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In the realm of combating acute lung injury (ALI) induced by a myriad of triggers including sepsis, pneumonia, aspiration, trauma, and pancreatitis, macrophages emerge as crucial players. However, traditional treatments such as systemic administration of glucocorticoids come with the baggage of severe side effects, curtailing their utility. Enter an innovative solution: a biomimetic drug delivery system fashioned from cryo-shocked macrophages, tailored for pulmonary drug delivery. Positron emission tomography (PET) imaging has shed light on the remarkable targeting abilities of live M1 macrophages, showcasing their unparalleled efficacy in homing in on local inflammatory foci when contrasted with naive, M1, and M2 macrophages. Building upon this foundation, liquid nitrogen-treated (LNT) M1 macrophages are developed, engineered to preserve their inflammation-targeting prowess while sidestepping the release of pro-inflammatory cytokines. This breakthrough allows for the delivery of glucocorticoids directly to inflamed lung tissues, efficiently quelling inflammation and mitigating pulmonary edema while drastically reducing systemic drug exposure. Inspired by the effectiveness of live M1 macrophages, the potential of glucocorticoid-loaded LNT M1 macrophages are harnessed, utilizing them as a stealthy "Trojan horse" in the battle against pneumonia-induced ALI. This innovative approach holds promise as a safe and potent treatment avenue for acute lung injury., (© 2024 Wiley‐VCH GmbH.)

Background: The human epidermal growth factor receptor 2 gene (HER2) has been identified as a potential therapeutic target in lung adenocarcinoma (LUAD). Non-invasive positron emission tomography (PET) imaging provides a reliable strategy for in vivo determination of HER2 expression through whole-body detection of abnormalities. The PET tracer 68 Ga-NOTA-MAL-Cys-MZHER 2:342 has shown promising results for HER2-positive breast and gastric cancers. This study aims to evaluate the performance of 68 Ga-NOTA-MAL-Cys-MZHER 2:342 in vitro and in vivo models and in clinical patients with HER2-positive LUAD., Methods: NOTA-MAL-Cys-MZHER 2:342 was synthesized and labeled with 68 Ga. Cell uptake, cell binding ability, and stability studies of 68 Ga-NOTA-MAL-Cys-MZHER 2:342 were assessed both in the Calu-3 lung cancer (LC) cell line and normal mice. In vivo assessment in tumor-bearing mice was conducted using microPET imaging and biodistribution experiments. Additionally, preliminary PET/CT imaging analysis was performed on HER2-positive LC patients., Results: 68 Ga-NOTA-MAL-Cys-MZHER 2:342 was prepared with a radiochemical purity (RCP) exceeding 95%. The tracer demonstrated high cell uptake in HER2-overexpressing Calu-3 cells, with an IC 50 of 158.9, an adequate 1.73 nM. Good stability was exhibited both in vitro and in vivo . MicroPET imaging of Calu-3-bearing mice revealed high tumor uptake and notable tumor-to-background ratios. Positive outcomes were also observed in two HER2-positive LUAD patients., Conclusion: 68 Ga-NOTA-MAL-Cys-MZHER 2:342 demonstrated satisfactory stability, sensitivity, and specificity. These findings suggest that 68 Ga-NOTA-MAL-Cys-MZHER 2:342 PET/CT imaging provides a novel tool for non-invasive visual assessment of HER2 expression in LUAD patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Wang, Zhu, Pan, Wang, Guo, Gao, Luo and Wang.)

Ocular complications of diabetes mellitus (DM) are the leading cause of vision loss. Ocular inflammation often occurs in the early stage of DM; however, there are no proven quantitative methods to evaluate the inflammatory status of eyes in DM. The 18 kDa translocator protein (TSPO) is an evolutionarily conserved cholesterol binding protein localized in the outer mitochondrial membrane. It is a biomarker of activated microglia/macrophages; however, its role in ocular inflammation is unclear. In this study, fluorine-18-DPA-714 ([ 18 F]-DPA-714) was evaluated as a specific TSPO probe by cell uptake, cell binding assays and micro positron emission tomography (microPET) imaging in both in vitro and in vivo models. Primary microglia/macrophages (PMs) extracted from the cornea, retina, choroid or sclera of neonatal rats with or without high glucose (50 mM) treatment were used as the in vitro model. Sprague-Dawley (SD) rats that received an intraperitoneal administration of streptozotocin (STZ, 60 mg/kg once) were used as the in vivo model. Increased cell uptake and high binding affinity of [ 18 F]-DPA-714 were observed in primary PMs under hyperglycemic stress. These findings were consistent with cellular morphological changes, cell activation, and TSPO up-regulation. [ 18 F]-DPA-714 PET imaging and biodistribution in the eyes of DM rats revealed that inflammation initiates in microglia/macrophages in the early stages (3 weeks and 6 weeks), corresponding with up-regulated TSPO levels. Thus, [ 18 F]-DPA-714 microPET imaging may be an effective approach for the early evaluation of ocular inflammation in DM., Competing Interests: Declaration of competing interest The authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Uveal melanoma (UM) is the most common primary intraocular tumor in adults, and early detection is critical to improve the clinical outcome of this disease. In this study, the diagnostic effectiveness of [ 18 F]AlF-NOTA-PRGD2 (an investigational medicinal product) positron emission tomography (PET) imaging in UM xenografts and UM patients were evaluated. The cell uptake, cell binding ability and in vitro stability of [ 18 F]AlF-NOTA-PRGD2 were evaluated in 92-1 UM cell line. MicroPET imaging and biodistribution study of [ 18 F]AlF-NOTA-PRGD2 were conducted in 92-1 UM xenografts. Then, UM patients were further recruited for evaluating the diagnostic effectiveness of [ 18 F]AlF-NOTA-PRGD2 PET imaging (approval no. NCT02441972 in clinicaltrials.gov). In addition, comparison of [ 18 F]AlF-NOTA-PRGD2 and 18 F-labelled fluorodeoxyglucose ([ 18 F]FDG) PET imaging in UM xenografts and UM patients were conducted., Results: The in vitro data showed that [ 18 F]AlF-NOTA-PRGD2 had a high cell uptake, cell binding ability and in vitro stability in 92-1 UM cell line. The in vivo data indicated that 92-1 UM tumors were clearly visualized with the [ 18 F]AlF-NOTA-PRGD2 tracer in the subcutaneous and ocular primary UM xenografts model at 60 min post-injection. And the tumor uptake of the tracer was 2.55 ± 0.44%ID/g and 1.73 ± 0.15%ID/g at these two tissue locations respectively, at 7 days after animal model construction. The clinical data showed that tumors in UM patients were clearly visualized with the [ 18 F]AlF-NOTA-PRGD2 tracer at 60 min post-injection. In addition, [ 18 F]AlF-NOTA-PRGD2 tracer showed higher sensitivity and specificity for PET imaging in UM xenografts and UM patients compared to [ 18 F]FDG tracer., Conclusion: [ 18 F]AlF-NOTA-PRGD2 PET imaging may be a more preferred approach in the diagnosis of primary UM compared to [ 18 F]FDG PET imaging. Additionally, due to the high tumor-to-background ratio, [ 18 F]AlF-NOTA-PRGD2 PET imaging seems also to be applicable for the diagnosis of UM patients with liver metastasis., Trial Registration: ClinicalTrials.gov: NCT02441972, Registered 1 January 2012, https://clinicaltrials.gov/study/NCT02441972 ., (© 2024. The Author(s).)

Fibrinogen-like protein 1 (FGL1) is a potential novel immune checkpoint target for malignant tumor diagnosis and therapy. Accurate detection of FGL1 levels in tumors via noninvasive PET imaging might be beneficial for managing the disease. To achieve this, multiple FGL1-targeting peptides (FGLP) were designed, and a promising candidate, 68 Ga-NOTA-FGLP2, was identified through a high-throughput screening approach using microPET imaging of 68 Ga-labeled peptides. Subsequent in vitro cell experiments showed that uptake values of 68 Ga-NOTA-FGLP2 in FGL1 positive Huh7 tumor cells were significantly higher than those in FGL1 negative U87 MG tumor cells. Further microPET imaging showed that the Huh7 xenografts were clearly visualized with a favorable contrast. ROI analysis showed that the uptake values of the tracer in Huh7 xenografts were 2.63 ± 0.07% ID/g at 30 min p.i.. After treatment with an excess of unlabeled FGLP2, the tumor uptake significantly decreased to 0.54 ± 0.05% ID/g at 30 min p.i.. Moreover, the uptake in U87 MG xenografts was 0.44 ± 0.06% ID/g at the same time point. The tracer was excreted mainly through the renal system. 18 F-FDG PET imaging was also performed in mice bearing Huh7 and U87 MG xenografts, respectively. However, there was no significant difference in the uptake between the tumors with different FGL1 expressions. Preclinical data indicated that 68 Ga-NOTA-FGLP2 might be a suitable radiotracer for in vivo noninvasive visualization of tumors with abundant expression of FGL1. Further investigation of 68 Ga-NOTA-FGLP2 for tumor diagnosis and therapy is undergoing.

Abstract: Uveal melanoma is the most common intraocular malignancy in adults with a high rate of metastasis and mortality. This study presented the PET/CT imaging of 18 F-AlF-NOTA-PRGD2 and 18 F-FDG in a patient with primary uveal melanoma. In addition to fundus photograph and ophthalmic ultrasonography, both 18 F-AlF-NOTA-PRGD2 and 18 F-FDG PET/CT imaging showed increased radioactive uptake in the lesions within the scan area. The tumoral lesions presented significantly higher uptake of 18 F-AlF-NOTA-PRGD2 compared with that of 18 F-FDG., Competing Interests: Conflicts of interest and sources of funding: none declared. This article was supported by the Project of Jiangsu Commission of Health (H2023150) and the Major Project of Wuxi Municipal Health Commission (Z202303)., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

An experimental study was carried out on a modified single-cylinder dual-fuel engine in reactivity-controlled compression ignition (RCCI) mode using pilot fuels with different physicochemical properties, and the effects of the pilot fuels and the two-stage injection strategy on the combustion and emission characteristics of the RCCI mode were explored. The results show that when coal-to-liquid (CTL) is used with a high cetane number as the pilot fuel, the reactivity stratification of the fuel-air mixture is more pronounced. With the advancement of pilot injection timing (SOI1), the heat release rate (HRR) of the CTL/gasoline mode gradually changes from a bimodal pattern to a unimodal pattern. Among them, the bimodal HRR includes CTL premixed combustion and gasoline flame propagation, as well as CTL diffused combustion and gasoline multipoint spontaneous combustion, while the unimodal HRR represents CTL premixed combustion and gasoline multipoint spontaneous combustion. However, the HRR of the fossil diesel/gasoline RCCI combustion mode always exhibits a unimodal form. With the advancement of the main injection timing (SOI2), the gravity center of heat release (CA50) is more advanced when using CTL as the pilot fuel due to the short ignition delay. Overall, compared to fossil diesel, using CTL as the pilot fuel is conducive to controlling the pressure rise rate, which expands the operating range of the RCCI combustion mode. Besides, for both pilot fuels of CTL and fossil diesel, the advancement of SOI1 lowers particle emissions, and the advancement of SOI2 reduces NOx emissions, while the two-stage injection achieves higher indicated thermal efficiency., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Noninvasive imaging of amyloid-β (Aβ) species in vivo is important for the early diagnosis of Alzheimer's disease (AD). In this paper, we report a near-infrared (NIR) fluorescence (FL) and positron emission tomography (PET) bimodal probe (NIR-[ 68 Ga]) for in vivo imaging of both soluble and insoluble Aβ species. NIR-[ 68 Ga] holds a high binding affinity, high selectivity and high sensitivity toward Aβ 42 monomers, oligomers, and aggregates in vitro . In vivo imaging results show that NIR-[ 68 Ga] can cross the blood-brain-barrier (BBB), and produce significantly higher PET and NIR FL bimodal signals in the brains of APP/PS1 transgenic AD mice relative to that of age-matched wild-type mice, which are also validated by the ex vivo autoradiography and histological staining images. Our results demonstrate that NIR-[ 68 Ga] is an efficient NIR FL and PET bimodal probe for the sensitive imaging of soluble and insoluble Aβ species in AD mice.

Advanced chemotherapeutic strategies including prodrug and nanocatalytic medicine have significantly advanced tumor-selective theranostics, but delicate prodrug screening, tedious synthesis, low degradability/biocompatibility of inorganic components, and unsatisfied reaction activity complicate treatment efficacies. Here, the intrinsic anticancer bioactivity of liquid metal nanodroplets (LMNDs) is explored through galvanic replacement. By utilizing a mechano-degradable ligand, the resultant size of the aqueous LMND is unexpectedly controlled as small as ≈20 nm (LMND20). It is demonstrated that LMND20 presents excellent tumor penetration and biocompatibility and activates tumor-selective carrier-to-drug conversion, synchronously depleting Cu 2+ ions and producing Ga 3+ ions through galvanic replacement. Together with abundant generation of reactive oxygen species, multiple anticancer pathways lead to selective apoptosis and anti-angiogenesis of breast cancer cells. Compared to the preclinical/clinical anticancer drugs of tetrathiomolybdate and Ga(NO 3 ) 3 , LMND20 administration significantly improves the therapeutic efficacy and survival in a BCap-37 xenograft mouse model, yet without obvious side effects., (© 2023 Wiley-VCH GmbH.)

The use of radiolabeled cells for positron emission tomography (PET) imaging tracking has been a promising approach for monitoring cell-based therapies. However, the presence of free radionuclides released from dead cells during tracking can interfere with the signal from living cells, leading to inaccurate results. In this study, the effectiveness of the iron chelators deferoxamine (DFO) and deferiprone in removing free radionuclides 89 Zr and 68 Ga, respectively, was demonstrated in vivo utilizing PET imaging. The use of DFO during PET imaging tracking of 89 Zr-labeled mesenchymal stem cells (MSCs) significantly reduced uptake in bone while preserving uptake in major organs, resulting in more accurate and reliable tracking. Furthermore, the clearance of free 89 Zr in vivo resulted in a significant reduction in radiation dose from 89 Zr-labeled MSCs. Additionally, the avoidance of free radionuclide accumulation in bone allowed for more precise observation of the homing process and persistence during bone marrow transplantation. The efficacy and safety of this solution suggest this finding has potential for widespread use in imaging tracking studies involving various cells. Moreover, since this method employed iron chelator drugs in clinical use, which makes it is a good prospect for clinical translation., Competing Interests: Author Jing Wang is a deputy director in Jiangsu Renocell Biotech Co., Ltd. The other authors have no conflicts of interest to declare., (© 2024 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)

Background: The chicken chorioallantoic membrane (CAM) model is a potential alternative to the mouse model based on the 3R principles. However, its value for determination of the in vivo behaviors of radiolabeled peptides through positron emission tomography (PET) imaging needed investigation. Herein, the chicken CAM tumor models were established, and their feasibility was evaluated for evaluating the imaging properties of radiolabeled peptides using a 68 Ga-labeled HER2 affibody., Methods: Two human breast cancer cell lines were inoculated into chicken CAM and mice, respectively. The tumor-targeting potential and pharmacokinetic profile of a 68 Ga-labeled affibody, 68 Ga-MZHER, in both tumor models were also determined., Results: The tumor-formation time in chicken CAM model was shorter than that of mouse model. The uptake values of human epithelial growth factor receptor-2 (HER2)-positive Bcap37 tumors in chicken CAM and mouse models were 5.36 ± 0.26% ID/g and 5.26 ± 0.43% ID/g at 30 min postinjection of 68 Ga-MZHER, respectively. At the same time points, the uptake values of HER2-negative MDA-MB-231 tumors in the chicken CAM models and mouse models were 1.57 ± 0.15% ID/g and 1.67 ± 0.25% ID/g, respectively. Ex vivo biodistribution confirmed that more radioactivity accumulated in Bcap37 tumors than in MDA-MD-231 tumors in both CAM and mouse models., Conclusion: In this study, the CAM tumor model was successfully prepared. The chicken CAM model is a novel tool for quickly determining the in vivo properties of radiolabeled peptides targeting biomarkers. It may be beneficial for early monitoring of the therapeutic effect of a new drug through PET imaging with specific peptides., (© 2024 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Inhaled PM 2.5 particles is harmful to human health. However, real-time tracking of PM 2.5 particles and dynamic evaluation of the pharmacokinetic behaviors in vivo are still challenging. Here, PET imaging is utilized to noninvasively monitor the in vivo behavior of PM 2.5 particles in rats. To mimic aerosol PM 2.5 particles suspended in ambient air, 89 Zr-labeled melanin nanoparticles ( 89 Zr-MNP) are nebulized into microscopic liquid particles with a mean size of 2.5 μm. Then, the 89 Zr-labeled PM 2.5 mimic particles ( 89 Zr-PM 2.5 ) are administrated into rats via inhalation. PET imaging showed that 89 Zr-PM 2.5 mainly accumulated in the lungs for up to 384 h after administration. Besides, we also observe that a small amount of 89 Zr-PM 2.5 can penetrate the brain through the inhalation. Further PET imaging showed that enhanced uptakes of 18 F-FDG and 18 F-DPA-714 were found in the brain of rats upon PM 2.5 mimic particle exposure, which revealed that pulmonary exposure to PM 2.5 could cause potential damages to the brain. Note that abnormal glucose metabolism was reversed, but the neuroinflammation was permanent and could not be alleviated after ceasing PM 2.5 exposure. Our results demonstrate that PET is a sensitive and feasible tool for evaluating the in vivo behaviors of PM 2.5., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: C-X-C motif chemokine ligand 9 (CXCL9), which is involved in the pathological processes of various human cancers, has become a hot topic in recent years. We developed a radiomic model to identify CXCL9 status in ovarian cancer (OC) and evaluated its prognostic significance., Methods: We analyzed enhanced CT scans, transcriptome sequencing data, and corresponding clinical characteristics of CXCL9 in OC using the TCIA and TCGA databases. We used the repeat least absolute shrinkage (LASSO) and recursive feature elimination(RFE) methods to determine radiomic features after extraction and normalization. We constructed a radiomic model for CXCL9 prediction based on logistic regression and internal tenfold cross-validation. Finally, a 60-month overall survival (OS) nomogram was established to analyze survival data based on Cox regression., Results: CXCL9 mRNA levels and several other genes involving in T-cell infiltration were significantly relevant to OS in OC patients. The radiomic score (rad&#95;score) of our radiomic model was calculated based on the five features for CXCL9 prediction. The areas under receiver operating characteristic (ROC) curves (AUC-ROC) for the training cohort was 0.781, while that for the validation cohort was 0.743. Patients with a high rad&#95;score had better overall survival (P < 0.001). In addition, calibration curves and decision curve analysis (DCA) showed good consistency between the prediction and actual observations, demonstrating the clinical utility of our model., Conclusion: In patients with OC, the radiomics signature(RS) of CT scans can distinguish the level of CXCL9 expression and predict prognosis, potentially fulfilling the ultimate purpose of precision medicine., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Multi-omics usually refers to the crossover application of multiple high-throughput screening technologies represented by genomics, transcriptomics, single-cell transcriptomics, proteomics and metabolomics, spatial transcriptomics, and so on, which play a great role in promoting the study of human diseases. Most of the current reviews focus on describing the development of multi-omics technologies, data integration, and application to a particular disease; however, few of them provide a comprehensive and systematic introduction of multi-omics. This review outlines the existing technical categories of multi-omics, cautions for experimental design, focuses on the integrated analysis methods of multi-omics, especially the approach of machine learning and deep learning in multi-omics data integration and the corresponding tools, and the application of multi-omics in medical researches (e.g., cancer, neurodegenerative diseases, aging, and drug target discovery) as well as the corresponding open-source analysis tools and databases, and finally, discusses the challenges and future directions of multi-omics integration and application in precision medicine. With the development of high-throughput technologies and data integration algorithms, as important directions of multi-omics for future disease research, single-cell multi-omics and spatial multi-omics also provided a detailed introduction. This review will provide important guidance for researchers, especially who are just entering into multi-omics medical research., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)

Purpose: Positron emission tomography (PET) is widely used in high-precision imaging, which may provide a simple and noninvasive method for the detection of pathology and therapeutic effects. [ 18 F]-DPA-714 is a second-generation translocator protein (TSPO) positron emission tomography radiotracer that shows great promise in a model of neuroinflammation. In this study, [ 18 F]-DPA-714 micro-PET imaging was used to evaluate retinal inflammation in mice exposed to blue light, a well-established model of age-related macular degeneration (AMD) for molecular mechanism research and drug screening., Methods: C57BL/6J melanized mice were subjected to 10,000, 15,000, and 20,000 lux blue light for 5 days (8 h/day) to develop the retinal injury model, and the structure and function of the retina were assessed using hematoxylin-eosin (HE) staining, electroretinography (ERG), and terminal-deoxynucleotidyl transferase (TdT)-mediated nick-end labeling (TUNEL) immunostaining. Then, [ 18 F]-DPA-714 was injected approximately 100 μCi through each tail vein, and static imaging was performed 1 h after injection. Finally, the mice eyeballs were collected for biodistribution and immune analysis., Results: The blue light exposure significantly destroyed the structure and function of the retina, and the uptake of [ 18 F]-DPA-714 in the retinas of the mice exposed to blue light were the most significantly upregulated, which was consistent with the biodistribution data. In addition, the immunohistochemical, western blot, and immunofluorescence data showed an increase in microglial TSPO expression., Conclusions: [ 18 F]-DPA-714 micro-PET imaging might be a good method for evaluating early inflammatory status during retinal pathology., (Copyright © 2023 Molecular Vision.)

Targets play an indispensable and pivotal role in the development of radiopharmaceuticals. However, the initial stages of drug discovery projects are often plagued by frequent failures due to inadequate information on druggability and suboptimal target selection. In this context, we aim to present a comprehensive review of the factors that influence target druggability for diagnostic radiopharmaceuticals. Specifically, we explore the crucial determinants of target specificity, abundance, localization, and positivity rate and their respective implications. Through a detailed analysis of existing protein targets, we elucidate the significance of each factor. By carefully considering and balancing these factors during the selection of targets, more efficacious and targeted radiopharmaceuticals are expected to be designed for the diagnosis of a wide range of diseases in the future., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

With endogenous redox systems and multiple enzymes, the storage and utilization of external energy is general in living cells, especially through photo/ultrasonic synthesis/catalysis due to in-situ generation of abundant reactive oxygen species (ROS). However, in artificial systems, because of extreme cavitation surroundings, ultrashort lifetime and increased diffusion distance, sonochemical energy is rapidly dissipated via electron-hole pairs recombination and ROS termination. Here, we integrate zeolitic imidazolate framework-90 (ZIF-90) and liquid metal (LM) with opposite charges by convenient sonosynthesis, and the resultant nanohybrid (LMND@ZIF-90) can efficiently capture sonogenerated holes and electrons, and thus suppress electron-hole pairs recombination. Unexpectedly, LMND@ZIF-90 can store the ultrasonic energy for over ten days and exhibit acid-responsive release to trigger persistent generation of various ROS including superoxide (O 2 • - ), hydroxyl radicals (•OH), and singlet oxygen ( 1 O 2 ), presenting significantly faster dye degradation rate (short to seconds) than previously reported sonocatalysts. Moreover, unique properties of gallium could additionally facilitate heavy metals removal through galvanic replacement and alloying. In summary, the LM/MOF nanohybrid constructed here demonstrates strong capacity for storing sonochemical energy as long-lived ROS, enabling enhanced water decontamination without energy input., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Emerging pollutants (EPs) have become a global concern, attracting tremendous attention because of serious threats to human and animal health. EP diversity emanates from their behaviour and ability to enter the body via multiple pathways and exhibit completely different distribution, transport, and excretion. To better understand the in vivo behaviour of EPs, we reviewed radiolabelling and in vivo radionuclide imaging tracking of various EPs, including micro- and nano-plastics, perfluoroalkyl substances, metal oxides, pharmaceutical and personal care products, and so on. Because this accurate and quantitative imaging approach requires the labelling of radionuclides onto EPs, the main strategies for radiolabelling were reviewed, such as synthesis with radioactive precursors, element exchange, proton beam activation, and modification. Spatial and temporal biodistribution of various EPs was summarised in a heat map, revealing that the absorption, transport, and excretion of EPs are markedly related to their type, size, and pathway into the body. These findings implicate the potential toxicity of diverse EPs in organs and tissues. Finally, we discussed the potential and challenges of radionuclide imaging tracking of EPs, which can be considered in future EPs studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: Positron emission tomography (PET) is widely used in high-precision imaging, which may provide a simple and noninvasive method for the detection of pathology and therapeutic effects. [ 18 F]-DPA-714 is a second-generation translocator protein (TSPO) positron emission tomography radiotracer that shows great promise in a model of neuroinflammation. In this study, [ 18 F]-DPA-714 micro-PET imaging was used to evaluate retinal inflammation in mice exposed to blue light, a well-established model of age-related macular degeneration (AMD) for molecular mechanism research and drug screening., Methods: C57BL/6J melanized mice were subjected to 10,000, 15,000, and 20,000 lux blue light for 5 days (8 h/day) to develop the retinal injury model, and the structure and function of the retina were assessed using hematoxylin-eosin (HE) staining, electroretinography (ERG), and terminal-deoxynucleotidyl transferase (TdT)-mediated nick-end labeling (TUNEL) immunostaining. Then, [ 18 F]-DPA-714 was injected approximately 100 μCi through each tail vein, and static imaging was performed 1 h after injection. Finally, the mice eyeballs were collected for biodistribution and immune analysis., Results: The blue light exposure significantly destroyed the structure and function of the retina, and the uptake of [ 18 F]-DPA-714 in the retinas of the mice exposed to blue light were the most significantly upregulated, which was consistent with the biodistribution data. In addition, the immunohistochemical, western blot, and immunofluorescence data showed an increase in microglial TSPO expression., Conclusions: [ 18 F]-DPA-714 micro-PET imaging might be a good method for evaluating early inflammatory status during retinal pathology., (Copyright © 2022 Molecular Vision.)

Background: A novel reporter system, streptavidin (SA)- [ 68  Ga]Ga-labeled biotin ([ 68  Ga]Ga-DOTA-biotin), was constructed and its ability for PET imaging the behaviors of CAR T cells were also evaluated in this study., Methods: In vitro activity and cytotoxicity of the SA transduced anti-CD19-CAR T (denoted as SA-CD19-CAR T) cells were determined. The feasibility of monitoring proliferation profiles of SA-CD19-CAR T cells using [ 68  Ga]Ga-DOTA-biotin was firstly investigated in a solid tumor model. Also, the pharmacodynamics and pharmacokinetics of the CAR T cells in whole-body hematologic neoplasms were evaluated by bioluminescence imaging and [ 68  Ga]Ga-DOTA-biotin PET imaging simultaneously., Results: After transduction with SA, the activity and cytotoxicity of the modified CAR T cells were not affected. PET images revealed that the uptakes of [ 68  Ga]Ga-DOTA-biotin in CD19 + K562 solid tumors were 0.67 ± 0.32 ID%/g and 1.26 ± 0.13 ID%/g at 30 min and 96 h p.i. after administration of SA-CD19-CAR T cells respectively. It confirmed that the SA-CD19-CAR T cells could effectively inhibit the growth of Raji hematologic tumors. However, low radioactivity related to the proliferation of CD19-CAR T cells was detected in the Raji model., Conclusion: SA-CD19-CAR T cells were constructed successfully without disturbing the antitumor functions of the cells. The proliferation of the CAR T cells in solid tumors could be early detected by [ 68  Ga]Ga-DOTA-biotin PET imaging., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Tumor necrosis factor-alpha (TNF-α) neutralization has become increasingly important in the treatment of inflammatory bowel diseases (IBD). A series of monoclonal antibodies were approved in the clinic for anti-TNF-α therapy. However, a comprehensive assessment of TNF-α levels throughout the colon, which facilitates the diagnosis of IBD and predicts anti-TNF-α efficacy, remains challenging. Here, we radiolabeled infliximab with long-lived radionuclides 89 Zr for immuno-positron emission tomography (PET) imaging of TNF-α in vivo . The increased TNF-α level was detected in the inflammatory colon of the dextran sodium sulfate-induced colitis mice. The immuno-PET imaging of 89 Zr-desferrioxamine-infliximab reveals a high uptake (7.1 ± 0.3%ID/g) in the inflammatory colon, which is significantly higher than in the healthy control and blocked groups. The colon-to-muscle ratio reached more than 10 and was maintained at a high level for 10 h after injection. The ex vivo biodistribution study also verified the superior uptake in the inflammatory colon. This study provides an in vivo immune-PET approach to molecular imaging of the pro-inflammatory cytokine TNF-α. It is promising in diagnosing and predicting efficacy in both IBD and other autoimmune diseases.

Using surface-initiated atom transfer radical polymerization (ATRP), block polymers with a series of quaternization degrees were coated on the surface of silica nanocapsules (SNCs) by the "grafting-from" technique. Molnupiravir, an antiviral medicine urgently approved for the treatment of SARS-CoV-2, was encapsulated in polymer-coated SNCs and further incorporated into well-defined films with polystyrene sulfonate (PSS) homopolymers by layer-by-layer (LBL) self-assembly via electrostatic interactions. We investigated the impact of the quaternization degree of the polymers and steric hindrance of functional groups on the growth mode, swelling/deswelling transition, and drug-delivering efficiency of the obtained LBL films. The SNCs were derived from coronas of parent block polymers of matched molecular weights-poly( N -isopropylacrylamide)- block -poly( N , N -dimethylaminoethyl methacrylate) (PNIPAM- b -PDMAEMA)-by quaternization with methyl sulfate. As revealed by the data results, SNCs with coronas with higher quaternization degrees resulted in a larger layering distance of the film structure because of weaker ionic pairing (due to the presence of a bulky methyl spacer) between SNCs and PSS. Interestingly, when comparing the drug release profile of the encapsulated drugs from SNC-based films, the release rate was slower in the case of capsule coronas with higher quaternization degrees because of the larger diffusion distance of the encapsulated drugs and stronger hydrophobic-hydrophobic interactions between SNCs and drug molecules., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Uveal melanoma (UM) is the most common primary intraocular tumor in adults, which is associated with poor prognosis. Up to 50% of UM patients develop metastasis. Therapeutics that have proven effective in cutaneous melanoma have little success in treating UM, possibly due to its low mutational burden. Therefore, new drug therapies are highly desired for UM. Our in vitro studies showed that Elaiophylin, a late-stage autophagy inhibitor, exhibited an outstanding anticancer activity in human UM cell lines and human UM primary cells through suppressing mitophagy, inducing oxidative stress and leading to autophagic cell death. Our mechanistic study revealed that Elaiophylin exerted its effect by down-regulating SIRT1 and thus influencing deacetylation and mitochondrial localization of FoxO3a. In our confirmatory experiments, SRT1720, a SIRT1 specific activator, could attenuate Elaiophylin-induced inhibition of mitophagy and elevation of oxidative stress, and such effects was partly reversed by FoxO3a knockdown. Our further in vivo studies showed that Elaiophylin dramatically inhibited tumor growth in the human UM xenograft mouse model, which was accompanied with a decreased SIRT1 expression. Thus, the current study is the first to demonstrate that Elaiophylin has a potent anti-cancer effect against UM, which activity is possibly mediated through regulating SIRT1-FoxO3a signaling axis. And Elaiophylin may be a new and promising drug candidate to treat human UM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhu, Zou, Meng, Ji, Wang, Shu, Chen, Pan, Wang and Zhou.)

Purpose: Radiolabeled FSH1 peptides are potential specific probes for FSHR imaging. However, moderate uptakes and fast washout from the tumors may limit its widespread use. In this study, 68 Ga labeled modified FSH1 analogs was prepared and the imaging properties were determined in the prostate cancer model with or without aprotinin., Methods: NOTA-MAL-FSH4 was synthesized and labeled with 68 Ga. The pharmacokinetic profile of the peptide after co-administration with aprotinin was determined through metabolism analyses and microPET imaging., Results: 68 Ga-NOTA-MAL-FSH4 was successfully prepared. The IC50 value of displacement 68 Ga-NOTA-MAL-FSH4 with FSH1 was 139.4 ± 1.16 nM. The PC-3 prostate tumor was visible after administration of the 68 Ga labeled tracer. In vitro RP-HPLC analysis revealed that the average percentage of intact peptide in the plasma, liver and tumor was 8.30, 9.57 and 7.06% respectively. In presence of aprotinin, the amounts of intact peptide increased to 34.32%, 20.63% and 15.39% in the counterparts respectively. MicroPET imaging showed that the uptakes of PC-3 tumors at 60mins after co-administration of 100 μg, 200 μg or 400 μg enzyme inhibitors were 2.91 ± 0.21%ID/g, 3.89 ± 0.16%ID/g and 9.21 ± 0.22%ID/g respectively., Conclusion: With the aid of a serine protease inhibitor, the performance of the 68 Ga labeled peptide was optimized, which may benefit further clinical application.

The proliferation of chimeric antigen receptor (CAR) T cells is closely related to their efficacy, but it is still a great challenge to monitor and quantify CAR T cells in vivo. Based on the high affinity (Kd ≈ 10 -15 M) of streptavidin (SA) and biotin, radiolabeled biotin may be used to quantify SA-transduced CAR T cells (SA-CAR T cells). Radio-thin-layer chromatography (radio-TLC) and positron emission tomography (PET) are highly sensitive for trace analysis. Our aim was to develop radio-TLC and PET methods to quantify SA-CAR T cells in vitro and in vivo. First, we developed [ 68 Ga]-DOTA-biotin. Commercially available SA was used as a standard, and quantitative standard curves were established in vitro and in vivo by radio-TLC and PET. Furthermore, the feasibility of the method was verified in Raji model mice. The linear range of radio-TLC was 0.02 ∼ 0.15 pmol/μL with R 2  = 0.9993 in vitro. The linear range of PET was 0.02 ∼ 0.76 pmol/μL with R 2  = 0.9986 in vivo. SA in CAR T cells can also be accurately quantified in a Raji leukemia model according to PET imaging. The radio-TLC/PET method established in this study is promising for using in the dynamic monitoring and analysis of SA-CAR T cells during therapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Osteoarthritis (OA) is a disabling joint disease associated with chronic inflammation. The polarization of macrophages plays the key role in inflammatory microenvironment of joint which is a therapeutic target for OA treatment. Herein, a boronate-stabilized polyphenol-poloxamer assembled dexamethasone nanodrug with reactive oxygen species (ROS)-responsive drug release behavior and ROS scavenging ability is prepared. Thanks to that, the nanodrug can efficiently inhibit the ROS and nitric oxide production in lipopolysaccharide-activated RAW264.7 macrophages and modulate macrophages M2 polarization at a much lower concentration than free drug dexamethasone. Furthermore, the monosodium iodoacetate-induced OA mice treated with this nanodrug is very similar with the normal mice with the evaluation of body weight and scores including clinical arthritis scores, claw circumference, and kinematics score. The inflammation associated angiogenesis is also reduced which revealed by 68 Ga-labeled arginine-glycine-aspartic acid peptide micro-positron emission tomography imaging. Cartilage degradation and bone erosion in the joints are also inhibited by the nanodrug, along with the inhibition of proinflammatory cytokines. In addition, the biosafety of this nanodrug is also verified. This nanodrug with excellent immunomodulation properties can be used not only for OA therapy but also for other inflammatory diseases associated with excess oxidative stress and macrophage polarization., (© 2021 Wiley-VCH GmbH.)

In recent years, chimeric antigen receptor T (CAR T)-cell therapy has shown great potential in treating haematologic disease, but no breakthrough has been achieved in solid tumours. In order to clarify the antitumour mechanism of CAR T cell in solid tumours, the pharmacokinetic (PK) and pharmacodynamic (PD) investigations of CD19 CAR T cell were performed in human leukaemic xenograft mouse models. For PK investigation, we radiolabelled CD19 CAR T cell with 89 Zr and used PET imaging in the CD19-positive and the CD19-negative K562-luc animal models. For PD evaluation, optical imaging, tumour volume measurement and DNA copy-number detection were performed. Unfortunately, the qPCR results of the DNA copy number in the blood were below the detection limit. The tumour-specific uptake was higher in the CD19-positive model than in the CD19-negative model, and this was consistent with the PD results. The preliminary PK and PD studies of CD19 CAR T cell in solid tumours are instructive. Considering the less efficiency of CAR T-cell therapy of solid tumours with the limited number of CAR T cells entering the interior of solid tumours, this study is suggestive for the subsequent CAR T-cell design and evaluation of solid tumour therapy., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Positron emission tomography (PET) has the potential for visualization and quantification of gastric emptying (GE). The traditional Chinese medicine (TCM) has been recognized promising for constipation. This study aimed to establish a PET imaging method for noninvasive GE measurement and to evaluate the efficacy of a TCM on delayed GE caused by constipation using PET imaging., Methods: [ 68 Ga]Ga-NOTA was synthesized as the tracer and sesame paste with different viscosity were selected as test meals. The dynamic PET scans were performed after [ 68 Ga]Ga-NOTA mixed with test meals were administered to normal mice. Two methods were utilized for the quantification of PET imaging. A constipation mouse model was treated with maren chengqi decoction (MCD), and the established PET imaging scans were performed after the treatment., Results: [ 68 Ga]Ga-NOTA was synthesized within 20 min, and its radiochemical purity was > 95%. PET images showed the dynamic process of GE. %ID/g, volume, and total activity correlated well with each other. Among which, the half of GE time derived from %ID/g for 4 test meals were 3.92 ± 0.87 min, 13.1 ± 1.25 min, 17.8 ± 1.31 min, and 59.7 ± 3.11 min, respectively. Constipation mice treated with MCD showed improved body weight and fecal conditions as well as ameliorated GE measured by [ 68 Ga]Ga-NOTA PET., Conclusions: A PET imaging method for noninvasive GE measurement was established with stable radiotracer, high image quality, and reliable quantification methods. The efficacy of MCD on delayed GE was demonstrated using PET.

CD47, an immune checkpoint receptor frequently unregulated in various blood and solid tumors, interacts with ligand SIPRα on innate immune cells, and conveys a "do not eat me" signal to inhibit macrophage-mediated tumor phagocytosis. This makes CD47 a valuable target for cancer immunotherapy. However, the therapeutic utility of CD47-SIRPα blockade monoclonal antibodies is largely compromised due to significant red blood cell (RBCs) toxicities and fast target-mediated clearance as a result of extensive expression of CD47 on normal cells. To overcome these limitations and further improve therapeutic efficacy, we designed IBI322, a CD47/PD-L1 bispecific antibody which attenuated CD47 activity in monovalent binding and blocked PD-L1 activity in bivalent binding. IBI322 selectively bound to CD47+PD-L1+ tumor cells, effectively inhibited CD47-SIRPα signal and triggered strong tumor cell phagocytosis in vitro, but only with minimal impact on CD47 single positive cells such as human RBCs. In addition, as a dual blocker of innate and adaptive immune checkpoints, IBI322 effectively accumulated in PD-L1-positive tumors and demonstrated synergistic activity in inducing complete tumor regression in vivo. Furthermore, IBI322 showed only marginal RBCs depletion and was well tolerated in non-human primates (NHP) after repeated weekly injections, suggesting a sufficient therapeutic window in future clinical development of IBI322 for cancer treatment.

Light therapy has been accepted as a promising therapeutic choice for depression. Positron emission tomography (PET) combined with specific radiotracers has great benefits for revealing pathogenesis and developing therapeutics. This study aimed to investigate the influences of light therapy on microglial activation and glucagon-like peptide-1 receptor (GLP-1R) expression in the brain of depressive rats using [ 18 F]DPA-714 and [ 18 F]exendin-4 PET. The results showed that chronic unpredictable mild stress (CUMS)-induced depressive rats had poorer performance in behavioral tests compared to normal rats (p < 0.05) and the depressive-like behavior could be ameliorated by light therapy. Besides, depressive rats had significantly higher [ 18 F]DPA-714 uptake and lower [ 18 F]FDG uptake compare to normal rats in 11 and 9 regions of interest (ROIs) of the brain, respectively (p < 0.05). After 5 weeks of light therapy, higher [ 18 F]FDG and [ 18 F]exendin-4 uptake was observed in most ROIs of light therapy-treated depressive rats compared to untreated depressive rats (p < 0.05) and no significant differences existed in [ 18 F]DPA-714 uptake between the two groups. This study demonstrated that light therapy can ameliorate depressive-like behavior, improve glucose metabolism, and halt the decline of brain GLP-1R expression of depressive rats, but have no effects on microglial activation caused by CUMS. Besides, this study validated that [ 18 F]DPA-714 and [ 18 F]exendin-4 PET have the potential for noninvasive evaluation of microglial activation and GLP-1R expression in the brain of depression.

Fluorinated polymers have attracted increasing attention in gene delivery and cytosolic protein delivery in recent years. In vivo tracking of fluorinated polymers will be of great importance to evaluate their biodistribution, clearance, and safety. However, tracking of polymeric carriers without changing their chemical structures remains a huge challenge. Herein, we reported a series of fluorinated poly-l-(lysine) (F-PLL) with high gene transfection efficiency and excellent biodegradation. Radionuclide 18 F was radiolabeled on F-PLL by halogen replacement without chemical modification. The radiolabeling of F-PLL offers positron emission tomography (PET) imaging for in vivo tracking of the polymers. The biodistribution of F-PLL and the DNA complexes revealed by micro-PET imaging illustrated the rapid clearance of fluorinated polymers from liver and intestine after intravenous administration. The results demonstrated that the polymer F-PLL will not be accumulated in the liver and spleen when administrated as a gene carrier. This work presents a new strategy for in vivo tracking fluorinated polymers via PET imaging.

Background: In the pathogenesis of Alzheimer's disease (AD), microglia play an increasingly important role. Molecular imaging of neuroinflammatory targeting microglia activation and the high expression of 18-kDa translocator protein (TSPO) has become a hot topic of research in recent years. Dynamic monitoring neuroinflammation is crucial for discovering the best time point of anti-inflammatory therapy. Motivated by this, Positron emission tomography (PET) imaging in an APP/PS1 mouse model of AD, using 18 F-labeled DPA-714 to monitor microglia activation and neuroinflammation, were performed in this paper. Methods: We prepared [ 18 F]DPA714 and tested the biological characteristics of the molecular probe in normal mice. To obtain a higher radiochemical yield, we improved the [ 18 F]-fluorination conditions in the precursor dosage, reaction temperature, and synthesis time. We performed [ 18 F]DPA714 PET scanning on APP/PS1 mice at 6-7, 9-10, 12-13, and 15-16 months of age, respectively. The same experiments were conducted in Wild-type (Wt) mice as a control. Referring to the [ 18 F]DPA714 concentrated situation in the brain, we performed blocking experiments with PK11195 (1 mg/kg) in 12-13-months-old APP/PS1 mice to confirm the specificity of [ 18 F]DPA714 for TSPO in the APP/PS1 mice. Reconstructed brain PET images, fused with the Magnetic Resonance Imaging (MRI) template atlas, and the volumes of interests (VOIs) of the hippocampus and cortex were determined. The distribution of [ 18 F]DPA714 in the brain tissues of 15-16-months-old APP/PS1 and Wt mice were studied by immunofluorescence staining. Results: Through the reaction of 18 F, with 2 mg precursor dissolved in 300 ul acetonitrile at 105°C for 10 min, we obtained the optimal radiochemical yield of 42.3 ± 5.1% (non-decay correction). Quantitative analysis of brain PET images showed that the [ 18 F]DPA714 uptake in the cortex and hippocampus of 12-13-months-old APP/PS1 mice was higher than that of the control mice of the same age (cortex/muscle: 2.77 ± 0.13 vs. 1.93 ± 0.32, p = 0.0014; hippocampus/muscle: 3.33 ± 0.10 vs. 2.10 ± 0.35, p = 0.0008). The same significant difference was found between 15- and 16-months-old APP/PS1 mice (cortex/muscle: 2.64 ± 0.14 vs. 1.86 ± 0.52, p=0.0159; hippocampus/muscle: 2.89 ± 0.53 vs. 1.77 ± 0.48, p = 0.0050). Immunofluorescence staining showed that the activation of microglia and the level of TSPO expression in the cortex and hippocampus of APP/PS1 mice were significantly higher than Wt mice. Conclusion: [ 18 F]DPA714, a molecular probe for targeting TSPO, showed great potential in monitoring microglia activation and neuroinflammation, which can be helpful in discovering the best time point for anti-inflammatory therapy in AD., (Copyright © 2020 Hu, Pan, Wang, Bao, Zuo, Guan, Hua, Yang and Zhao.)

Rationale: Anti-tumor necrosis factor (TNF) therapy is a very effective way to treat inflammatory bowel disease. However, systemic exposure to anti-TNF-α antibodies through current clinical systemic administration can cause serious adverse effects in many patients. Here, we report a facile prepared self-assembled supramolecular nanoparticle based on natural polyphenol tannic acid and poly(ethylene glycol) containing polymer for oral antibody delivery. Method: This supramolecular nanoparticle was fabricated within minutes in aqueous solution and easily scaled up to gram level due to their pH-dependent reversible assembly. DSS-induced colitis model was prepared to evaluate the ability of inflammatory colon targeting ability and therapeutic efficacy of this antibody-loaded nanoparticles. Results: This polyphenol-based nanoparticle can be aqueous assembly without organic solvent and thus scaled up easily. The oral administration of antibody loaded nanoparticle achieved high accumulation in the inflamed colon and low systemic exposure. The novel formulation of anti-TNF-α antibodies administrated orally achieved high efficacy in the treatment of colitis mice compared with free antibodies administered orally. The average weight, colon length, and inflammatory factors in colon and serum of colitis mice after the treatment of novel formulation of anti-TNF-α antibodies even reached the similar level to healthy controls. Conclusion: This polyphenol-based supramolecular nanoparticle is a promising platform for oral delivery of antibodies for the treatment of inflammatory bowel diseases, which may have promising clinical translation prospects., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Human epidermal growth factor receptor-2 (HER2) is an essential biomarker for tumor treatment. Affibody is an ideal vector for preparing HER2 specific probes because of high affinity and rapid clearance from normal tissues, etc. Zirconium-89 is a PET imaging isotope with a long half-life and suitable for monitoring biological processes for more extended periods. In this study, a novel 89 Zr-labeled HER2 affibody, [ 89 Zr]Zr-DFO-MAL-Cys-MZHER2, was synthesized, and its imaging characters were also assessed., Results: The precursor, DFO-MAL-Cys-MZHER2, was obtained with a yield of nearly 50%. The radiochemical yield of [ 89 Zr]Zr -DFO-MAL-Cys-MZHER2 was 90.2 ± 1.9%, and the radiochemical purity was higher than 95%. The total synthesis time was only 30 min. The probe was stable in PBS and serum. The tracer accumulated in HER2 overexpressing human ovarian cancer SKOV-3 cells. In vivo studies in mice bearing tumors showed that the probe was highly retained in SKOV-3 xenografts even for 48 h. The tumors were visualized with good contrast to normal tissues. ROI analysis revealed that the average uptake values in the tumor were greater than 5% IA/g during 48 h postinjection. On the contrary, the counterparts of MCF-7 tumors kept low levels ( ~ 1% IA/g). The outcome was consistent with the immunohistochemical analysis and ex vivo autoradiography. The probe quickly cleared from the normal organs except kidneys and mainly excreted through the urinary system., Conclusion: The novel HER2 affibody for PET imaging was easily prepared with satisfactory labeling yield and radiochemical purity. [ 89 Zr]Zr-DFO-MAL-Cys-MZHER2 is a potential candidate for detecting HER2 expression. It may play specific roles in clinical cancer theranostics.

Positron emission tomography (PET) has great benefits for developing therapeutics and quantifying pathological markers in neuropsychiatric disorders. This study aimed to firstly demonstrate the feasibility of PET imaging for glucagon-like peptide-1 receptor (GLP-1R) in Alzheimer's disease (AD) and evaluate the GLP-1R expression. Besides, microglial activation, dopamine D2 receptor (D2R) expression, and glucose metabolism in the brain of APP/PS1/tau transgenic model of AD (3×Tg-AD) were also investigated by PET. [ 18 F]FBEM-Cys 39 -exendin-4, [ 18 F]DPA-714, [ 18 F]fallypride, and [ 18 F]FDG were prepared and PET imaging acquisitions for 3×Tg-AD mice and wild-type (WT) mice were performed at 15, 30, and 60 min post-injection. Fifteen regions of interest (ROIs) were selected and %ID/g was calculated. The results showed that the uptake of [ 18 F]FBEM-Cys 39 -exendin-4 in 10 ROIs of 3×Tg-AD mice at 60 min post-injection was significantly lower than that of WT mice (p < 0.05). Besides, 3×Tg-AD mice showed significantly higher [ 18 F]DPA-714 uptake in 7 ROIs and lower [ 18 F]fallypride uptake in 4 ROIs compared to WT mice. [ 18 F]FDG PET showed no significant differences in any ROIs between the two groups. A positive correlation between the uptake of [ 18 F]fallypride and [ 18 F]FBEM-Cys 39 -exendin-4 could be found in the whole brain. In summary, these results validated the feasibility of GLP-1R PET in AD and demonstrated the reduced GLP-1R and D2R expression as well as increased microglial activation caused by AD., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Selecting the dose for efficacy and first-in-human studies of bispecific antibodies (BsAbs) is a challenging process. Herein, positron emission tomography (PET) imaging with 89 Zr-labeled IBI322, an anti-CD47/PD-L1 BsAb, was used to optimize the safety and effective therapy dose. By labeling with 89 Zr, we aimed to assess the pharmacokinetics (PK), safety, and target engagement of IBI322 with dose escalation dynamic PET imaging in humanized transgenic animal models bearing MC38 tumors (knock-in of hCD47 and hPDL1). 89 Zr-labeled IBI322 specifically accumulated in tumors with a tumor-to-muscle ratio of 12.37 ± 1.42 at 168 h (0.22 mg/kg) and the biodistribution of normal tissues from PET imaging could be used for preliminary safety prediction. According to the Pearson correlation analysis between the ELISA-quantified serum concentration and heart uptake (%ID/g) (r = 0.980), a modified Patlak model was proposed. The exploratory target-mediated 50% (0.38 mg/kg) and 90% (0.63 mg/kg) inhibitory mass doses were calculated with the current modified Patlak model. The preliminary pharmacodynamics (PD) study with 0.34 mg/kg revealed that the dose prediction was rational. In conclusion, dose escalation PET imaging with 89 Zr-labeled antibodies is promising for PK/PD modeling and safety prediction, and helpful for determining rational dosing for preclinical and clinical trials of BsAbs.

Objective: Overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancers provides promising opportunities for imaging and targeted therapy. Developing HER2 targeted positron emission tomography (PET) probes might be benefit for management of the disease. Small high-affinity scaffold proteins, affibodies, are ideal vectors for imaging HER2 overexpressed tumors. Despite of the initial success on development of 18 F labeled ZHER 2:342 affibody, the tedious synthesis producers, low yields and unfavorable pharmacokinetics may hinder the clinical use. 68 Ga is an attractive positron emitter for PET imaging. A simple preparation of 68 Ga labeled ZHER 2:342 analog, 68 Ga-NOTA-MAL-Cys-MZHER 2:342 , was reported in the study. The in vivo performances of the tracer for assessing HER2 status in breast cancers were also evaluated., Methods: NOTA-MAL conjugated Cys-MZHER 2:342 was radiolabeled with 68 Ga. The probe was evaluated by in vitro tests including stability and cell binding studies in breast cancer cells with different HER2 levels. In vivo evaluation was performed in mice bearing tumors using microPET imaging and biodistribution experiments. A PET/CT imaging study was initially performed in patients with breast cancers., Results: The tracer was synthesized in a straightforward chelation method with satisfactory non-decay corrected yield (81±5%) and radiochemical purity (>95%). In vivo micro-PET imaging showed that HER2 high levels expressed BT474 xenografts were more clear visualized than HER2 low levels expressed MCF-7 tumors (16.12 ± 2.69 ID%/g vs 1.32 ± 0.19 ID%/g at 1 h post-injection). The outcome was consistent with the immunohistochemical analysis. No significant radioactivity was accumulated in healthy tissues (less than 2% ID/g) except kidneys. In a preliminary clinical study, 68 Ga-NOTA-MAL-Cys-MZHER 2:342 PET imaging allowed more high-contrast detection of HER2 positive primary tumors (maximum standardized uptake value = 2.16±0.27) than those in HER2 negative primary focus (maximum standardized uptake value = 0.32±0.05). No detectable side-effects were found., Conclusion: In summary, this study indicates the significant efficiency of the 68 Ga labeled HER2 affibody. Preclinical and clinical studies support the possibility of monitoring HER2 levels in breast cancers using 68 Ga-NOTA-MAL-Cys-MZHER 2:342 ., Advances in Knowledge: The research investigated the feasibility of a 68 Ga labeled HER2 affibody modified with a hydrophilic linker for breast cancer PET imaging. Favorable outcomes showed that the probe might be valuable for determining HER2 status of the disease.

In recent years, ferroptosis has been investigated widely as a new form of cell death. Development of nanodrugs for ferroptosis induction in cancer cells may be a promising approach for cancer treatment. Here, we developed a type of nanoparticle consisting of the antitumor drug doxorubicin and exogenous ferritin. The drug loading process did not change the size of ferritin obviously. And this nanoparticle could induce the accumulation of ROS and cell ferroptosis for transferrin receptor overexpressed tumor cell, HT29. The ferroptosis process was also confirmed using inhibitors for ferroptosis. The cytotoxicity of this nanoparticle is similar to that of free DOX. This study provides a new strategy for targeting and killing transferrin receptor overexpressed tumor cells., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Ferroptosis and autophagy are the two forms of the regulation of cell death that play important roles in cancer therapy. However, little is known about the combination of the therapeutic effects of ferroptosis and autophagy in cancer therapy. Here, in this study, we constructed a novel carrier-free nanodrug called nanoparticle ferritin-bound erastin and rapamycin (NFER). The NFER nanodrug was prepared by the emulsification technique; it exhibited an average size of 78.8 nm and zeta potential of -25.9 ± 3.3 mV. Controllable drug encapsulation efficiency and loading ratios in NFER could be obtained. This nanodrug showed high stability in both water and PBS for several days. The release studies demonstrated that rapamycin and erastin could reach equilibrium after 24 h and 36 h, respectively; the maximum values of the released percentages of both reached beyond 30%. An in vitro study revealed that NFER showed robust ferroptosis-inducing capability by the downregulation of glutathione peroxidase-4 (GPX4) and lipid peroxidation accumulation. The autophagy process induced by rapamycin in NFER also played an important role in strengthening ferroptosis. The selective cancer cell killing ability of NFER was verified in cancer cells and normal cells. The ferroptosis-induced cytotoxicity was confirmed through several ferroptosis and autophagy inhibitors. Furthermore, the NFER nanodrug showed an improved control of tumor recurrence in the 4T1 tumor resection model. In summary, these results demonstrated that NFER exhibited excellent properties as a nanodrug, and the cell death induced by NFER was through an autophagy-associated ferroptosis pathway. This study based on protein nanodrug-induced autophagy-associated ferroptosis would provide a new insight into cancer therapy.

We describe layer-by-layer (LbL) buildup and pH-responsive behavior of multilayer films of alginate/chitosan/alginate -modified silica nanocapsules (SNCs) and chitosan (CS) biopolymers via electrostatic interaction. The SNC/CS films exhibit pH-triggered swelling/deswelling transitions under physiological conditions. Fulvestrant, an FDA-approved selective estrogen receptor down-regulator agent for the treatment of breast cancer, was encapsulated in SNCs and further incorporated into the LbL films. The drug release profile from the films was dependent on pH value of the surrounding environment. At pH 7.4, the films were able to efficiently entrap fulvestrant, with only ∼38% released in 120 days, whereas exposure to a lower pH value (pH 5.0) triggered faster fulvestrant release in phosphate buffer solution at 37 °C. Atomic force microscopy and ellipsometry showed that the films retained their structural integrity in PBS after several swelling/deswelling cycles. SNC/CS LbL films demonstrated repeated on/off drug release under external triggers, allowing consistent fulvestrant release (∼14-18% of encapsulated fulvestrant released for each cycle) over a 10-day period without significant change in drug release rate. This work demonstrates the first proof-of-concept platform of SNC-incorporated films with well-defined internal structure, good stability, high loading capacity, and controlled/sustained release profile for on-demand drug delivery. With great versatility to use various active compounds and building blocks, the films may have high potential for broad applications such as implantable biosensors and antifouling coatings.

Glucagon-like peptide-1 receptor (GLP-1R) is a kind of G protein coupled receptor which regulates the insulin secretion and serves as potential target in the diagnosis of functional pancreas neuroendocrine tumor. The aim of this study was to evaluate the feasibility of GLP-1R targeted tracer [ 68 Ga]Ga-NOTA-MAL-Cys 39 -exendin-4 in the detection of insulinoma., Methods: NOTA-MAL-Cys 39 -exendin-4 was synthesized and then radiolabeled with gallium-68 in iQS® Ga-68 Fluidic Labeling Module. The in vitro binding affinity and cell uptake studies were evaluated in INS-1 cells. The in vivo micro-PET/CT imaging and biodistribution studies were performed on INS-1 xenograft tumor models., Results: [ 68 Ga]Ga-NOTA-MAL-Cys 39 -exendin-4 can be efficiently radiolabelled with a yield of about 85% (non-decay corrected) and radiochemical purity of >95% with a favorable stability. The molar activity was at least 145.5 GBq/μmol. The affinity (IC50) for [ 68 Ga]Ga-NOTA-MAL-Cys 39 -exendin-4 was 12.99 ± 0.81 nM. Micro-PET/CT images showed intense tumor uptake with good contrast to background. Biodistribution study showed the predominant uptake was in the kidney, followed by pancreas, and the liver and spleen just showed mild uptake in the blood-pool phase with rapid clearance. At 1 h post- injection, the tumor to blood, muscle and pancreas ratios were 30.64, 40.21 and 6.46, respectively. Blocking studies showed significantly decreased tumor uptake, which further confirmed binding affinity of [ 68 Ga]Ga-NOTA-MAL-Cys 39 -exendin-4 to GLP-1R., Conclusion: [ 68 Ga]Ga-NOTA-MAL-Cys 39 -exendin-4 was easily synthesized with high yield, favorable biodistribution and high affinity to islet tumor cell, making the tracer may have great potential in the detection of GLP-1R positive tumor such as an insulinoma., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The recombinant vaccinia virus VG9 and the STAT3 inhibitor Stattic were combined to kill cancer cells via both oncolytic activity and inhibition of STAT3 phosphorylation in cells. The combinatory anti-tumour activity of these compounds was superior to the activity of VG9 or Stattic alone in vivo. The inhibition of tumour growth occurred via increased apoptosis and autophagy pathways. Furthermore, the combinatory anti-tumour activity was more efficient than that of VG9 or Stattic alone on xenografts, especially in nude mice.

To realize the diagnosis of HER2-positive gastric cancer via PET imaging, herein, a new kind of 18 F-labeled HER2 affibody probe was created; the bifunctional maleimide derivative 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA-MAL) was first coupled to a polypeptide, and the resulting compound was subsequently labeled with the 18 FAl complex. The binding characteristics of the probe were assessed using both in vitro studies and in vivo microPET imaging and biodistribution experiments. Immunohistochemical staining was performed to confirm the expression level of HER2 in the studied cell lines and tumors. The probe was successfully produced with the radiochemical purity of more than 95%. The NCI N87 cell-associated radioactivity was 19.31 ± 1.01% AD, and it decreased to 0.83 ± 0.04% AD per 10 6 cells after blocking HER2 as early as 15 minutes post-incubation ( p < 0.05). A competition binding assay between radiolabeled and non-radioactive affibody molecules with NCI N87 indicated that the IC 50 was 8.10 nM. The microPET imaging and biodistribution of human gastric cancer xenografts demonstrated that the probe could specifically accumulate in tumors at early time points. Protein detection confirmed a strong HER2 expression in NCIN87 and a weak HER2 expression in SGC7901. In conclusion, 18 FAl-NOTA-MAL-Cys-GGGRDN(M 0 )-Z HER2:342 was successfully prepared via a one-step method. The favorable preclinical data showed specific and effective tumor targeting capacity of the proposed probe; this revealed that the probe proposed herein might have potential application in gastric cancer imaging., Competing Interests: None., (This journal is © The Royal Society of Chemistry.)

Radiolabelled ligands of glucagon-like peptide 1 receptor (GLP-1R) have been used to image the GLP-1R-expressing tissues (e.g., islets and insulinoma). Here, we introduced human glucagon-like peptide 1 receptor (hglp-1r) gene as a novel radionuclide reporter gene to broaden its applications in molecular imaging in vivo. Transient and stable baculoviral vectors (BV) were re-constructed and used to transfer the hglp-1r gene or enhanced green fluorescent protein (egfp) reporter gene into the stem cells or tumor cells. Cell proliferation assay and flow cytometry analysis demonstrated that BV-mediated reporter gene transferring and expression was biosafe and highly efficient. The BV-mediated exogenous hGLP-1R in target cells showed same ligand-receptor binding characteristics compared with its counterpart in insulinoma cells. Furthermore, the ligand-receptor binding assay showed a high affinity (IC 50  = 0.3708 nM) and robust correlation (R 2  = 0.9264) between the fluorescein-tagged or radiolabeled ligand probes and exogenous hGLP-1R in target cells. The target cells transferred with BV-mediated hGLP-1R could be clearly visualized in nude mice by micro-PET, which was capable of the purposes of short-term tracking transplanted stem cells or long-term monitoring tumor formation. Then, the image-based analysis and bio-distribution analysis quantitatively confirmed high target-to-background ratio of hGLP-1R-expressing cells. This study also investigated the endogenous GLP-1R-expressing organs/tissues in nude mice in the hGLP-1R radionuclide reporter gene imaging. Summarily, we evaluated the utility of hglp-1r gene as a novel radionuclide reporter gene, and demonstrated that it was a favorable and promising candidate of molecular imaging tool, which would expand the spectrum of radionuclide reporter gene imaging systems.

In this study, a nonlinear analysis method called improved information entropy (IIE) is proposed on the basis of constructing a special probability mass function for the normalized analysis of Shannon entropy for a time series. The definition is directly applied to several typical time series, and the characteristic of IIE is analyzed. This method can distinguish different kinds of signals and reflects the complexity of one-dimensional time series of high sensitivity to the changes in signal. Thus, the method is applied to the fault diagnosis of a rolling bearing. Experimental results show that the method can effectively extract the sensitive characteristics of the bearing running state and has fast operation time and minimal parameter requirements.

Background: Glucagon-like peptide 1 receptor (GLP-1R) is an important biomarker for diagnosis and therapy of the endocrine cancers due to overexpression. Recently, in human prostate cancer cell lines the receptor was also observed, therefore it may be a potential target for the disease. 18F-Al-NOTA-MAL-Cys39- exendin-4 holds great promise for GLP-1R. Therefore, the feasibility of the 18F-labeled exendin-4 analog for prostate cancer imaging was investigated., Methods: New probe 18F-Al-NOTA-MAL-Cys39-exendin-4 was made through one-step fluorination. Prostate cancer PC3 cell xenograft model mice were established to primarily evaluate the imaging properties of the tracer via small animal PET studies in vivo. Pathological studies and Western Blots were also performed., Results: PC-3 prostate xenografts were clearly imaged under baseline conditions. At 30 and 60 min postinjection, the tumor uptakes were 2.90±0.41%ID/g and 2.26±0.32 %ID/g respectively. The presence of cys39-exendin-4 significantly reduced the tumor uptake to 0.82±0.10 %ID/g at 60 min p.i. Findings of ex vivo biodistribution studies were similar to those of in vivo PET imaging. The tumors to blood and muscles were significantly improved with the increase of time due to rapid clearance of the tracer from normal organs. Low levels of radioactivity were also detected in the GLP-1R positive tumor and normal organs after coinjection with excessive unlabeled peptides. Immunohistochemistry and Western Blots results confirmed that GLP-1R was widely expressed in PC-3 prostate cancers., Conclusion: 18F-Al labeled exendin-4 analog might be a promising tracer for in vivo detecting GLP-1R positive prostate cancer with the advantage of facile synthesis and favorable pharmacokinetics. It may be useful in differential diagnosis, molecularly targeted therapy and prognosis of the cancers., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Radioiodine is widely used in nuclear medicine, mainly serving as a tracer and therapeutic agent, and benefits from its various radioactive isotopes of iodine including I-123, I-124, I-125, I-131 and so on. Melanin is a natural material widely dispersed in the human skin, hair and eyes. The excellent biocompatibility and multifunctional abilities of melanin make it a perfect carrier for biomedical applications. Here, we fabricated theranostic radioiodine-labelled melanin nanoparticles (MNPs) through a novel Ag-I two-step method. The Ag-I labelling method for MNP radioiodine-labelling has advantages including a faster labelling time, higher labelling yield, and higher stability than the chloramine-T oxidation method reported previously. The obtained MNP-Ag- 131 I can be used for both single-photon emission computed tomography and Cherenkov radiation imaging. The β-rays of 131 I also make it a good candidate as a cancer cell killer. The theranostic properties of this nanoparticle were also proved in a xenograft tumor model in vivo. In summary, this study provides a new concept for radioiodine labelling nanoparticles, which can be further investigated in various imaging and radiotherapy applications with different radioactive isotopes of iodine.

The glucagon-like peptide-1 receptor (GLP-1R) has been demonstrated as a potential therapeutic target for some neurological diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and stroke. Besides, its distribution and density in brain regions are closely associated with cognition, motor function, learning and memory. Given the relationship between age and these neurological diseases, we firstly examined the influences of age on GLP-1R expression using [ 18 F]AlF-NOTA-MAL-Cys 39 -exendin-4 microPET imaging. The image showed that GLP-1R expression in nearly all regions of the brain of aged rats was evidently lower than that of normal rats. Significant differences were found in olfactory, striatum, hypothalamus, substantial nigra, and hippocampus, which have inseparable relations with some mental and neurological diseases such as PD and AD. Data obtained from biodistribution and immunohistochemistry staining also confirmed the image results. Taken together, these results illustrated decreased expression of GLP-1R in the brain of aged rats can be detected by [ 18 F]AlF-NOTA-MAL-Cys 39 -exendin-4, which implied GLP-1R as a reliable target and GLP-1R PET imaging could be a promising technology in the field of neurological diseases., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Self-assembled supramolecular nanoparticles have remarkable benefits in bioimaging and drug delivery. Here it is first reported that polyphenol and poloxamer self-assemble supramolecular nanoparticles (PPNPs). PPNPs are fabricated by multivalent hydrogen bonding between tannic acid and Pluronic F-127 together with hydrophobic interactions of poly(propylene oxide) chains, to be applied in tumor near-infrared fluorescence (NIRF) imaging and positron emission tomography (PET) imaging. With near-infrared fluorescent dyes such as IR780 encapsulated via hydrophobic interactions, PPNPs are used in NIRF imaging. PPNPs with excess phenolic hydroxyl groups chelating positron emitting radionuclide 89 Zr function as a PET contrast agent. The in vivo results show surprisingly higher fluorescence intensity in tumors than in other tissues. In addition, PPNPs exhibit good biocompatibility in various cell lines and do not induce hemolysis in vitro. In this study, it is demonstrated that biodegradable and biocompatible PPNPs are an excellent bimodal contrast agent for in vivo tumor imaging., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: To compare the differential diagnostic values of 18 F-Alfatide II PET/CT between tuberculosis and lung cancer patients and in patients with sarcoidosis and common inflammation., Methods: Nine inflammation patients (4 tuberculosis, 3 sarcoidosis, and 2 common inflammation) and 11 lung cancer patients were included in this study. All patients underwent 18 F-FDG and 18 F-Alfatide II PET/CT within 2 weeks, followed by biopsy and surgery. The maximized standard uptake value (SUVmax) and the mean standard uptake value (SUVmean) were evaluated., Results: The active tuberculosis lesions showed a high accumulation of 18 F-FDG, but varying degrees of accumulation of 18 F-Alfatide II, including negative results. The SUVmax of 18 F-Alfatide II in malignant lesions was significantly higher than that in tuberculosis (4.08 ± 1.51 versus 2.63 ± 1.34, P = 0.0078). Three patients with sarcoidosis showed negative results in 18 F-Alfatide II PET/CT., Conclusions: The expression of α V β 3 is much lower in tuberculosis as compared to that in lung cancer, and accumulation of 18 F-Alfatide II varied even in lesions of the same patient. The negative results of sarcoidosis patients led to the speculation that α V β 3 was not expressed in those lesions.