética , Gases Nobres/química , Animais , Técnicas Biossensoriais , Encéfalo/patologia , Humanos , Pulmão/patologiaRESUMO
Fluorine-19 ((19)F) MRI of the lungs using inhaled inert fluorinated gases can potentially provide high quality images of the lungs that are similar in quality to those from hyperpolarized (HP) noble gas MRI. Inert fluorinated gases have the advantages of being nontoxic, abundant, and inexpensive compared with HP gases. Due to the high gyromagnetic ratio of (19)F, there is sufficient thermally polarized signal for imaging, and averaging within a single breath-hold is possible due to short longitudinal relaxation times. Therefore, the gases do not need to be hyperpolarized prior to their use in MRI. This eliminates the need for an expensive polarizer and expensive isotopes. Inert fluorinated gas MRI of the lungs has been previously demonstrated in animals, and more recently in healthy volunteers and patients with lung diseases. The ongoing improvements in image quality demonstrate the potential of (19)F MRI for visualizing the distribution of ventilation in human lungs and detecting functional biomarkers. In this brief review, the development of inert fluorinated gas MRI, current progress, and future prospects are discussed. The current state of HP noble gas MRI is also briefly discussed in order to provide context to the development of this new imaging modality. Overall, this may be a viable clinical imaging modality that can provide useful information for the diagnosis and management of chronic respiratory diseases.
Assuntos
Halogenação , Pulmão/fisiologia , Imageamento por Ressonância Magnética/métodos , Gases Nobres , Animais , Gravitação , Humanos , RespiraçãoRESUMO
PURPOSE: Radiation induced lung injury (RILI) is a common side effect for patients undergoing thoracic radiation therapy (RT). RILI can lead to temporary or permanent loss of lung function and in extreme cases, death. Combining functional lung imaging information with conventional radiation treatment plans may lead to more desirable treatment plans that reduce lung toxicity and improve the quality of life for lung cancer survivors. Magnetic Resonance Imaging of the lung following inhalation of hyperpolarized(129)Xe may provide a useful nonionizing approach for probing changes in lung function and structure associated with RILI before, during, or after RT (early and late time-points). METHODS: In this study, dynamic(129)Xe MR spectroscopy was used to measure whole-lung gas transfer time constants for lung tissue and red blood cells (RBC), respectively (TTr_tissue and TTr_RBC) in groups of rats at two weeks and six weeks following 14 Gy whole-lung exposure to radiation from a (60)Co source. A separate group of six healthy age-matched rats served as a control group. RESULTS: TTr_tissue values at two weeks post-irradiation (51.6 ± 6.8 ms) were found to be significantly elevated (p < 0.05) with respect to the healthy control group (37.2 ± 4.8 ms). TTr_RBC did not show any significant changes between groups. TTr_tissue was strongly correlated with TTr_RBC in the control group (r = 0.9601 p < 0.05) and uncorrelated in the irradiated groups. Measurements of arterial partial pressure of oxygen obtained by arterial blood sampling were found to be significantly decreased (p < 0.05) in the two-week group (54.2 ± 12.3 mm Hg) compared to those from a representative control group (85.0 ± 10.0 mm Hg). Histology of a separate group of similarly irradiated animals confirmed the presence of inflammation due to radiation exposure with alveolar wall thicknesses that were significantly different (p < 0.05). At six weeks post-irradiation, TTr_tissue returned to values (35.6 ± 9.6 ms) that were not significantly different from baseline. CONCLUSIONS: Whole-lung tissue transfer time constants for(129)Xe (TTr_tissue) can be used to detect the early phase of RILI in a rat model involving 14 Gy thoracic (60)Co exposure as early as two weeks post-irradiation. This knowledge combined with more sophisticated models of gas exchange and imaging techniques, may allow functional lung avoidance radiation therapy planning to be achievable, providing more beneficial treatment plans and improved quality of life for recovering lung cancer patients.
Assuntos
Lesão Pulmonar/metabolismo , Pulmão/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Lesões por Radiação/metabolismo , Isótopos de Xenônio , Administração por Inalação , Animais , Gasometria , Radioisótopos de Cobalto/efeitos adversos , Eritrócitos/metabolismo , Pulmão/patologia , Pulmão/efeitos da radiação , Lesão Pulmonar/patologia , Oxigênio/metabolismo , Pressão Parcial , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia , Lesões por Radiação/patologia , Ratos Sprague-Dawley , Fatores de TempoRESUMO
PURPOSE: MRI using hyperpolarized noble gases, (3)He and (129)Xe, provides noninvasive assessments of lung structure and function. Previous work demonstrated that absolute ventilated lung volumes (aVLV) measured in rats using hyperpolarized (3)He agree well with micro-CT. METHODS: In this work, aVLV measurements were performed in rats using hyperpolarized (129)Xe MRI and compared with hyperpolarized (3)He measurements of aVLV under matched ventilation conditions. Whole-lung compliance was also determined. Partial volume, apparent diffusion coefficient, and effective transverse relaxation time corrections were applied during postprocessing to reduce bias between methods. RESULTS: Mean apparent diffusion coefficient of the trachea was 0.83 ± 0.09 cm(2)/s and 0.067 ± 0.011 cm(2)/s for (3)He and (129)Xe, respectively. Mean apparent diffusion coefficient of parenchyma was 0.21 ± 0.07 cm(2)/s and 0.027 ± 0.008 cm(2)/s for (3)He and (129)Xe, respectively. Mean transverse relaxation time values were 1.57 ± 0.25 ms and 2.80 ± 0.25 ms for (3)He and (129)Xe, respectively, in a model trachea and 3.18 ± 1.00 ms and 4.88 ± 0.60 ms for (3)He and (129)Xe, respectively, for lung parenchyma. Mean aVLV values were 7.07 ± 0.67 mL and 6.99 ± 1.00 mL at 14 cmH2O and 4.88 ± 0.71 mL and 5.36 ± 0.76 mL at 10 cmH2O obtained with (3)He and (129)Xe, respectively, demonstrating good agreement between (129)Xe and (3)He. CONCLUSIONS: (129)Xe offers an important alternative to (3)He for hyperpolarized gas MRI of aVLV in rats.