Molecular Imaging and Biology最新文献

Purpose: Tuberculosis (TB) continues to afflict global health. Therefore, a deeper understanding of the host response mechanisms that underly pathogenesis versus disease control upon infection with Mycobacterium tuberculosis (Mtb) is required to leverage the development of improved therapeutic or prophylactic TB treatment regimens. In the present work positron emission tomography (PET) using [¹⁸F]DPA714 is piloted as a tracer of the mitochondrial translocator protein TSPO that mainly targets macrophages.

Procedures: We compared two tracers: [¹⁸F]DPA714 to the widely applied marker [¹⁸F]FDG to visualize the development of experimental pulmonary TB in three rhesus monkeys (Macaca mulatta), that were infected with Mtb by repeated low dose exposure. Next to baseline recordings prior to infectious challenge, two PETs at a two-weeks interval were acquired early after the manifestation of TB infection for each of the respective tracers.

Results & conclusions: Here, we demonstrate that both PET tracers detected Mtb infection. The inflammatory response tracked by [¹⁸F]FDG progressively increased in line with the developing TB pathology, while [¹⁸F]DPA714 showed a transient signal in lungs and lung-draining hilar lymph nodes. This study underpins the potential value of different tracers to investigate cellular and molecular host response cascades in experimental medicine settings, in this case, into a (transient) local involvement of myeloid immune cell activation versus inflammation-associated glucose consumption in pulmonary TB.

Purpose: Influenza (flu) is a respiratory illness caused by lung infection with influenza viruses. This study establishes lung [¹⁸F]FDG uptake by PET/CT as an accurate measure of lung inflammation associated with influenza A virus (IAV) H1N1 infection.

Procedures: Immunocompetent BALB/c mice were infected with a highly lethal dose of influenza A virus (PR8 strain) and intravenously injected with [¹⁸F]FDG. Ex vivo tissue biodistribution was assessed by gamma counting, while in vivo tissue biodistribution was analyzed by VOI analysis of PET/CT images. Disease severity was also investigated by VOI measurements of high-resolution lung CT images. Infection and inflammation were confirmed by immunohistochemical staining; while viral replication and expression of inflammatory proteins (cytokines and chemokines) were measured in lung tissues by qRT-PCR and multiplex ELISA, respectively.

Results: Ex vivo tissue biodistribution of [¹⁸F]FDG revealed that the lungs were the only relevant imaging target in influenza-infected mice. Lung [¹⁸F]FDG uptake on PET/CT images increased with disease severity and exhibited 1.53-fold increase on day 1 and up to 2.63-fold increase on day 6 post-infection compared to pre-infection levels. Lung uptake correlated with the increased production of pro-inflammatory proteins associated with influenza infection.

Conclusions: Lung [¹⁸F]FDG uptake on PET images is a non-invasive molecular biomarker of influenza-A virus-induced lung inflammation and disease, effectively distinguishing infected from non-infected lungs as early as day 1 post-infection.

Nanophotonics-the manipulation of light at the nanometer scale within biological systems-is transforming molecular imaging and photobiology, enabling advanced in vivo imaging, diagnostics, and therapy guidance. This review outlines core nanophotonic principles, including surface plasmon resonance, optical confinement, and photon-matter interactions, underpinning emerging molecular imaging probes and diagnostic tools. Biocompatible nanomaterials such as quantum dots, gold nanoparticles, and photonic metamaterials enable highly sensitive, selective imaging and biosensing for early, minimally invasive disease detection and monitoring. Targeted photothermal and photodynamic therapies using near-infrared (NIR) and NIR-II light advance image-guided interventions, allowing deeper tissue penetration with minimal collateral damage. We also discuss the integration of nanophotonic components into lab-on-a-chip and microfluidic platforms for point-of-care diagnostics, accelerating clinical translation. Additionally, machine learning enhances molecular imaging analysis and probe optimization, enabling real-time data interpretation and predictive modeling tailored to patient-specific profiles. This article is a narrative review that emphasizes recent advancements from 2021-2025, identified through targeted database searches, highlighting progress, research gaps, and future perspectives for disease-specific applications. While these advances hold promise, challenges remain in biocompatibility, light penetration, scalability, and regulatory approval. Collectively, integrating nanophotonics with molecular imaging, machine learning, and personalized medicine frameworks marks a step toward next-generation precision diagnostics and image-guided therapeutics.

Ostrich eggs have recently attracted interest as an alternative model in preclinical nuclear medicine imaging. The ability to be used in clinical PET/CT (positron emission tomography/computed tomography) systems and their ethical profile are advantageous over conventional rodent models and other avian systems. Nevertheless, concerns regarding radiation exposure during repeated CT (computed tomography) imaging of developing embryos remain inadequately addressed. This study aimed to characterize the attenuation impact of eggshells in ostrich eggs and to evaluate the potential for organ-specific dose assessment. A representative ostrich egg was selected from a cohort of 168 eggs and used to construct a dimensionally matched 3D-printed phantom. Organ weights of 83 embryos were documented on development day (DD) 37 to provide a basis for future organ-level dosimetric modeling. Thermoluminescence dosimeters (TLDs) were positioned along the z-axis within both the egg and phantom, and CT dose distributions were measured using a clinical PET/CT system. The mean absorbed dose in the real egg was 16.3 ± 2.0% lower than in the phantom, attributable to radiation attenuation by the 1.89 ± 0.12 mm thick eggshell. CTDI (computed tomography dose index) values remained stable across developmental stages (DD 0-37). Our findings confirm that the ostrich eggshell exerts a significant shielding effect during CT imaging. While ostrich eggs are suitable for serial in-ovo imaging, embryo positioning remains a major limitation for precise dosimetry. Organ weight data enable potential use of AI (artificial intelligence)-based modeling to improve spatial dosimetry accuracy. This study provides essential groundwork for dose optimization and radioprotection in preclinical imaging protocols using ostrich eggs.

Theranostics, a concept combining "therapy" and "diagnostics", is poised to enter an exponential growth phase. By using specific diagnostic markers to guide the selection and application of targeted treatments directed at those markers, this approach aims to improve effectiveness and reduce unnecessary interventions. While several agents have been approved by the FDA recently, multiple additional theranostics are being developed, studied in clinical trials and expected to enter clinical practice in short order. As part of the "Translation of New Therapy (TNT) Interest Group's Radiotheranostics Kick-off" pre-meeting of the annual World Molecular Imaging Conference (WMIC) 2024 over 350 attendees with 10% leaders from industry, 60% senior and junior investigators in academia and 30% trainees discussed the key challenges and opportunities in implementing a theranostic research program in academia, which are addressed in this white paper. Overarching themes included funding, regulatory hurdles, and workforce training. Panel recommendations included leveraging existing expertise and patient populations, securing revenue streams, exploring alternative funding sources, and developing a multifaceted approach to promote training, education and public awareness, including fostering academic-industry partnerships. By shedding light on the gap between research and real-world program implementation, this white paper and forthcoming pre-meetings at WMIC aim to define a practical framework for building successful programs based on insights from recent research.

Introduction: Obesity and type 2 diabetes (T2D) influence the tumor microenvironment by altering glucose metabolism, which has been shown to decrease immune cell infiltration and activation. Positron emission tomography (PET) imaging provides a non-invasive method to detect molecular markers of immune populations in the tumor microenvironment and systemic organs. The goal of this study is to utilize advanced molecular imaging to quantify differences in innate and adaptive immune responses in diabetic obese mice systemically and within the tumor microenvironment.

Methods: 5-6-week-old female C57BL6/J mice were placed on a high-fat diet (HFD) composed of 60% kcal fat or control low-fat diet with 10% kcal fat. Animals were treated with subsequent low doses of streptozotocin to induce T2D and blood glucose was monitored. Following induction of diabetes, E0771-luc + cells were implanted into the 4th mammary fat pad and allowed to grow to a tumor volume of 100mm³. PET imaging was acquired over the course of 5 days with the following tracers: [¹⁸F]-FDG PET for glucose metabolism, [⁶⁸Ga]Ga-RP832c (CD206) PET for M2 macrophages, and [⁶⁸Ga]Ga-GZP PET for granzyme B, an indicator of effector cell activation, and [¹⁸F]-DPA-714 PET for neuroinflammation. Regions of interest were identified for the tumor, brain, kidneys, heart, muscle, brown adipose tissue (BAT), to characterize differences in important organs and tumor tissue. Metrics of standardized uptake value (SUV) were extracted from imaging data including mean, max, peak, and tumor-to-background ratios. Following the final imaging timepoint, tumors were extracted for biological characterization via flow cytometry.

Results: Diabetic obese mice have no difference in tumor glucose metabolism, but have decreased FDG uptake in the brain and BAT compared to controls. Obesity and T2D systemically affect innate and adaptive immune infiltration and activation including significantly increased RP832c and GZP in muscle, heart, brain, and BAT. Hyperglycemic tumors had trending decreases in GZP SUV_mean and increased RP832c SUV_mean. Flow cytometry shows diabetic obese tumors have a significant increase in CD206 + macrophages and no significant difference in GZB + CD8 + T cells compared to controls.

Conclusion: PET imaging reveals that obesity and T2D alter glucose metabolism and immune activation while suppressing tumor-immune activation in diabetic obese mice both within the tumor microenvironment and systemically.

Purpose: CD4⁺ T cells (T helper and T reg) play an important role in the immune system and are influential in autoimmune diseases (e.g., rheumatoid arthritis, inflammatory bowel disease) and cancer (antitumor immunity). Non-invasive, whole-body anti-CD4 immunoPET can provide dynamic and spatial information (localization, proliferation, and migration) on CD4⁺ T cells. The cys-diabody format enables site-specific radiolabeling and rapid renal clearance, which results in high-contrast images at early time points.

Procedures: In this work, an anti-CD4 cys-diabody based on the hybridoma GK1.5 was reengineered by CDR-grafting (GK1.5 FR cDb) for higher expression in mammalian cell lines. An N-glycosylation motif in the variable light chain domain framework was removed by site-directed mutagenesis, resulting in GK1.5 N80D cDb. To investigate the impact of the variable domain glycan on the in vivo biodistribution and pharmacokinetics, both cys-diabodies were site-specifically conjugated with deferoxamine-maleimide and radiolabeled by chelation of zirconium-89. Serial immunoPET/CT imaging was used for non-invasive, whole-body assessment of specific targeting, biodistribution, and differential clearance of the two novel anti-CD4 cys-diabodies.

Results: The anti-CD4 cys diabody was successfully re-engineered by CDR-grafting (GK1.5 FR cDb) and aglycosylation (GK1.5 N80D cDb), resulting in a higher expression yield (~ tenfold increase) without impacting antigen specificity or affinity. Both cys-diabody variants were successfully ⁸⁹Zr-radiolabeled with similar specific activity and radiochemical purity. ImmunoPET imaging of ⁸⁹Zr-GK1.5 FR cDb and ⁸⁹Zr-GK1.5 N80D cDb in immunocompetent mice showed CD4 antigen-specific lymphoid tissue uptake in vivo. ⁸⁹Zr-GK1.5 FR cDb exhibited rapid hepatic clearance, resulting in significantly reduced uptake in lymph nodes and the spleen. Removal of the N-glycosylation motif in ⁸⁹Zr-GK1.5 N80D cDb restored diabody-typical biodistribution (renal clearance), resulting in higher target tissue uptake.

Conclusion: The novel reengineered anti-CD4 GK1.5 N80D cDb overcomes the previous production yield bottleneck and provides same-day ⁸⁹Zr-immunoPET imaging for non-invasive, whole-body visualization of murine CD4⁺ T cells.

Purpose: In target-specific cancer imaging, antibodies and their fragments are conjugated with fluorescent dyes to work as targeting molecules. We have recently developed indocyanine green (ICG) derivatives with anionic functional groups at the benzoindolenine moiety. When the ICG derivatives are used for antibody-based imaging, the chemical characteristics of the conjugated dyes may influence the pharmacokinetics of the targeting molecules. Therefore, in this study, we evaluated the in vivo pharmacokinetics of IgG and Fab conjugated with the ICG derivatives bearing anionic functional groups.

Procedures: A linker for conjugation was introduced into the methine chain of ICG and ICG derivatives possessing sulfonic acid (SC-Cy) or carboxylic acid (CC-Cy) groups at the benzoindolenine moiety. ICG, SC-Cy, or CC-Cy was conjugated with IgG, innate trastuzumab, and its Fab fragment. To evaluate the pharmacokinetics of these IgG-dyes and Fab-dyes, in vivo fluorescence imaging was performed in tumor-bearing mice at 0.25-96 h after intravenous administration of the imaging agents.

Results: The three IgG-dyes exhibited similar pharmacokinetics and tumor accumulation profiles post injection. Thus, the differences in the dye's chemical properties had minimal influence when the ICG derivatives were conjugated with IgG. In contrast, the pharmacokinetics and tumor accumulation profiles of the Fab-dyes were remarkably different. While Fab-SC-Cy exhibited high accumulation in the kidney but no accumulation in the tumors, Fab-CC-Cy showed higher tumor accumulation. This could be attributed to the excessively high negative charge density in the benzoindolenine moiety of SC-Cy, which influenced the excretion route of the Fab fragment.

Conclusions: The IgG conjugated with SC-Cy or CC-Cy dyes exhibited favorable pharmacokinetics profiles. In contrast, Fab-CC-Cy demonstrated superior performance in tumor imaging compared to Fab-SC-Cy. Our findings suggest that introducing anionic functional groups into the benzoindolenine moiety of ICG could lead to the development of near-infrared dyes that could be useful in antibody-based tumor imaging.

Purpose: Acute myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide. Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator influencing numerous physiological processes. S1PR1 is the predominant isoform of the S1P receptor in cardiomyocytes and vascular endothelial cells. S1PR1 plays a critical role in preventing adverse cardiac remodeling. The importance of S1PR1 in cardiac physiology has led to the development of novel treatments for MI, including S1PR1 gene delivery strategies aimed at preventing heart failure. Monitoring the dynamic changes of S1PR1 post-MI is clinically significant for assessing cardiac remodeling. This study validated the ability of specific S1PR1 PET radiotracer [¹⁸F]FS1P1 to track changes in this signaling pathway, thereby providing a non-invasive diagnostic tool to quantify S1PR1 expression for investigating MI in vivo.

Procedures: We characterized the S1PR1 radiotracer [¹⁸F]FS1P1 in an echo-guided mouse model of MI. [¹⁸F]FDG PET was used to delineate the infarct area. Masson trichrome staining was used to identify cardiac fibrosis. Immunofluorescence (IF) experiment was conducted to demonstrate changes in S1PR1 expression after MI. Autoradiography was performed to evaluate the distribution of [¹⁸F]FS1P1 in MI heart tissues. MI (n = 4) and sham (n = 4) mice were scanned with [¹⁸F]FS1P1 PET at 2 days and 2 weeks post-MI, radioactivity uptake in the myocardium was calculated as the percentage of the injected dose per gram (%ID/g).

Results: The uptake of [¹⁸F]FS1P1 was significantly decreased by 31.8% in the infarct region at 2 days post-MI compared to the sham group (1.3 ± 0.3 vs. 1.9 ± 0.3), and decreased by 37.6% at 2 weeks post-MI (1.2 ± 0.5). Additionally, [¹⁸F]FS1P1 signal decreased by 20.8% in the non-infarct remote area at 2 weeks post-MI compared with the sham control (1.6 ± 0.4 vs. 2.0 ± 0.2). Autoradiography study confirmed the trend of decreased [¹⁸F]FS1P1 uptake in the MI tissues. IF studies confirmed that the change in the [¹⁸F]FS1P1 PET signal corresponded with the change in S1PR1 expression.

Conclusions: This study demonstrated the downregulation of S1PR1 expression following MI and validated the use of [¹⁸F]FS1P1 PET imaging as an effective tool for detecting changes in S1PR1 expression post-MI.

Purpose: Ischemic stroke is a significant threat to human life and health, and timely diagnosis is essential for improving patient outcomes. Magnetic Particle Imaging (MPI), as an emerging high-sensitivity imaging technology, holds significant potential for the diagnosis of ischemic stroke. It is necessary to conduct multimodal MPI research based on the characteristics of the animal model and the detection needs of ischemic stroke.

Procedures: We used tree shrews, which have a close phylogenetic relationship with primates, as experimental subjects and established a photothrombotic (PT) stroke model. Considering the body size of tree shrews and the high-sensitivity detection requirements for ischemic stroke, a dedicated MPI receiving system for tree shrews was developed based on the primate brain MPI equipment. After validating the MPI system's performance, multimodal MPI fusion imaging of the tree shrew brain was performed by combining magnetic resonance imaging (MRI) and computed tomography (CT).

Results: The sensitivity of the receiving system for tree shrews is 0.017 mg Fe/mL, which is 8 times higher than that of the original system. Within one hour after the establishment of the PT stroke model, the MPI signal intensity in ischemic stroke tree shrews was approximately 25% lower than in the control group, while MRI showed no significant differences. On the 6th and 12th days after ischemic stroke onset, MRI images revealed clear lesion locations. Anatomical results of the tree shrew brain revealed significant lesions, confirming the successful establishment of the PT stroke model.

Conclusions: The dedicated MPI receiving system developed in this study significantly enhanced MPI sensitivity. The multimodal MPI imaging platform integrates the advantages of MRI and CT structural imaging based on high-sensitivity detection, enabling early detection of ischemic stroke in tree shrews.