Molecular Imaging and Biology最新文献

Purpose: In our previous phase 2 trial, patients with locally advanced (LARC) or locally recurrent rectal cancer (LRRC) received SGM-101, a CEA-targeted fluorescent agent, to enable real-time near-infrared fluorescence (NIRF) guided surgery. This study demonstrated that SGM-101 enabled additional tumor removal in some patients and supported less invasive surgery in others. Despite this positive intraoperative effect, the impact on long-term tumor control is unknown. Therefore, in this article we report the long-term outcomes of all rectal cancer patients that participated to the trial.

Procedures: For all 29 LARC and LRRC patients that participated in the SGM-101 phase 2 trial, follow-up data were collected. Main outcome measure was 5-year local tumor control.

Results: The median follow-up of all patients was 5.0 years (IQR 4.5-5.5). Of the 12 LARC patients, three (25%) patients developed a local recurrence. The two patients in whom NIRF-guided surgery resulted in less invasive surgery remained locally recurrence-free. Among the 17 patients undergoing curative surgery for LRRC, 11 (65%) patients developed a local re-recurrence. Of the three patients who had an R0 instead of R1 as a direct result of SGM-101 guided surgery, one patient developed a local re-recurrence (33%), while the other two remained local recurrence-free.

Conclusions: This is the first study to report follow-up data on patients undergoing tumor-targeted NIRF-guided surgery. Although SGM-101 resulted in warranted changes in surgical management intra-operatively, no improved long-term benefit could be observed for the entire cohort. However, the subset of patients whose surgical approach was modified based on NIRF - either by performing less invasive surgery or removing additional malignant tissue-showed favorable long-term outcomes. Results from ongoing large trials are awaited.

Purpose: The progression rate and course of radioiodine refractory differentiated thyroid cancer (RAIR-DTC) vary significantly, yet there lacks a precise method for predicting its progression. We hypothesized that using the liver as a reference organ can enable selective patient stratification. We aimed to establish fluorine-18 fluorodeoxyglucose positron emission tomography ([¹⁸F] FDG-PET) tumor to-liver ratio (TLR score) to predict outcome for RAIR-DTC.

Procedures: This study included 64 patients with RAIR-DTC undergoing baseline ¹⁸F-FDG PET/CT. Patients were categorized by visual TLR (vTLR) into high (most lesions show higher uptake than the liver) or low (most lesions show lower uptake than the liver) groups using 3D maximum intensity projection (MIP) images. Quantitative TLR (qTLR) scores, including qTLR max (tumor SUVmax/liver SUVmax) and qTLRmean (tumor SUVmean/liver SUVmean), were semiautomatically derived from baseline PET, with high (≥ 1.5) and low (< 1.5) groups defined. Outcome data were progression-free survival (PFS).

Results: Among 64 patients, the distribution of high-TLR versus low-TLR groups varied across scoring methods: vTLR score allocated 36 (56.3%) high vs 28 (43.7%) low, qTLRmax score identified 29 (45.3%) high vs 35 (54.7%) low, and qTLRmean score demonstrated the most divergent pattern with 21 (32.8%) high vs 43 (67.2%) low. Agreement among qTLRmax, vTLR and qTLRmean score was moderate (Fleiss weighted k, 0.579). The median PFS of the high and low groups by vTLR score was 16.0, 29.0 months (P = 0.010) respectively, by qTLRmax score was 14.0, 27.0 months (P = 0.041), respectively, by qTLRmean score was 14.0, 28.0 months (P = 0.004), respectively.

Conclusions: The TLR score was prognostic for PFS of RAIR-DTC. The vTLR score assessed on 3D MIP PET images yielded substantial reproducibility and combining qTLR score provided reliable prognostic value.

Radiopharmaceuticals based on antibody biomolecules are widely used in oncology for positron emission tomography (PET). Trastuzumab, an antibody that targets the epidermal growth factor receptor 2 (HER2), has been extensively studied for both preclinical and clinical cancer imaging. This MIB guide specifically focuses on the radiolabeling of the antibody trastuzumab with zirconium-89 (⁸⁹Zr) and copper-64 (⁶⁴Cu) for PET imaging. The guide describes the steps for conjugating trastuzumab with p-SCN-Bn-deferoxamine (DFO) or 2,2',2''-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (p-SCN-Bn-NOTA) chelators through conjugation between the isothiocyanate (-SCN) functional group on the chelator with lysines on the trastuzumab. We also describe subsequent radiolabeling steps with ⁸⁹Zr or ⁶⁴Cu. The steps described here can be adapted to the radiolabeling of other antibodies upon protocol optimization.

Purpose: After percutaneous coronary intervention (PCI), dual antiplatelet therapy (DAPT) is required to prevent thrombosis, but systemic DAPT may increase bleeding risk. This study aimed to develop a new concept of antiplatelet therapy administered via local infusion of PLGA-Fe₃O₄-ticagrelor microspheres (PFTm).

Procedures: PLGA loaded with Fe₃O₄ and ticagrelor magnetic microspheres were constructed. In vitro study, the morphology, relaxation rate, drug release rate, encapsulation efficiency, and biocompatibility of PFTm were evaluated. In vivo study, vascular injury model of rabbit abdominal aorta was established by Fogarty balloon. The injured rabbit aorta wall was infused PFTm by infusion balloon in the local PFTm therapy group, while the rabbit was injected PFTm intravenously in the systemic PFTm therapy group. The non-therapy control group and healthy control group did not receive PFTm treatment. MR T2WI was performed pre-operation, post-operation to detect PFTm distribution. Then, the targeted abdominal aorta segments were harvest for pathological examination.

Results: The PFTm was spherical with a size of 930.5 ± 134 nm and SPAN was 0.35. The ticagrelor encapsulation efficiency was 82% ± 2%, and the release rate reached 88% ± 2% within 96 h. The r2 of the PFTm was 332.0 mM^-1 s^-1. All rabbits were successfully established abdominal aorta injury model. MRI showed significant decrease of SNR in aortic wall which represented PFTm infused into aortic wall. Pathology showed that local thrombus was significant inhibited in the local PFTm therapy group compared with the other groups.

Conclusions: The new concept of releasing drugs in a sustained manner for local antiplatelet therapy after PCI was successfully established.

Purpose: There are few prospective studies addressed toward the role of ⁶⁸Gallium-labelled prostate-specific membrane antigen-11 ([⁶⁸Ga]Ga-PSMA-11) compared to [¹⁸F]Fluorocholine ([¹⁸F]FCH) PET/CT in clinical decision-making as prostate-specific PET-tracers. This study aims to evaluate the impact of PET/CT using [⁶⁸Ga]Ga-PSMA-11 and [¹⁸F]FCH in clinical management of recurrent prostate cancer (PCa) and correlates imaging findings with clinical characteristics of PCa.

Procedures: Forty-six patients with PCa (mean age 68.3 ± 6.3 years) with biochemical recurrence were enrolled in this prospective crossover trial. All patients underwent both [⁶⁸Ga]Ga-PSMA-11 and [¹⁸F]FCH PET/CT within a maximum interval of 12 days (median 7d). A standard randomization tool randomized the sequence of PET/CT imaging. Clinical decision-making occurred in an interdisciplinary meeting considering PET/CT findings. PET/CT-blinded readings were performed 3 months after imaging followed by a consensus meeting for final interpretation of detected lesions.

Results: Both imaging modalities detected 136 total malignant lesions. [⁶⁸Ga]Ga-PSMA-11 and [¹⁸F]FCH PET/CT detected 125 and 60 lesions with a sensitivity of 96% and 48%, respectively. Tumor-to-background ratios and semi-quantitative PET parameters on [⁶⁸Ga]Ga-PSMA-11 were significantly higher in 54 (41.2%) tracer-avid congruent lesions detected on both imaging modalities. [⁶⁸Ga]Ga-PSMA-11 PET/CT exclusively detected 71 (52.2%) lesions, while 6 (4.4%) lesions were solely seen on [¹⁸F]FCH PET/CT. [⁶⁸Ga]Ga-PSMA-11 and [¹⁸F]FCH PET/CT were positive in 35/46 (76%) and 26/46 (57%) patients, respectively. PET/CT imaging led to a major treatment change in 4 (8.7%) patients, of which [¹⁸F]FCH PET/CT had superior impact in one patient.

Conclusions: [⁶⁸Ga]Ga-PSMA-11 PET/CT revealed superior diagnostic performance to [¹⁸F]FCH PET/CT in patients with recurrent PCa, specifically with very low PSA levels ≤ 1 ng/ml. Moreover, it led to more accurate staging and clinical management of the disease. [¹⁸F]FCH PET/CT may play a complementary role in rare, select high-risk cases with negative [⁶⁸Ga]Ga-PSMA-11 PET/CT and ongoing ADT.

Purpose: Monocarboxylate transporters (MCTs) play a pivotal role in tumor metabolic symbiosis, acid resistance, and metastatic progression. Herein, we report the development of [¹⁸F]FEtO-CHC, a novel MCTs-targeted positron emission tomography (PET) radiotracer, and systematically evaluate its potential for non-invasive tumor imaging.

Procedures: The radiosynthesis of [¹⁸F]FEtO-CHC and its non-radioactive analog was achieved through optimized precursor synthesis and fluorination protocols. Comprehensive in vitro characterization encompassed: radiochemical purity and stability assessments, cellular uptake kinetics and inhibition assays in MCT-expressing BxPC3 (pancreatic) and 4T1 (breast) cancer models, biodistribution and dynamic micro-PET/CT imaging in tumor-bearing murine models.

Results: [¹⁸F]FEtO-CHC, a CHC-derived radioligand, was synthesized via streamlined one-step radiosynthesis with 52.08 ± 6.74% decay-corrected yield (n=7), >99% radiochemical purity, and excellent stability. Cellular studies demonstrated MCTs-dependent uptake with significant suppression (>70%) by α-CHC competition. In vivo pharmacokinetics revealed favorable metabolic stability with dual hepatorenal clearance. Tumor uptake correlated with MCT expression levels, as confirmed by immunohistochemistry.

Conclusions: This study establishes an efficient one-step radiosynthetic approach for [¹⁸F]FEtO-CHC production and validates its specificity as a MCT-targeted PET probe, offering potential utility in tumor imaging with further structural optimization.

Purpose: Zebrafish are a useful organism for investigating liver disease due to their genetic similarities with humans, particularly in genes associated with liver function. It has been posited that liver function can be assessed non-invasively by MRI, measuring the hepatic accumulation of gadolinium-based contrast agents (GBCAs). We characterized the hepatic uptake of various hepatospecific and non-hepatospecific clinical GBCAs in zebrafish.

Procedures: To introduce GBCAs systemically, zebrafish swam for 30 min in water containing 5 mM of various clinical hepatospecific or non-hepatospecific GBCAs. Fish were then sacrificed and underwent 3D, T1-weighted, high-resolution MRI at 9.4 T. In vitro MRI and transport studies of the same GBCAs were conducted in HEK293T cells transiently expressing OATP1D1, OATP1B2 and OATP1B3.

Results: T1-weighted ex-vivo MRI of zebrafish showed hyperintensity in the liver, gall bladder, bile ducts, and intestine for fish swimming in gadoxetate, but not for in gadobenate nor gadoterate. In vitro cell experiments confirm that gadoxetate but not gadobenate is efficiently transported by OATP1D1.

Conclusion: Zebrafish liver accumulates gadoxetate but not gadobenate via OATP1D1 transport, among the two clinical hepatospecific MRI GBCAs, and also does not accumulate gadoterate, a non-hepatospecific GBCA. This pattern of GBCA hepatic uptake is similar to humans but differs from all other non-primates reported, which exhibit high hepatic uptake of both gadoxetate and gadobenate.

Purpose: Targeted and broadly applicable molecular targets are important for image guided surgery. Xenoantigens represent a particularly interesting class of targets. This study evaluates the xenoantigen N-glycolyl-neuraminic acid GM3 ganglioside (Neu5Gc-GM3) as a potential fluorescence-guided surgical tool.

Procedures: The antibody 14F7hT is conjugated to the near-infrared dye (IRDye800CW) and characterized under GLP conditions. The quality and stability of the 14F7hT-IRDye800CW probe was assessed. In vivo imaging using 14F7hT-IRDye800CW in mice with Neu5Gc GM3 positive and negative xenografts were compared to a control IgG-IRDye800CW probe targeting an epitope not present on the xenografts. Biodistribution, pharmacokinetics, and toxicity were evaluated.

Results: The 14F7hT-IRDye800CW probe was 98 ± 2% pure as determined by micro-capillary electrophoresis. The KDapp as determined by binding cell-lines expressing the target was unchanged after conjugation. We demonstrate a peak accumulation window of 12 - 48 h in murine xenografts with male and female CD-1 nude mice administered 0.5 nmoles of the probe (i.v.) and very low uptake in other tissues. Preclinical toxicity studies in male and female balb/c mice support a no observed adverse effect level (NOAEL) of 50 mg/kg in mice.

Conclusions: The 14F7hT-IRDye800CW probe was found to be safe and have low non-specific uptake in a model organism known to express the target. These data support future clinical development of the probe.

Background: The sigma-1 receptor (Sig-1R) plays diverse roles in regulating Endoplasmic Reticulum (ER) stress, calcium handling, and ion channel activity under pathological conditions, offering cardioprotective effects in pressure overload-induced dysfunction. However, its role in post-myocardial ischemia damage remains unclear. This study evaluated the cardioprotective effects of Sig-1R activation by fluvoxamine following myocardial ischemia in rats.

Method and results: Wistar rats underwent 20 min of coronary artery occlusion followed by reperfusion. Rats received either saline (control) or fluvoxamine for two weeks. ECG-gated SPECT with ^99mTc-MIBI was performed on days 1, 14, and 28 post-reperfusion to measure the end-diastolic volume (EDV), end-systolic volume (ESV), left ventricular ejection fraction (LVEF), and summed rest score (SRS). Autoradiography and histological analyses were performed on day 29. Fluvoxamine significantly improved LVEF after two weeks (D14-D1: 6 ± 7, p = 0.03), with the improvement persisting to the 28th day (8 ± 5, p < 0.01). Autoradiography revealed a smaller non-salvaged area (0.15 ± 0.19 vs. 0.42 ± 0.32, p < 0.05) and more salvaged myocardium (0.33 ± 0.13 vs. 0.14 ± 0.14, p < 0.05) in the fluvoxamine group. Histology showed less fibrosis (0.06 ± 0.05 vs. 0.11 ± 0.08, p < 0.05) and reduced macrophage infiltration (0.08 ± 0.05 vs. 0.16 ± 0.08, p < 0.001) with fluvoxamine.

Conclusions: Sig-1R stimulation by fluvoxamine suppresses LV remodelling and enhances LVEF recovery post-ischemia, suggesting its potential as a novel cardioprotective strategy.

Purpose: Lung cancer is increasingly diagnosed at early stages, but intraoperative localization of early lesions remains challenging. Intraoperative molecular imaging (IMI) aids in localization of tumors during surgery; however, no optical agents are targeted specifically for early-stage lesions. The sodium-glucose cotransporter 2 (SGLT2) has been implicated in early lung carcinogenesis. This study aimed to describe SGLT2 expression in early-stage lung adenocarcinoma (LUAD) and develop and validate a novel SGLT2-targeted near-infrared (NIR) contrast agent, GlucoGlo, for imaging LUAD.

Procedures: SGLT2 expression was confirmed by immunohistochemistry (IHC) in human samples. GlucoGlo optical properties were characterized and compared to common NIR dyes. Sensitivity and specificity for SGLT2 were assessed using preclinical in vitro and in vivo mouse models.

Results: On IHC, stage I LUAD displayed higher SGLT2 expression than stage II-III LUAD and normal lung tissue. GlucoGlo exhibited similar depth of penetration and resolution to FDA-approved contrast agents. SGLT2-expressing cell lines treated with GlucoGlo displayed higher fluorescence than the control cell line, confirming SGLT2-dependent uptake. Fluorescence increased with both incubation time and GlucoGlo concentration. Glucose and unconjugated GlucoGlo ligand competitively inhibited GlucoGlo in a dose-dependent manner, indicating high affinity and specificity. GlucoGlo selectively accumulated in SGLT2-expressing flank xenografts, with mean SBR of 2.23 and was inhibited by pretreatment with unconjugated GlucoGlo ligand.

Conclusions: These findings support the potential of GlucoGlo as a targeted IMI contrast agent for early-stage LUAD, and they provide a foundation for future in vivo studies and translational development.