Molecular Imaging and Biology最新文献

Purpose: To assess hypoxia-associated host-tumour vascular adaptations and glycolytic metabolism in the chick chorioallantoic membrane (CAM) glioblastoma model.

Procedures: U251 GBM cells were conditioned under normoxia (21% O₂) or hypoxia (1% O₂) for 72 h before implantation onto the CAM on embryonic day 7 (E7). Imaging was performed on E13 using MRI (control-CAM n = 8, normoxic-tumour n = 7, hypoxic-tumour n = 6) and brightfield microscopy (control-CAM n = 7, normoxic-tumour n = 8, hypoxic-tumour n = 7). Tumours were harvested on E14 for histology and gene expression analyses. In a separate cohort of 25 GBM-CAM tumours grown under normoxic conditioning, the correlation of glucose metabolism was assessed using [¹⁸F]FDG-PET on E12 followed by lactate MRS on E13 (n = 8).

Results: Normoxia- and hypoxia-conditioned tumour-bearing CAMs exhibited vascular remodelling and significant upregulation of VEGFA and ADM compared to cultured cells. αSMA staining confirmed vessel infiltration in normoxia-conditioned tumours. CAIX staining revealed a hypoxic core in these tumours while hypoxia-conditioned tumours displayed heterogeneous staining. In both conditions, GLUT1 staining colocalised with CAIX staining, indicating hypoxia-associated glycolysis. GLUT1, PDK1 and LDHA expression was elevated in CAM tumours relative to tumour cells in vitro. In the metabolic imaging cohort, most tumours exhibited [¹⁸F]FDG uptake and lactate signal. However, no statistically significant relationship was observed between the two methods.

Conclusions: The CAM model provides a versatile platform for investigating GBM vascularisation and metabolism. Hypoxic conditioning amplifies transcriptional and vascular changes to the CAM. Although both [¹⁸F]FDG uptake and lactate were measurable, no significant correlation between the two was observed, potentially reflecting variability in tumour engraftment, vascular delivery of [¹⁸F]FDG, and microenvironmental influences on lactate accumulation.

Purpose: Tumor-specific immunotherapies selectively target tumor cells with reduced toxicity compared to conventional treatments. Pattern recognition receptors, such as retinoic acid-inducible gene I (RIG-I)-like receptors, have been used to induce broad antitumor responses but their off-target effects and delivery issues hinder their clinical translation. To overcome these challenges, we present a strategy that involves the intracellular assembly of the RIG-I agonist on a tumor-specific RNA template (e.g., miRNA-21) by delivering a 5'-triphosphate single-stranded RNA RIG-I agonist (RIGA-miRNA-21) by a superparamagnetic nanoparticle carrier (TTX) to initiate specific RIG-I signaling and antitumor immune responses. Magnetic properties of TTX enable its detection by magnetic resonance imaging (MRI) supporting the concept of image-guided therapy.

Procedures: A single-stranded anti-miR-21 5'-triphosphate RIG-I agonist was conjugated to the dextran coat of the nanoparticles through disulfide bonds producing TTX-RIGA-miR-21 and tested in vitro and in vivo in B16-F10 melanoma model. Delivery of the TTX carrier was demonstrated in mice bearing B16-F10 tumors by MRI. Therapeutic studies included intravenous injections of TTX-RIGA-miR-21 or controls for 7 days starting on Day 4 after tumor implantation. On Day 15, animals were rechallenged with additional B16-F10 cells implanted on the opposite side.

Results: We demonstrated that TTX-RIGA-miR21 was able to induce miRNA-21-dependent RIG-I signaling and apoptosis in melanoma cells, inhibit tumor growth, and induce immunity against tumor rechallenge in an animal model.

Conclusions: Our template-driven approach brings RIG-I closer to becoming a clinically relevant target in oncology by specifically activating immune responses within tumor cells through systemic RIG-I agonist delivery.

When differentiated thyroid cancer stops taking up radioiodine, treatment becomes significantly more challenging, and the disease often behaves more aggressively. Systemic therapies such as multikinase inhibitors and mutation-specific drugs have expanded available options, but many patients experience side effects, and responses can vary widely. At the same time, advances in molecular imaging and targeted radionuclide therapy are changing how this condition is managed. Short-term MAPK inhibition can restore iodine uptake in some patients, creating an opportunity to give radioiodine again. For patients with spreading or fast-growing disease, a growing range of theranostic agents, including ¹⁷⁷Lu and ²²⁵Ac-based treatments directed at SSTR, PSMA, or FAP, provides a more targeted approach that is guided by PET imaging and has shown promising activity in early clinical experience- The increasing use of quantitative PET information, radiomic analysis, and personalized dosimetry may further support better treatment selection. Despite these developments, the optimal combination of radionuclide therapy with redifferentiation strategies, multikinase inhibitors, and gene-targeted treatments remains unclear. This review brings together current and emerging treatment approaches for radioiodine-refractory thyroid cancer and discusses how theranostics may become part of routine care.

Purpose: The standard 2-day dual-tracer PET protocol provides more information but is time consuming. Thus, this study aimed to validate the feasibility of 1-day ⁶⁸Ga-DOTATATE and ¹⁸F-FDG dual-low-activity PET/MR imaging in patient with neuroendocrine neoplasms (NENs).

Procedures: Fourteen NENs patients who underwent 1-day ⁶⁸Ga-DOTATATE and ¹⁸F-FDG dual-low-activity PET/MR, and another 14 patients matched with the same primary tumor sites and tumor grades who underwent 2-day ⁶⁸Ga-DOTATATE and ¹⁸F-FDG PET/MR were retrospectively enrolled. Imaging analysis was performed, including lesion detection rate and diagnostic confidence. Additionally, the diagnostic confidence was also assessed based on ⁶⁸Ga-DOTATATE PET, ¹⁸F-FDG PET and PET/MR, respectively.

Results: The 1-day protocol detected 39 out of 40 lesions in 14 patients, while the 2-day protocol detected 65 out of 66 lesions in 14 patients. No significant differences were observed in lesion detection (all P > 0.05). There was no significant difference in diagnostic confidence between the 1-day protocol and the 2-day protocol for ⁶⁸Ga-DOTATATE PET (median [IQR]: 3[2-3] vs. 3[2-3]), ¹⁸F-FDG PET (1[1-2] vs. 1[1-1]), and PET/MR (4[3-5] vs. 5[4-5]) in all lesions (all P > 0.05).

Conclusion: The 1-day ⁶⁸Ga-DOTATATE and ¹⁸F-FDG dual-low-activity PET/MR imaging protocol in patients with NENs is feasible and provides equivalent lesion detection and diagnostic confidence compared to the 2-day protocol.

Background: The clinical success of fluorescence-guided surgery is dependent on tumor-specific probes that can achieve high tumor-to-background contrast. Conventional near-infrared (NIR) fluorophores often alter the pharmacokinetic properties of the parental molecule that result in aggregation, altered biodistribution, and impaired tumor targeting.

Methods: This present study evaluates two charge-balanced heptamethine cyanine dyes, FNIR-Tag-766 and FNIR-Tag-804, conjugated to a humanized anti-carcinoembryonic antigen antibody (M5A). Their performance was compared to the standard M5A-IR800CW conjugate in both subcutaneous and orthotopic colorectal cancer xenograft models in mice. Mean fluorescence intensity (MFI), tumor-to-background ratio (TBR), and ex vivo biodistribution were compared.

Results: The M5A-FNIR-766 conjugate produced a greater MFI in tumors at all timepoints compared to M5A-IR800CW, resulting in a significantly improved TBR. Ex vivo analysis at 96 h confirmed higher tumor accumulation for M5A-FNIR-766 and revealed a reduction in hepatic signal for both M5A-FNIR-Tag conjugates. The observations were concordant in the clinically relevant orthotopic model.

Conclusion: Antibody-fluorophore conjugates linked to the charge-modified FNIR-Tag dyes provide improved tumor-specific signals and a more favorable biodistribution profile than the same antibody conjugated to a conventional dye. By achieving superior performance through intrinsic fluorophore design rather than complex bioconjugation strategies, the approach provides a clinically translatable advancement for tumor-specific FGS.

Molecular imaging exhibits remarkable potential in immune cell tracking and advancing personalized clinical management, providing not only diagnostic and prognostic information but also enabling treatment efficacy quantification and therapeutic optimization. Macrophages play an essential role in the pathogenesis and progression of various cardiovascular diseases. This review comprehensively examines the characteristics of diverse molecular imaging modalities and their applications in macrophage imaging, encompassing major cardiovascular conditions, including atherosclerosis, myocardial infarction, and cardiac transplantation. We anticipate that advancements in novel noninvasive molecular imaging technologies for macrophages will ultimately facilitate clinical diagnosis, outcome prediction, treatment strategy formulation, and therapy response monitoring, thereby providing critical technical support for precision medicine practice.

Trimethoprim (TMP) is a reversible inhibitor of the prokaryotic enzyme dihydrofolate reductase (DHFR) used for the treatment or prophylaxis of bacterial infections. [¹¹C]trimethoprim ([¹¹C]TMP) is a positron emission tomography (PET) imaging isotopologue of TMP. TMP binds with 30,000-fold greater affinity to bacterial DHFR over the homologous mammalian enzyme in vitro, suggesting [¹¹C]TMP may selectively accumulate in tissues with cells expressing bacterial DHFR. This study characterizes the biodistribution and dosimetry of [¹¹C]TMP, informing its use in imaging bacterial infections and tracking mammalian cells expressing eDHFR as a reporter gene.

Methods: Four males with suspected infection, aged 59 ± 10 years old (mean ± SD) received 3 serial PET/CT scans after injection of 346 ± 305 MBq (range 129-797 MBq) of [¹¹C]TMP. Organ activities were measured in MIM v6.7, including brain, kidneys, spleen, liver, heart, lungs, bladder, intestines, gallbladder, pancreas, thyroid, and red marrow. Dosimetry calculations were performed in Olinda | EXM v1.1. Additionally, a dynamic whole-body PET/CT scan was performed on a separate participant. The associated trial was registered as NCT03424525.

Results: [¹¹C]TMP injections were well tolerated with no adverse events. The average injected activity of 346 MBq of [¹¹C]TMP yielded an estimated average dose of 4.9 mSv in the highest uptake organ (liver), 4.1 mSv in the spleen, and an effective dose of 1.6 mSv. Suspected sites of infection displayed uptake above background.

Conclusion: [¹¹C]TMP PET was safe and demonstrated low background uptake in most tissues. The data suggests feasibility for evaluation of varied bacterial infections, including musculoskeletal infections. Absorbed doses allow multiple [¹¹C]TMP PET scans each year within Radioactive Drug Research Committee (RDRC) limits, potentially enabling monitoring of infections and treatment response.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) represents a highly aggressive malignancy with a 5-year survival rate below 10% and poor prognosis. Early diagnosis of PDAC remains a significant challenge due to its nonspecific symptomatology, insufficient reliable biomarkers, aggressive tumor progression with early metastatic spread, and limited effective screening protocols. Recent research indicates cannabinoid type 2 receptor (CB2R) overexpression in PDAC, leading to the development of [¹⁸F]JR-1004 as a potential CB2R-targeted PET probe to address diagnostic challenges in this aggressive malignancy.

Procedures: The probe development utilized computer-aided drug design, incorporating modifications to a triaryl sulfonamide CB2R inverse agonist lead compound. Essential pharmacophoric elements (central sulfonamide, flanking aromatic rings) were preserved, while the para-methoxy group underwent conversion to a tosylate precursor for radiolabeling. Radiolabeling with ¹⁸F was performed using a JiRui OnePlatform 3.1 s synthesizer (synthesis time: 70 min).

Results: The radiochemical purity and yield achieved values exceeding 95% and 16.7%, respectively. In vitro studies confirmed [¹⁸F]JR-1004's specific binding affinity in CB2R-overexpressing cells, with uptake significantly reduced by a CB2R antagonist administration. PET imaging in PDAC mouse models revealed significant accumulation in tumor regions, with receptor specificity validated through CB2R blocking studies. Biodistribution analysis revealed primary probe metabolism through the hepatobiliary system, with maximal uptake in the liver and pancreas. The probe's targeting profile demonstrates notable improvements for PDAC detection compared to the relatively nonspecific uptake patterns of [¹⁸F]FDG PET in pancreatic imaging.

Conclusions: This investigation presents an innovative molecular imaging approach for early PDAC diagnosis, exhibiting considerable potential for clinical implementation.

Purpose: Accurate staging of prostate cancer is essential for therapeutic decision-making. While PSMA PET-CT reports offer rich clinical data, their unstructured format hinders large-scale analysis. Recent advances in large language models (LLMs) offer new opportunities to extract structured information from narrative radiology reports. However, their ability to perform multi-step clinical reasoning, particularly for cancer staging, remains underexplored.

Methods: In this feasibility study, 80 anonymized, Turkish-language PSMA PET-CT reports were independently interpreted by two LLMs-Gemini 2.5 Pro (Google) and ChatGPT 4o (OpenAI). Using a structured prompt containing an embedded knowledge base (AJCC/CHAARTED criteria) and few-shot examples, both LLMs generated classifications for T, N, M, and overall clinical stage/disease volume. Outputs were benchmarked against expert classifications by a senior nuclear medicine specialist. Performance was evaluated using accuracy, precision, recall, F1-score, and Cohen's kappa.

Results: For the composite task of classifying clinical stage and disease volume, Gemini 2.5 Pro achieved an accuracy of 93.8% (95% CI: 86.0-97.9) and a Cohen's kappa of 0.910 (95% CI: 0.834-0.986), while ChatGPT 4o achieved 91.3% accuracy (95% CI: 82.8-96.4) with a kappa of 0.874 (95% CI: 0.786-0.962). For T staging, Gemini showed a higher accuracy point estimate (95.0% [95% CI: 87.7-98.6] vs. 91.3% [95% CI: 82.8-96.4]), while both models excelled at the binary N and M classifications, achieving accuracies above 95% and kappa values indicating near-perfect agreement (κ > 0.900).

Conclusions: LLMs, when guided by expert-informed prompt engineering, can accurately stage prostate cancer from free-text PSMA PET-CT reports and may serve as a powerful assistive tool for data automation, research acceleration, and quality assurance.

Purpose: Lymphocyte-activation gene 3 (LAG-3), a next-generation immune checkpoint, has emerged as a promising therapeutic target, but noninvasive tools for evaluating LAG-3 expression remain limited. Herein, we explored an antibody-dependent molecular imaging strategy for noninvasive detection based on a LAG-3-specific antibody, HuL13.

Procedures: The anti-LAG-3 antibody HuL13 was radiolabeled with ¹²⁴I via electrophilic substitution. LAG-3-expressing A549 cells were constructed by infection with the lentivirus. The specificity and affinity of ¹²⁴I-HuL13 to LAG-3 receptor were evaluated by cell uptake assay and saturation binding assay. Micro-PET/CT imaging studies were conducted in BALB/c nude mice bearing LAG-3⁺ A549 tumors. Immunohistochemistry (IHC) validated LAG-3 expression in tumors.

Results: The ¹²⁴I-HuL13 exhibited a good radiochemical yield of 95.59 ± 1.27%, high radiochemical purity (RCP, > 99%), and excellent stability. Cell binding assays demonstrated that ¹²⁴I-HuL13 had a higher binding ability to LAG-3⁺ A549 cells compared to control cells. The equilibrium dissociation constant (Kd) of ¹²⁴I-HuL13 was 23.02 nM for LAG-3⁺ A549 cells. In vivo pharmacokinetics revealed favorable metabolic stability (t_1/2β = 12.07 h). Micro-PET/CT images showed that ¹²⁴I-HuL13 significantly accumulated in LAG-3⁺ A549 tumor from 24 h after injection (SUVmax = 0.34 ± 0.03 at 24 h), and high contrast tumor to background imaging was clearly observed. IHC confirmed LAG-3 expression correlated with probe uptake.

Conclusions: ¹²⁴I-HuL13 is a novel LAG-3-targeted PET imaging radiotracer with excellent stability. This study highlights ¹²⁴I-HuL13 as a robust tool for noninvasive LAG-3 imaging, offering potential for optimizing LAG-3-targeted immunotherapy in clinical settings.