Search

Objective. To investigate the biodistribution and kinetic constants of 68Ga-DOTATATE in normal organs through dynamic total-body positron emission tomography/computed tomography (PET/CT). Methods. Seven patients who experienced endoscopic resection of gastric neuroendocrine tumor were enrolled. Dynamic total-body PET/CT scans over 60 min were performed. Time-activity curves were obtained by drawing regions of interest in normal organs. Rate constants, including K1, k2, k3, and vB, were computed using a two-tissue compartment model. Factor analysis was used to compare the rate constants among subjects and regions. Hierarchical cluster analysis was performed to identify organs with similar kinetic characteristics. Results. The highest uptake of 68Ga-DOTATATE was observed in the spleen followed by kidneys, adrenals, liver, pituitary gland, pancreas head, prostate, pancreas body, and thyroid, parotid, and submandibular glands. Low background level of 68Ga-DOTATATE uptake was observed in the nasal mucosa, bone, blood pool, and cerebrum. In addition, the uptake in the pancreas head was noted to be higher than the pancreas body ( P < 0.001 ) on the basis of each time point of dynamic PET. There were differences of rate constants among different organs. The mean K1 ranged from 0.0507 min−1 in the left nasal mucosa to 1.21 min−1 in the left kidney, and mean k2 ranged from 0.0174 min−1 in the spleen to 4.4487 min−1 in the left cerebrum. The mean k3 ranged from 0.0563 min−1 in the right cerebrum to 4.6309 min−1 in the left adrenal, and mean vB ranged from 0.0001 in the left cerebrum to 0.2489 in the right adrenal. However, none of the rate constants was significantly different among subjects or among different sites within a single organ. Three groups of organs with similar kinetic characteristics were identified: (1) cerebrum; (2) pituitary gland, liver, adrenal, and prostate; and (3) nasal mucosa, parotid and submandibular glands, thyroid, spleen, pancreas, kidney, and bone. Conclusion. Uptake and clearance of 68Ga-DOTATATE, in terms of kinetic constants, were different in different organs. The kinetic parameters of 68Ga-DOTATATE in different organs provide a reference for future dynamic PET imaging.

In this study, aqueous film-forming foam, fluoroprotein foam, and synthetic foam were applied to extinguish the transformer oil pool fires. The fire-extinguishing performance and burn-back resistance were investigated using a laboratory fire-extinguishing system. Moreover, the emission products were analyzed to evaluate the gas-phase pollution characteristics. Results show that aqueous film-forming foam presents the highest fire-extinguishing efficiency, while fluoroprotein foam has the best burn-back performance. Flue gas and gas chromatography–mass spectrometer analyses demonstrate that the use of fluoroprotein foam results in much higher CO emissions than other foams, and the pollutants are mainly from various hydrocarbons produced by incomplete combustion of transformer oil. Synthetic foam and aqueous film-forming foam lead to higher SO2 and NO emissions, and pollutants are mainly dominated by alcohols and ethers. Noteworthily, when using aqueous film-forming foam to extinguish oil pool fire, a persistent organic pollutant, perfluorooctanoic acid, is detected in the gas phase.

Xiaonan Zhou,1,2,&ast; Kai Zhu,1,2,&ast; Yiqiu Zhang,3– 5,&ast; Yang Ming,1,2 Dai Shi,3– 5 Hui Tan,3– 5 Bitao Xiang,1,2 Shichao Zhu,1,2 Dengfeng Cheng,3– 5 Hao Lai,1,2 Chunsheng Wang,1,2 Guobing Liu3– 5 1Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 2Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, People’s Republic of China; 3Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 4Institute of Nuclear Medicine, Fudan University, Shanghai, 200032, People’s Republic of China; 5Shanghai Institute of Medical Imaging, Shanghai, 200032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guobing Liu, Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, No. 180 in Fenglin Road, Shanghai, 200032, People’s Republic of China, Tel +8618317086732, Fax +86-21-62489191, Email liu.guobing@zs-hospital.sh.cn Chunsheng Wang, Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, No. 180 in Fenglin Road, Shanghai, 200032, People’s Republic of China, Email wangchunsheng@fudan.edu.cnPurpose: To investigate the feasibility of a pre-targeted imaging strategy based on the cycloaddition between 1,2,4,5-terazine (Tz) and trans-cyclooctene (TCO) for evaluating CD11b expression in inflammatory aortic aneurysm (AA) using single photon emission computed tomography/computed tomography (SPECT/CT).Methods: C57BL/6J mice were fed β-aminopropionitrile (1 g/kg/day) for 4 weeks to establish AA models. Anti-CD11b-TCO was synthesized and 99mTc-HYNIC-PEG11-Tz was designed for pre-targeted SPECT/CT. The affinity and specificity of the probe for the inflammatory cell line Raw-264.7 were investigated. Then, anti-CD11b-TCO pre-targeted and 99mTc-HYNIC-PEG11-Tz based SPECT/CT were performed to detect in vivo inflammation in AA. Finally, ex vivo aortic breast-specific gamma imaging (BSGI), Western blot assays, and immunohistochemical CD11b staining were performed to confirm the in vivo findings of SPECT/CT.Results: In the AA models, 65.22% (15/23) had aortic lesions, including 43.48% (10/23) AA lesions. The anti-CD11b-TCO presented with a high TCO coupling ratio (7.43), and the 99mTc-HYNIC-PEG11-Tz showed high radio-purity (> 95%), good in vitro stability and a rapid clearance rate. Additionally, anti-CD11b-TCO and 99mTc-HYNIC-PEG11-Tz presented high click rate (∼ 89%). The in vitro clicked compound, 99mTc-HYNIC-PEG11-Tz/TCO-anti-CD11b, showed high affinity and specificity for Raw-264.7 cells. 99mTc-HYNIC-PEG11-Tz/TCO-anti-CD11b pre-targeting SPECT/CT successfully demonstrated inflammatory AA with a high AA-to-background ratio in AA mice, compared to AA mice that were injected with 99mTc-HYNIC-Tz/TCO-IgG (8.13 versus 3.71, P < 0.001) and control mice injected with 99mTc-HYNIC-Tz/TCO-anti-CD11b (8.13 versus 3.66, P < 0.001). This result was confirmed by ex vivo BSGI performed immediately after SPECT/CT and immunohistochemical CD11b staining.Conclusion: SPECT/CT imaging using the anti-CD11b-TCO/Tz-PEG11-HYNIC-99mTc based pre-targeting imaging strategy allows for the detection of inflammation in progressive AA.Keywords: aortic aneurysm, inflammation, SPECT/CT, CD11b, macrophage

Gastric cancer (GC) is a common cancer worldwide, with high incidence and mortality rates. Therefore, early and precise diagnosis is critical to improving GC prognosis. Tumor-associated myeloid cells infiltrate the tumor microenvironment (TME) and can produce immunosuppressive effects in the early stage of the tumor. The surface integrin receptor CD11b is widely expressed in the specific subsets of myeloid cells, and it has the characteristics of high abundance, high specificity, and high potential for targeted immunotherapy. In this study, two strategies for labeling anti-CD11b, including 89Zr-DFO-anti-CD11b and pretargeted imaging (68Ga-NOTA-polypeptide-PEG11-Tz/anti-CD11b-TCO), were used to evaluate the value of early diagnosis of GC and confirm the advantages of the pretargeted strategy for the diagnosis of GC. Pretargeted molecular probe 68Ga-NOTA-polypeptide-PEG11-Tz was synthesized. The binding affinity of the Tz-radioligand to CD11b was evaluated in vitro, and its blood pharmacokinetic test was performed in vivo. Moreover, the anti-CD11b antibody was conjugated with a p-isothiocyanatobenzyl-desferrioxamine (SCN-DFO) chelator and radiolabeled with zirconium-89. Biodistribution and positron-emission computed tomography imaging experiments were performed in MGC-803 tumor-bearing model mice to evaluate the value of the early diagnosis of GC. Histological evaluation of MGC-803 tumors was conducted to confirm the infiltration of the GC TME with CD11b+ myeloid cells. 68Ga-NOTA-polypeptide-PEG11-Tz was successfully radiosynthesized, with the radiochemical purity above 95%, as confirmed by reversed-phase high-performance liquid chromatography. The radioligand showed favorable stability in normal saline and phosphate-buffered saline, good affinity to RAW264.7 cells, and rapid blood clearance in mice. The results of biodistribution and imaging experiments using the pretargeted method showed that the tumor/muscle ratios were 5.17 ± 2.98, 5.94 ± 1.46, and 4.46 ± 2.73 at the pretargeting intervals of 24, 48, and 72 h, respectively. The experimental results using the method of the directly labeling antibody (89Zr-DFO-anti-CD11b) showed that, despite radioactive accumulation in the tumor, there was a higher level of radioactive accumulation in normal tissues. The tumor/muscle ratios were 1.09 ± 0.67, 1.66 ± 0.95, 2.94 ± 1.24, 3.64 ± 1.21, and 3.55 ± 1.64 at 1, 24, 48, 72, and 120 h. The current research proved the value of 68Ga-NOTA-polypeptide-PEG11-Tz/anti-CD11b-TCO in the diagnosis of GC using the pretargeted strategy. Compared to 89Zr-DFO-anti-CD11b, the image contrast achieved by the pretargeted strategy was relatively improved, and the background accumulation of the probe was relatively low. These advantages can improve the diagnostic efficiency for GC and provide supporting evidence for radioimmunotherapy targeting CD11b receptors.

The objective was to dynamically monitor the progression of atherosclerotic plaques in ApoE−/− mice with 18F–NaF PET imaging. The ApoE−/− mice were used to develop atherosclerosis models, and the C57BL/6 J mice were used as control. 18F–NaF PET was performed when the mice were 12, 20, and 30 weeks of age. Serum lipids and lipoproteins profiles, inflammatory cytokines, and calcification factors were tested by ELISA. The lipid distribution, morphology, and calcification of plaque were evaluated by Oil Red O, HE, and alizarin red staining. The correlation between imaging and the extent of calcification was analyzed by Pearson correlation analysis. The uptake of 18F–NaF in the aorta was gradually increased with each weekly extension. Compared with the ApoE−/− mice at the age of 12 weeks and 20 weeks, the levels of lipoprotein, inflammatory cytokines, and calcification factors were higher at 30 weeks. In Oil Red O, HE, and alizarin red staining, the extent of the lipid area and calcification increased with time. The correlation analysis showed that the uptake of 18F–NaF in the aorta was related to the extent of calcification. 18F–NaF may dynamically monitor the progression of atherosclerotic plaques and ongoing microcalcification formation.

This study aimed to dynamically monitor myocardial cell death using 99m Tc-Duramycin single-photon emission computed tomography/computed tomography (micro-SPECT/CT) imaging in acute myocardial infarction (AMI) and the anti-apoptosis effect of atorvastatin for cardioprotection. Mice were randomized into three groups: AMI group, AMI with atorvastatin treatment (T-AMI) group, and sham group. Three groups of model mice were randomly selected at day 1 (D1), day 3 (D3), and day 7 (D7) day after surgery with 99m Tc-Duramycin micro-SPECT/CT imaging. The lesion-to-normal myocardial tissue ratio (L/N) average values were 2.62 on D1, 3.89 on D3, and 1.20 on D7 for the uptake of 99m Tc-duramycin in the infarcted region in the AMI group. The sham group presented no positive imaging in myocardium, and the L/N average values were 1.09, 1.14, and 1.10 on D1, D3, and D7, respectively. Meanwhile, 99m Tc-linear-duramycin imaging showed no radioactive uptake in the infarction region. The T-AMI group imaging showed tracer uptake decreased obviously compared to the uptake in the infarcted region in AMI mice. 99m Tc-Duramycin SPECT/CT imaging allowed non-invasive monitoring of myocardial cell death in a mouse model of AMI and an assessment of atorvastatin anti-apoptosis effect for cardioprotection by in vivo molecular imaging.

Programmed cell death-ligand 1 (PD-L1) is expressed on tumor cells (TC) and tumor-infiltrating immune cells (IC). We conducted a retrospective study to investigate the relationship between PD-L1 expression on TC/IC and 18F-FDG uptake in patients with surgically resected non-small cell lung cancer (NSCLC). Total 362 NSCLC patients (297 adenocarcinoma and 65 squamous cell carcinoma) who underwent preoperative 18F-FDG-PET/CT imaging were analyzed retrospectively. Immunohistochemistry analysis was performed for PD-L1 expression on TC and IC in NSCLC specimens with 28–8 antibody. The cut-off value of 5% for defining PD-L1 positivity was determined according to previous trials. The association between PD-L1 expression and clinicopathological variables were analyzed, including age, gender, smoking status, tumor diameter, lymph node metastasis, stage and the maximum standardized uptake value (SUVmax). PD-L1 positive expression was 50.8% (184/362) in NSCLC patients. Its positive expression on TC and IC were 24.3% (88/362) and 42.5% (154/362), respectively. SUVmax was significantly higher in patients with PD-L1 positive expression on TC or IC than that with negative. Multivariate analysis demonstrated that PD-L1 expression were correlated with SUVmax. The best cut-off value of SUVmax for PD-L1 expression on TC/IC was 8.5 [area under the curve (AUC) = 0.607, 95% CI 0.549–0.665, P = 0.001, sensitivity 50.5% and specificity 71.4%] determined by ROC curve. High SUVmax is linked to PD-L1 expression on TC and IC in our patients with surgically resected non-small cell lung cancer. 18F-FDG-PET/CT imaging may be used to predict the PD-L1 expression on TC and IC in NSCLC patients.

Objective The uptake of F-fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) is known to be linked to programmed death ligand 1 (PD-L1) expression on tumor cells (TC). However, the association between PD-L1 expression on immune cells (IC) and F-FDG accumulation is still unclear. Here, we conducted a clinicopathological study to investigate the relationship between PD-L1 expression on TC/IC and F-FDG uptake in patients with surgically resected pulmonary adenocarcinoma (ADC). Methods A total of 450 ADC patients who underwent preoperative F-FDG-PET/CT imaging were analyzed retrospectively. Immunohistochemistry analysis was performed for PD-L1 expression on TC and IC in ADC specimens with SP142. PD-L1 expression was performed on whole-tissue sections and given scores (0/1/2/3) according to percent of PD-L1 cells in TC and IC. Results Compared to TC0 and IC0, PD-L1 positive expression was 90.4% (407/450) in ADC specimens. Both PD-L1 expression score on TC and IC were associated with maximum standardized uptake (SUVmax). SUVmax augmented with increasing PD-L1 expression (TC0 and IC0, 4.3 ± 3.4; TC or IC1/2/3, 7.7 ± 5.6; TC or IC2/3, 8.1 ± 5.6; TC or IC3, 8.4 ± 5.4). The best cut-off value of PD-L1 expression, determined by receiver operating characteristic curve, was 5.1 for TC or IC1/2/3 [area under the curve (AUC) = 0.713, sensitivity 62.2%, specificity 72.1%]. Multivariate analysis demonstrated that TC or IC1/2/3 subset was correlated with histological subtype, PD-1 expression on IC and SUVmax. Conclusion High SUVmax is associated with PD-L1 expression on TC and IC in surgically resected pulmonary ADC. F-FDG-PET/CT imaging can be a potential tool to evaluate PD-L1 expression in pulmonary ADC.

Gastric cancer (GC) is a common cancer worldwide, with high incidence and mortality rates. Therefore, early and precise diagnosis is critical to improving GC prognosis. Tumor-associated myeloid cells infiltrate the tumor microenvironment (TME) and can produce immunosuppressive effects in the early stage of the tumor. The surface integrin receptor CD11b is widely expressed in the specific subsets of myeloid cells, and it has the characteristics of high abundance, high specificity, and high potential for targeted immunotherapy. In this study, two strategies for labeling anti-CD11b, including

P2X7 receptors have been considered as a promising biomarker for vulnerable atherosclerotic plaques, which are highly expressed by that instability-associated factors such as macrophages. Thus, we aim to investigate the feasibility of using specific P2X7-targetedThe radioligandWe innovatively apply a new type P2X7-targeted PET probe (

This study is aimed at investigating the feasibility of cetuximab (Cet) F(ab')Cet-F(ab')HT29 cells had low EGFR expression while MGC803 cell exhibited the high EGFR expression. Cet-F(ab')SPECT/CT imaging using

Mutations in isocitrate dehydrogenase 1 (IDH1) are commonly found in various human malignancies. Inhibitors of several mutant IDH1 enzymes have entered clinical trials as target therapeutic drugs for the treatment of patients with IDH1 mutations. Herein, we report the synthesis and evaluation of two

The discharge current of propagating lightning leaders is critical to understand lightning physics and to design lightning protection systems but almost impossible to be measured directly with present-day technology. In this paper, we have investigated the relationship between luminosity and discharge current of propagating positive leaders in laboratory high voltage atmospheric discharges. The continuously propagating positive leader channels were recorded by high-speed video frames. The brightness distribution of the propagating positive leader channel, which was evaluated by the gray value across the central line, obeyed a normal distribution. The mean grayscale pixel value of the propagating positive leader channel central lines obtained in high-speed video frames was compared with the average discharge current measured in the exposure duration of corresponding frames. There is a statistically significant linearity correlation between the discharge current and the channel luminosity of the propagating positive leader. The result further suggests a potential that the discharge current of propagating positive lightning leaders may be obtained based on the optical information observed in the time domain.

Objectives: The epidermal growth factor receptor (EGFR) signaling pathway is widely recognized to play an important role in development and progression of many malignant tumors, including ...

The exceptional speed and biorthogonality of the inverse electron-demand Diels–Alder (IEDDA) click chemistry between 1,2,4,5-tetrazines and strained alkene dienophiles have made it promising in the realm of pretargeted imaging and therapy. During the past 10 years, the IEDDA-pretargeted strategies have been tested and have already proven capable of producing images with high tumor-to-background ratios and improving therapeutic effect. This review will focus on recent applications of click chemistry ligations in the pretargeted imaging studies of single photon emission computed tomography (SPECT), positron emission tomography (PET), and pretargeted radioimmunotherapy investigations. Additionally, the influence factors of stability, reactivity, and pharmacokinetic properties of TCO tag modified immunoconjugates and radiolabeled Tz derivatives were also summarized in this article, which should be carefully considered in the system design in order to develop a successful pretargeted methodology. We hope that this review will not only equip readers with a knowledge of pretargeted methodology based on IEDDA click chemistry but also inspire synthetic chemists and radiochemists to develop pretargeted radiopharmaceutical components in a more innovative way with various influence factors considered.

Inflammation is a defense reaction produced by the body to protect against pathogenic factors, whereas the persistent state of inflammation or excessive inflammatory response is the pathological basis of many afflictions. As the main type of activated inflammatory cells in the inflammatory environment, macrophages exert great influence on the outcome of inflammation. For example, “M1” macrophages play a role in promoting inflammation and inhibiting cell proliferation, while “M2” macrophages have an anti-inflammatory effect, promoting cell proliferation and tissue repair. Therefore, correctly identifying macrophage subtypes can help clinical diagnosis and treatment. Positron emission tomography (PET) imaging can be used to recognize macrophages in vivo at the molecular level using various positron nuclides called markers, thereby enabling early diagnosis, prognostic evaluation, and therapeutic efficacy judgment of inflammatory diseases, as well as the development of possible treatment plans. Currently, PET imaging agents that target macrophages can be roughly classified into metabolic, enzyme, cytokine, and receptor imaging agents. However, the first three types of imaging agents have not shown good macrophage specificity and have certain limitations in distinguishing macrophage subtypes. Take metabolic imaging agents, 18F-FDG, as an example. Although activated macrophage cells present high uptake of 18F-FDG, 18F-FDG is still not a specific macrophages-target imaging agent, as its uptake is high in many activated immune cells and other proliferating cell resulting in high non-specific background radioactivity and dramatically lower the diagnostic accuracy. Besides, 18F-FDG, as a non-specific imaging agent, is oftentimes influenced by varying conditions, thereby producing false positive results when used for inflammatory cell imaging. Thus, there is a need to develop specific agents for inflammation imaging. Since macrophages have many characteristic proteins on their surface, different macrophage subtypes exhibit characteristic protein expression. Therefore, the development of radioactive molecular probes for these characteristic receptor proteins will benefit macrophage-specific imaging. Transporter-18 kD (TSPO) is currently the most widely studied macrophage-specific imaging target. However, due to the genetic polymorphism of TSPO, different TSPO PET imaging agents exhibit different TSPO binding affinities. In addition, regardless of macrophages’ polarization (pro- or anti-inflammatory state), activated macrophages display similar TSPO expression. These shortcomings limit the potential interest in TSPO. However, limitations of the TSPO have led to the identification of other molecular targets to develop new tracers of activated macrophages, and there are a lot of specific receptors have been proposed so far. Therefore, in this review, we survey alternative biological targets of recent interest in macrophage activation imaging, including purinergic receptor P2X7, cannabinoid receptors, chemokine receptors, folate receptor β, mannose receptors, adenosine 2A receptor, and others, and examine the potential of these imaging molecular targets in the activation of macrophage expression. In addition, we describe promising PET imaging agents for these targets.

Purpose To explore the feasibility of a low dose regimen with short acquisition time of 68Ga-DOTATATE total-body PET/CT without compromising image quality of patients with NETs. Methods Fifty-seven consecutive NETs patients who underwent 68Ga-DOTATATE total-body PET/CT, with a low dose regimen (0.8-1.2 MBq/kg) of 68Ga-DOTATATE and acquisition time of 10 min prior to any treatment, were enrolled in the present study. The PET data were split into 1 min, 2 min, 3 min, 4 min, 5 min, 8 min and 10 min reconstruction groups, referenced as R1, R2, R3, R4, R5, R8 and R10. The subjective evaluation of image quality was scored in 5-point Likert scale based on three aspects: the overall impression of the image quality, the image noise, the lesion detectability. The objective image quality was assessed by the signal-to-noise ratio of liver (SNRL), the coefficient of variation (CV), the SUVmax, SUVmean, SD of liver, mediastinal blood pool and lesion, the tumor-liver ratio (TLR), the tumor-mediastinal blood pool-ratio (TMR) of lesion. Results The sufficient subjective image quality with a score of 3.44±0.53 could be obtained at 3 min acquisition duration, with a kappa value of 0.90. In quantitative analysis, the value of SNRL is over 10 in all reconstruction groups. As the acquisition time increases, SNRL was increased and CV was decreased within 3 min, while SNRL and CV showed no significant different between R4-R10. There was no significant different in TMR and TLR of lesion between R1-R10 (all p < 0.05). Referenced as PET images of R10, 90 SSTR-positive lesions are identified, and all those lesions are found in the R1-R10 groups (100%).Conclusion The low-dose (0.8-1.2 MBq/kg) 68Ga-DOTATATE total-body PET/CT not only shortens acquisition time, but maintains a sufficient image quality for the NETs patients.

The most important physics underlying lightning is the leader discharge. The presence or absence of space stems/leaders in leader steps is the key to the polarity asymmetry of leaders, which describes the difference in macroscopic behavior between positive and negative leaders and is a long-term consensus among lightning physicists. It is generally believed that negative leader steps are led by space stem, and there is no space stem/leader in positive leader discharges. Here we report the emergence of the space stem and the bidirectional development of the space leader in positive leader steps in moist air, using a high-speed camera with unprecedented spatial-temporal resolution. The lifetime of space stem/leader in positive leader steps is shorter than that in negative leader steps, causing the uncover of space stem/leader in previous studies. The bidirectional development of space leaders in positive leader steps may be an important source for VHF radiations, illuminating insight into the outstanding problem that how positive lightning leaders produce VHF radiation.

Ferritins are spherical iron storage proteins within cells, composed of 24 subunits of two types, heavy-chain ferritin (HFn) and light-chain ferritin. Ferritins auto-assemble naturally into hollow nanocages with an outer diameter of 12 nm and an interior cavity 8 nm in diameter. Since the intrinsic tumor-targeting property of human HFn was first reported in 2012, HFn has been extensively explored for tumor-targeted delivery of anticancer drugs and diagnostic molecules, including radioisotopes and fluorophores, as well as inorganic nanoparticles (NPs) and chemotherapeutic drugs. This protocol provides four detailed procedures describing how to load four types of cargoes within HFn nanocages that are capable of accurately controlling cargo loading: synthesis of inorganic metal nanoparticles within the cavity of a wild-type human HFn nanocage (Procedure 1, requires ~5 h); loading of doxorubicin into the cavity of a wild-type human HFn nanocage (Procedure 2, requires ~3 d); loading Gd3+ into the cavity of a genetically engineered human HFn nanocage (Procedure 3, requires ~20 h); and loading 64Cu2+ radioisotope into the cavity of a genetically engineered human HFn nanocage (Procedure 4, requires ~3 h). Subsequent use of these HFn-based formulations is advantageous as they have intrinsic tumor-targeting capability and lack immunogenicity. Human HFn generated as described in this protocol can therefore be used to deliver therapeutic drugs and diagnostic signals as multifunctional nanomedicines.

Objectives The aim of the study was to summarize the features of immunoglobulin G4-related lung disease (IgG4-RLD) on fluorine 18-fluorodeoxyglucose (F-FDG) PET/computed tomography (CT). Methods In this retrospective case series, 12 consecutive patients (9 men and 3 women, mean age 55.4 ± 13.7 years) with IgG4-RLD were included. The clinicopathological information and features of F-FDG PET/CT imaging were analyzed. Results Six (50%) patients had pulmonary involvement alone and six (50%) patients had extrapulmonary involvement with intense F-FDG uptake. Pulmonary manifestations included mass (25%, 3/12), solid nodule (solitary 25%, 3/12; multiple 50%, 6/12), multiple ground-glass opacities (GGOs) (50%, 6/12), thickening of alveolar interstitium (50%, 6/12), and thickening of bronchovascular bundle (33.3%, 4/12). The maximum standardized uptake value (SUVmax) of the solid nodules and masses, multiple GGOs, bronchovascular bundle and the thickening of septa was 4.0 ± 2.5, 2.3 ± 1.8, 1.4 ± 0.6, and 0.9 ± 0.5, respectively. The SUVmax statistically significant linear association with the diameter of masses or solid nodules (P value = 0.03), but no significant inverse linear association (P value = 0.06) with the concentration of serum IgG4 concentration. Conclusions The image patterns of IgG4-RLD on F-FDG PET/CT are varying. Multiple pulmonary manifestations or multiple organ involvement, especially in combination with elevated levels of serum IgG and IgG4, may help to make the diagnosis. A potential major application of PET-CT would be evaluation of response to treatment, and the impact of PET/CT on IgG4-RLD management is worth investigating further in the future.

Previously, we successfully developed a pretargeted imaging strategy (atezolizumab-TCO/[99mTc]HYNIC-PEG11-Tz) for evaluating programmed cell death ligand-1 (PD-L1) expression in xenograft mice. However, the surplus unclicked [99mTc]HYNIC-PEG11-Tz is cleared somewhat sluggishly through the intestines, which is not ideal for colorectal cancer (CRC) imaging. To shift the excretion of the Tz-radioligand to the renal system, we developed a novel Tz-radioligand by adding a polypeptide linker between HYNIC and PEG11. Pretargeted molecular probes [99mTc]HYNIC-polypeptide-PEG11-Tz and cetuximab-TCO were synthesized. [99mTc]HYNIC-polypeptide-PEG11-Tz was evaluated for in vitro stability and in vivo blood pharmacokinetics. In vitro ligation reactivity of [99mTc]HYNIC-polypeptide-PEG11-Tz towards cetuximab-TCO was also tested. Biodistribution assay and imaging of [99mTc]HYNIC-polypeptide-PEG11-Tz were performed to observe its excretion pathway. Pretargeted biodistribution was measured at three different accumulation intervals to determine the optimal pretargeted interval time. Pretargeted (cetuximab-TCO 48 h/[99mTc]HYNIC-PEG11-Tz 6 h) and (cetuximab-TCO 48 h/[99mTc]HYNIC-Polypeptide-PEG11-Tz 6 h) imagings were compared to examine the effect of the excretion pathway on tumor imaging. [99mTc]HYNIC-polypeptide-PEG11-Tz showed favorable in vitro stability and rapid blood clearance in mice. SEC-HPLC revealed almost complete reaction between cetuximab-TCO and [99mTc]HYNIC-polypeptide-PEG11-Tz in vitro, with the 8:1 Tz-to-mAb reaction providing a conversion yield of 87.83 ± 3.27 %. Biodistribution and imaging analyses showed that the Tz-radioligand was cleared through the kidneys. After 24, 48, and 72 h of accumulation in HCT116 tumor, the tumor-to-blood ratio of cetuximab-TCO was 0.83 ± 0.13, 1.40 ± 0.31, and 1.15 ± 0.21, respectively. Both pretargeted (cetuximab-TCO 48 h/[99mTc]HYNIC-PEG11-Tz 6 h) and (cetuximab-TCO 48 h/[99mTc]HYNIC-polypeptide-PEG11-Tz 6 h) clearly delineated HCT116 tumor. Pretargeted imaging strategy using cetuximab-TCO/[99mTc]HYNIC-polypeptide-PEG11-Tz could be used for diagnosing CRC, as the surplus unclicked [99mTc]HYNIC-polypeptide-PEG11-Tz was cleared through the urinary system, leading to low abdominal uptake background. Our novel pretargeted imaging strategy (cetuximab-TCO/[99mTc]HYNIC-polypeptide-PEG11-Tz) was useful for imaging CRC, broadening the application scope of pretargeted imaging strategy. The pretargeted imaging strategy clearly delineated HCT116 tumor, showing that its use could be extended to selection of internalizing antibodies.

c-MET-positive NSCLC is an important subtype accounting for about 5%~22% of lung cancer. NSCLC patients with activating c-MET are intensively sensitive to c-MET selective receptor tyrosine kinase (RTK) inhibitors, so we aimed to develop a specific PET probe targeting to c-MET-positive NSCLC for potential patients screened by PET/CT. Herein, PET tracer

Objective: Previously, we successfully developed a 6-hydrazinonicotinic acid (HYNIC)-modified terazine (Tz) derivative (HYNIC-PEG11-Tz) and labeled with Technetium-99m (99mTc) with a high radiochemical purity. The pretargeted imaging strategy using Atezolizumab-TCO/99mTc-HYNIC-PEG11-Tz is a powerful tool for evaluating Programmed Cell Death Ligand-1 (PD-L1) expression in xenograft mice tumor models. However, the surplus unclicked 99mTc-HYNIC-PEG11-Tz is cleared somewhat sluggishly through the intestines. This is certainly not an ideal situation for imaging for abdominal tumors, especially for colorectal cancer. In order to shift the excretion of the Tz-radioligand to the renal system, we have sought to develop a novel Tz-radioligand by add a polypeptide linker between HYNIC and PEG11. Methods: A polypeptide-modified Tz (HYNIC-Polypeptide-PEG11-Tz) was synthesized and radiolabeled with 99mTc, and the Cetuximab was covalently modified with transcyclooctene (TCO-NHS). The stability of 99mTc-HYNIC-Polypeptide-PEG11-Tz was evaluated in vitro, and its blood pharmacokinetic test was performed in vivo. Determination of the n-octanol/PBS distribution coefficient was performed on 99mTc-HYNIC-PEG11-Tz and 99mTc-HYNIC-Polypeptide-PEG11-Tz to determine the effect of linker modification on their hydrophobicity. In vitro ligation reactivity of 99mTc-HYNIC-Polypeptide-PEG11-Tz towards Cetuximab-TCO was tested. Pretargeted HCT116 cell immunoreactivity binding assay was evaluated. The biodistribution and imaging of 99mTc-HYNIC-Polypeptide-PEG11-Tz was performed to observe the clear pathway of this novel Tz-radioligand. Pretargeted biodistribution of three different accumulation intervals (24 h, 48 h, and 72 h) was performed to determine the optimal pretargeted interval time in nude mice bearing HCT116 tumor xenografts. Comparison of pretargeted (Cetuximab-TCO 48h/99mTc-HYNIC-PEG11-Tz 6h) and (Cetuximab-TCO 48h/ 99mTc-HYNIC-Polypeptide-PEG11-Tz 6h) imaging was performed to show the effect of the two Tz-radioligands with different excretion pathway on tumor imaging. Results: HYNIC-Polypeptide-PEG11-Tz was successfully radiosynthesized with 99mTc, and a radiochemical purity greater than 95% were obtained as confirmed by radio high-performance liquid chromatography (HPLC). 99mTc-HYNIC-Polypeptide-PEG11-Tz showed favorable stability in NS, PBS, and FBS and rapid blood clearance in mice. Liquid chromatograph-mass spectrometer (LC-MS) indicated the presence of an average 8.1 TCO moieties per Cetuximab. Size exclusion HPLC revealed almost complete reaction between Cetuximab-TCO and 99mTc-HYNIC-Polypeptide-PEG11-Tz in vitro, with the 8:1 Tz-to-mAb reaction providing a conversion yield of 87.83±3.27%. Pretargeted cell immunoreactivity binding assay showed high affinity to HCT116 cells. The biodistribution and imaging of 99mTc-HYNIC-Polypeptide-PEG11-Tz demonstrated that the Tz-radioligand was cleared through kidneys. After allowing 24h, 48h and 72h for accumulation of Cetuximab-TCO in HCT116 tumor, pretargeted biodistribution revealed an uptake of the radiotracer in the tumor with tumor-to-blood ratio of 0.83, 1.40, and 1.15, respectively. Both pretargeted (Cetuximab-TCO 48h/99mTc-HYNIC-PEG11-Tz 6h) and (Cetuximab-TCO 48h/ 99mTc-HYNIC-Polypeptide-PEG11-Tz 6h) imaging delineated the HCT116 tumor clearly. However, pretargeted imaging strategy using Cetuximab-TCO 48h/99mTc-HYNIC-Polypeptide-PEG11-Tz 6h) could be used for diagnosing colorectal cancer since the surplus unclicked 99mTc-HYNIC-Polypeptide-PEG11-Tz is cleared through urinary system and produces low abdominal uptake background. Conclusion: We developed a novel pretargeted imaging strategy (Cetuximab-TCO/99mTc-HYNIC-Polypeptide-PEG11-Tz) for imaging colorectal cancer since the surplus unclicked 99mTc-HYNIC-Polypeptide-PEG11-Tz produces low abdominal uptake background, which broadens the application scope of pretargeted imaging strategy.

Background: The objective of this study was to evaluate the feasibility of dynamic monitoring of myocardial cell death using 99m Tc-Duramycin single photon emission computed tomography/computed tomography (micro-SPECT/CT) imaging in a mouse model of acute myocardial infarction, and the anti-apoptosis effect of atorvastatin for cardio protection. Methods: Forty-five male Kunming mice were randomized into three groups: acute myocardial infarction (AMI) group, acute myocardial infarction with atorvastatin treatment (T-AMI) group, and the sham group. The mice of the AMI group and T-AMI group were subjected left coronary artery ligation. The T-AMI group was orally administered with atorvastatin 20 mg/ (kg day) 24 h before the surgery, the other two groups received only saline. Three groups of model mice were randomly selected at day 1 (D1), day 3 (D3), and day 7 (D7) day after surgery with 99m Tc-Duramycin micro-SPECT/CT imaging. Transthoracic echocardiography test was performed at D3 and D7 after surgery. The pathological evaluation, TUNEL assay and Western blot analysis were performed on heart specimens on D1, D3 and D7. Results: For up-taking of 99m Tc-duramycin in infarcted region, the mean value of semi-quantitative of AMI group were 2.62 on D1, 3.89 on D3 and 1.20 on D7. And for the T-AMI group, the mean value of semi-quantitative were 2.20 on D1, 2.97 on D3 and 1.30 on D7. The sham group had no positive imaging in myocardium, the mean value of semi-quantitative were 1.09, 1.14 and 1.10 on D1, D3 and D7, respectively. Meanwhile, 99m Tc-linear-duramycin imaging as control showed that there’s no radioactive uptake in the area of infarction region. But the T-AMI group imaging showed the tracer uptake decreased obviously compared to the uptake of AMI mice in infarcted region (L/N: 2.2 versus 2.62; 2.97 versus 3.89) on D3 and D7. LVEF was significantly reduced on D3 (42.67±2.51%) and D7 (27.71±2.52%) compared with the sham group (71.00±2.65%). The number of TUNEL positive cells decreased significantly on D3 (37.00±3.01 vs 51.00±3.61) and D7 (21.67±2.08 vs 27.65±2.51) post-MI after atorvastatin treatment. Additionally, the atorvastatin increased the expression level of anti-apoptotic protein BCL-2 and decreased the expression level of pro-apoptotic protein BAX. Conclusions: 99m Tc-Duramycin SPECT/CT imaging allowed to the non-invasively monitoring of myocardial cell death in a mouse model of acute myocardial infarction. Furthermore, this investigation and analysis could be used to assess and verify the anti-apoptosis effect of atorvastatin for cardio protection by in-vivo molecular imaging.

Objective A novel 99m Tc-tricine-EDDA-Hynic-c-Met molecular probe was synthetized, and nude mice models of human non-small-cell lung cancer (NSCLC) were established in order to preliminarily investigate that whether the molecular probe can be used to screen c-Met inhibitor for targeted drug therapy in NSCLC. Methods With Hynic as the chelating agent, 99m TcO4 -labeled c-Met receptor was used to synthetize 99m Tc-tricine-EDDA-HYNIC-c-Met. Two nude mice successfully transplanted with H1993 tumor and two nude mice transplanted with H292 tumor were injected with 99m Tc-tricine-EDDA-HYNIC-c-Met through the tail vein. After 2 and 4 hr, micro-SPECT/CT imaging was performed. Results micro-SPECT/CT imaging of nude mice transplanted with H1993 and H292 tumors using 99m Tc-tricine-EDDA-HYNIC-c-Met showed that uptake of 99m Tc-tricine-EDDA-HYNIC-c-Met was high in H1993 tumor, while it was mild in H292 tumor both at 2 and 4 hr postinjection. Semiquantitative analysis of the ratio of radioactivity intensity at tumor site to radioactivity intensity of adjacent muscles (T/N value) showed that the average T/N value of H1993 and H292 tumors at 2 hr was 3.90 and 2.85, while it was 4.88 and 2.36 at 4 hr. Conclusion micro-SPECT/CT imaging through 99m Tc-tricine-EDDA-HYNIC-c-Met can be used to screen c-Met indicators of NSCLC in H1993 nude mice models for targeted drug therapy.

Objective Vesicular acetylcholine transporter (VAChT) is a rate-limiting factor for synaptic acetylcholine transport. Our study focused on whether [18 F] VAT, a novel positron emission tomography (PET) tracer, could be used in detecting cognitive deficits in epilepsy. Methods Morris water maze test was used to evaluate learning and memory deficits in pilocarpine-induced chronic epilepsy rats 12 weeks after status epilepticus. Interictal [18 F] VAT PET was performed 13 weeks after status epilepticus to evaluate the level of VAChT in cholinergic pathways compared with [18 F] fluorodeoxyglucose PET. The association between VAChT levels and memory measures was analyzed. Neuropathological tests were performed. Results Epileptic rats exhibited significant memory deficits in Morris water maze test. [18 F] VAT uptake decreased in septum, hippocampus, thalamus, and basal forebrain, and correlated to memory function. Of note, the level of VAChT in basal forebrain significantly decreased, yet no glucose hypometabolism was detected. Immunofluorescence and Western blot demonstrated decreased expression of VAChT in hippocampus and basal forebrain in the epilepsy group, but no change of expression of acetyltransferase or activity of acetylcholinesterase was detected. Significance [18 F] VAT PET is a promising method to test the level of VAChT as a valuable biomarker for memory deficits in pilocarpine-induced chronic epileptic rats.

Coronary artery disease (CAD) is a major cause of death worldwide. It is significantly important to assess the coronary lesion and its pathophysiological relevance comprehensively. Coronary computed tomography angiography (CTA) or myocardial perfusion imaging alone suffers from some limitations in the evaluation of CAD. Through the integration and spatial colocalization of complementary morphological and functional information, the results of published hybrid single-photon emission computed tomography (SPECT)/CTA studies in patients with CAD are promising for detecting functionally relevant coronary artery lesion and evaluating the relationship between diseased coronary artery, coronary artery anomaly, myocardial bridging, or coronary calcification and myocardial ischemia. Compared with other diagnostic procedures, such as CTA, myocardial perfusion imaging alone, and side-by-side SPECT-CTA analysis, SPECT/CTA imaging has incremental value in the evaluation of CAD. Hybrid SPECT/CTA imaging can provide the physicians with more clinical evidence that helps with the treatment strategy decision-making process, thus acting as a gatekeeper to reduce unnecessary invasive examinations and revascularization procedures. In addition, follow-up SPECT/CTA fusion imaging plays a role in predicting prognosis by displaying clearly the relationship between postoperative vessel and myocardial blood supply. However, several limitations should be considered, including the increased radiation exposure, the limited number of patients, and the lack of a uniform gold standard. More data are needed to better specify the role of hybrid SPECT/CTA imaging in the management of CAD.