Molecular Imaging and Biology最新文献

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.

Purpose: Targeted radionuclide therapy against cancer stem cell-specific markers, such as CD133, constitutes a promising strategy to eliminate resilient cancer stem cells for improved outcomes in refractory tumors. Here, we report the synthesis and evaluation of [¹⁷⁷Lu]Lu-DOTA-RW03, a CD133-targeted radioimmunotherapy.

Procedures: A fully human, anti-CD133 antibody (RW03) was conjugated with DOTA-NHS and radiolabeled with lutetium-177 to yield [¹⁷⁷Lu]Lu-DOTA-RW03. Radioligand binding assays on [¹⁷⁷Lu]Lu-DOTA-RW03 were performed using CD133 expressing HT-29 cells to determine binding affinity and immunoreactive fraction. Immunodeficient mice (n = 15) bearing HT-29 tumors were divided into 4 cohorts to establish the biodistribution of [¹⁷⁷Lu]Lu-DOTA-RW03 at 24, 48, and 96 h post-injection (n = 5 per cohort). Additional biodistribution and SPECT imaging studies were performed to establish tumor specificity and dose-dependent tumor uptake. In a dose-escalation therapy study, HT-29 tumor bearing mice (n = 20) were treated with either 4.0 ± 0.1, 9.6 ± 0.1, or 14.1 ± 0.2 MBq of [¹⁷⁷Lu]Lu-DOTA-RW03 or a vehicle control (n = 5 mice per cohort). Tumors from the therapy study were processed ex vivo for immunohistochemical and histopathological analysis.

Results: Radioimmunoconjugate [¹⁷⁷Lu]Lu-DOTA-RW03 (4.4 ± 0.1 DOTA per antibody) was isolated in 50 ± 10% radiochemical yield, 17-28 GBq/µmol molar activity, and in > 98% radiochemical purity. In vitro, the radiolabeled antibody exhibited excellent binding affinity (0.30 ± 0.03 nM) and > 75% immunoreactivity. The biodistribution of [¹⁷⁷Lu]Lu-DOTA-RW03 revealed notable tumor uptake (65 ± 5%ID/g, 96 h post-injection) and a favorable tumor-to-blood ratio (5:1, 96 h post-injection). In vivo antigen specificity was confirmed by a significant reduction (75%) in tumor uptake when [¹⁷⁷Lu]Lu-DOTA-RW03 was co-administered with a 200-fold molar excess of unlabeled RW03. The radioimmunoconjugate exhibited promising therapeutic efficacy in the treatment of CD133 expressing colorectal xenograft mouse model, with dose-dependent reductions in tumor growth rate and increased survival time. Histopathological and immunohistochemical analyses revealed elevated cell proliferation and extensive liquefactive necrosis at late stages into treatment, which provides an opportunity for multidosing and combination treatment strategies.

Conclusions: These findings underscore the potential of [¹⁷⁷Lu]Lu-DOTA-RW03 as an effective therapy through targeting CD133 expressing cancer cells.

Background: Lutetium-177 (¹⁷⁷Lu) is a promising radionuclide for targeted cancer therapy due to its favorable theranostic properties. Transarterial lipiodol embolization is widely used for hepatocellular carcinoma (HCC), but the potential of ¹⁷⁷Lu emulsified into lipiodol (¹⁷⁷Lu-lipiodol) remains underexplored. This study aimed to evaluate the partition coefficient, biodistribution, and antitumor efficacy of ¹⁷⁷Lu-lipiodol in a preclinical xenograft model.

Methods: After synthesizing ¹⁷⁷Lu-oxine from ¹⁷⁷Lu-chloride, the product was emulsified in lipiodol. Its radiochemical purity and partition coefficient were measured. F344 NJcl rnu/nu rats (n = 5) bearing bilateral thigh tumors (HC-4 cells) were randomized to receive ¹⁷⁷Lu-lipiodol (2.8 MBq in 50 μL) or non-labeled lipiodol (50 μL) via surgical exposure and direct puncture of the right femoral artery. SPECT/CT images were acquired over 14 days, and biodistribution was confirmed by gamma counting at day 28. Tumor volumes and body weights were monitored to assess treatment response and toxicity.

Results: The ¹⁷⁷Lu-lipiodol emulsion was obtained with a high radiochemical purity (> 99%). SPECT/CT showed high tumor accumulation (34.0% ± 4.4% immediately post-injection) that persisted up to day 28 (7.3% ± 1.2% of injected dose). Tumor growth was significantly suppressed with a treated-to-untreated volume ratio of 0.45 at day 14 (p = 0.017) and 0.59 at day 21 (p = 0.001). While off-target uptake was limited, moderate splenic accumulation (26.6% ± 17.5% ID) was noted. No marked body weight changes or gross organ abnormalities were observed.

Conclusion: ¹⁷⁷Lu-lipiodol for HCC therapy demonstrated effective tumor targeting and growth suppression of HCC in a preclinical xenograft model.

Background: Pulmonary delivery of agents to lung is an effective method for the diagnosis and therapy of lung cancer.

Purpose: To demonstrate that pulmonary delivery of perfluorocarbon (PFC) nanoparticles for orthotopic lung tumor model is better than intravenous injection for subcutaneous tumor, and to confirm that the nanoparticles can be uptaked by tumor tissue which showed by ¹⁹F MR imaging and tissue staining.

Methods: We detected the targeted ability of folate receptor (FR) targeted PFC nanoparticles with H460 cells in vitro. Subcutaneous and orthotopic lung cancer models were established. When the tumors could be detected by MR after two weeks, PFC nanoparticles were administrated intratracheally in orthotopic group and intravenously in subcutaneous group. ¹⁹F MR scanning was performed in mice models at before and different time points (4, 24, and 48 h) after delivery. Mice were euthanized after MR imaging, and tumor tissues were taken out, HE and fluorescent staining were performed respectively. In addition, orthotopic tumor tissue was obtained for transmission electron microscopy (TEM) examination.

Results: The orthotopic tumor model showed a significant ¹⁹F MRI enhancement effect in the tumor region after PFC nanoparticles delivered intratracheally than subcutaneous model. As time went on, the accumulation of nanoparticles in the tumor area increased, and the ¹⁹F signal increased gradually. The ¹⁹F SNR in the tumor region of orthotopic group was significantly higher than that of subcutaneous group at 24 and 48 h after delivery (p < 0.001). Histological experiments showed that PFC nanoparticles accumulated in the tumor region especially in orthotopic group.

Conclusion: Pulmonary delivery of PFC nanoparticles is a novel and effective method for orthotopic lung cancer xenograft model, and the PFC nanoparticles can be detected by ¹⁹F MR imaging in vivo.

Purpose: Survival and treatment intensity in patients with head and neck squamous cell carcinoma (HNSCC) is determined by the presence of lymph node (LN) metastasis, and as a result surgical removal of potentially affected LN remains a mainstay practice. Fluorescence guided surgery (FGS) using targeted optical agents is an expanding field that shows great potential for aiding diagnosis of metastatic LN. Given variations in fluorescence background, a reference standard for regions of interest is necessary for cross patient comparison. The present study aims to determine whether tissue with native target expression can be used as a background to determine metastatic LN in patients with HNSCC infused with anti-epidermal growth factor receptor (EGFR) targeted imaging agents.

Procedures: Twenty-two patients infused with panitumumab-IRDye800 or cetuximab-IRDye800 prior to surgery were included. Fluorescence imaging and analysis was performed on resected LNs (N = 843) using the submandibular glands (SMG) and skin as reference standard tissue with known EGFR antigen expression.

Results: Sixteen patients (72.7%) had at least one positive LN on final pathology. The LN to SMG (LN/SMG) and LN to skin (LN/skin) ratios were significantly higher in metastatic LN compared to benign LN (p < 0.0001 for both). Using patient-specific ratios to determine an optimal LN/skin cutoff was the most sensitive (95.2%) and directly comparing the LN/skin ratio of all patients to determine a cutoff was the most specific (86.3%).

Conclusions: In HNSCC patients infused with a molecularly targeted fluorescent tracer, endogenous expression of the target antigen can be used as a reference standard to detect LN metastasis. Additionally, the performance of the background in determining metastatic LN can be improved by utilizing patient-specific reference standards.

Purpose: Measuring hepatic flux rates of transportable substrates has the potential for assessing liver function. PET imaging of a PET-enabled substrate may provide a more straightforward measurement of time-dependent substrate concentration through the liver than MRI using an MRI contrast agent. Here we synthesized and evaluated the hepatobiliary transport of a new hepatospecific PET agent designed for stable Cu²⁺ chelation and transport by hepatic OATPs, [⁶⁴Cu]Cu-EOB-NOTA.

Procedures: EOB-NOTA was synthesized, its two enantiomers separated by chiral HPLC, and individually radiolabeled with [⁶⁴Cu]Cu²⁺. Cocktails of each enantiomer of [⁶⁴Cu]Cu-EOB-NOTA and Gd-EOB-DTPA were formulated for simultaneous PET/MRI imaging of hepatic flux by PET and MRI. Two mouse models were evaluated: wild-type mice and mice expressing only human hepatic OATPs.

Results: In wild-type mice, [⁶⁴Cu]Cu-EOB-NOTA hepatic influx and efflux was high, but slower compared to Gd-EOB-DTPA. Neither enantiomer of [⁶⁴Cu]Cu-EOB-NOTA exhibited detectable transport into the liver in mice expressing human OATPs. This was validated by waste clearance studies and in vitro uptake assays in cells engineered to express rodent and human OATPs.

Conclusion: [⁶⁴Cu]Cu-EOB-NOTA exhibited no detectable hepatic uptake by transgenic mice expressing human hepatic transporters. This finding was surprising given the efficient transport of the structurally similar metal chelate Gd-EOB-DTPA, and underscores challenges in the design of imaging molecular probes, including poor predictability for hepatic transport, and the value of validating new agents in mice expressing human hepatic transporters.

Purpose: This study investigated the effects of laterality, age, gender, BMI, and physical activity level on iliac bone turnover using [¹⁸F]NaF PET/CT.

Procedures: Fifty-nine males and 44 females from the CAMONA study were analyzed. A region of interest (ROI) was drawn to segment the iliac bone using Hounsfield unit thresholds and morphological closing algorithm. [¹⁸F]NaF SUVmean was compared between the left and right iliac bones using a paired t-test, while Pearson correlation coefficient assessed changes with age, BMI, and physical activity level.

Results: [¹⁸F]NaF uptake was higher in right iliac bone than left in males, females, and the combined-group. In males, SUVmean was 2.98 ± 1.63 (1.1-7.87) on left and 3.71 ± 1.49 (1.49-3.7) on right. In females, SUVmean was 2.59 ± 1.14 (0.88-6.27) on left and 3.72 ± 1.04 (2.22-6.51) on right. Combined, SUVmean was 2.81 ± 1.44 (0.88-7.87) on left and 3.71 ± 1.31 (0.89-8.07) on right. [¹⁸F]NaF uptake negatively correlated with age (right: r = - 0.27, P = 0.006; left: r = - 0.22, P = 0.02), stronger in females (right: r = - 0.30, P = 0.04; left: r = - 0.31, P = 0.04) than males (right: r = - 0.26, P = 0.04; left: r = - 0.18, P = 0.18). SUVmean correlated positively with BMI in males (right: r = 0.47, P = 0.0002; left: r = 0.38, P = 0.0027), females (right: r = 0.36, P = 0.0168; left: r = 0.30, P = 0.0505), and combined-group (right: r = 0.43, P < 0.0001; left: r = 0.37, P = 0.0001). No significant correlation was found between SUVmean and physical activity in males, while in females, a negative correlation was observed on left (r = - 0.37, P = 0.0390) but not on right (r = - 0.27, P = 0.1302), and when combined, the correlation remained significant on left (r = - 0.24, P = 0.0372) but not on right (r = - 0.16, P = 0.1541).

Conclusions: [¹⁸F]NaF uptake was higher in the right iliac bone and declined with age, particularly in females. The positive correlation between SUVmean and BMI; and the negative correlation between SUVmean and physical activity suggest metabolic influences on bone turnover. [¹⁸F]NaF PET/CT may serve as a tool for assessing bone metabolism and turnover in asymptomatic individuals.