Physiological tracer distribution and benign lesion incidental uptake of Al18F-NOTA-FAPI-04 on PET/CT imaging.

OBJECTIVE: To systematically investigate the physiological distribution and benign lesion incidental uptake of Al18F-NOTA-FAPI-04 (18F-FAPI) in cancer patients to establish the normal uptake range in relevant organs and lesions. METHODS: Twenty patients who underwent 18F-FAPI PET/CT imaging were retrospectively assessed. Organ and benign lesion tracer uptake was quantified based on standardized uptake values (SUVmax and SUVmean). We compared the variation in tracer uptake in certain organs between men and women, analyzed the possible reasons for diffuse uptake in the thyroid, and assessed tracer uptake variations in the uterus in different menstrual cycle phases. Incidental tracer uptake in benign lesions was also assessed. RESULTS: Physiological 18F-FAPI uptake was observed in the urinary tract, biliary tract system, submandibular glands, pancreas, thyroid, uterus, intestine, prostate gland, parotid gland, myocardium, kidney cortex, and muscles, but not the brain, lungs, liver, spleen, colon, and breasts. The SUVmean for each organ was similar for women and men (all P > 0.05). Diffuse tracer uptake in the thyroid was caused by normal thyroid or thyroiditis; there were no statistically significant differences between them (SUVmax: t = -1.3, P = 0.25; SUVmean: t = -1.1, P = 0.31). There was a significant difference for uterus uptake among different menstrual cycle phases (SUVmax: F = 5.08, P = 0.04; SUVmean: F = 5.19, P = 0.04). Incidental benign lesion tracer uptake was observed in patients with esophagitis, thyroiditis, arthritis, fractures, and uterine fibroids. CONCLUSION: This study provides a reference range for 18F-FAPI uptake in relevant organs and benign lesions. Benign lesion 18F-FAPI uptake may reduce 18F-FAPI PET/CT specificity.

Evaluation of 18F-PSMA-1007 PET/CT in prostate cancer patients with biochemical recurrence after radical prostatectomy.

PURPOSE: Prostate-specific membrane antigen (PSMA) ligands targeting has shown promising results in staging of prostate cancer (PCa). The aim of present study was to evaluate the value of 18F-PSMA-1007 PET/CT in PCa patients with biochemical recurrence. METHODS: 71 patients with PCa after radical prostatectomy (RP) were included in the present study. Median prostate-specific antigen (PSA) level was 1.27 ng/mL (range 0.01-67.40 ng/mL, n = 69). All patients underwent whole-body PET/CT imaging after injection of 333±38 MBq 18F-PSMA-1007. The distribution of PSMA-positive lesions was assessed. The influence of PSA level, androgen deprivation therapy and primary Gleason score on PSMA-positive finding and uptake of 18F-PSMA-1007 were evaluated. RESULTS: 56 (79%) patients showed at least one pathological finding on 18F-PSMA-1007 PET/CT. The rates of positive scans were 50%, 80%, 100%, 100% among patients with PSA levels ≤0.5, 0.51-1.0, 1.1-2.0 and >2.0 ng/mL, respectively. The median Gleason score was 8 (range 7-10), and higher Gleason score (≤7 vs. ≥8) leads to higher detection rates (58.3% (14/24) vs. 88.9% (32/36), P = 0.006). The median SUVmax of positive findings in patients with PSA levels ≤0.5, 0.51-1.0, 1.1-2.0 and >2.0 ng/mL were 4.51, 4.27, 11.50 and 14.08, respectively. The median SUVmax in patients with PSA level >2.0 ng/mL was significantly higher than that in patients with PSA ≤2.0 ng/mL (14.08 vs. 6.13, P<0.001). CONCLUSION: 18F-PSMA-1007 PET/CT demonstrated a high detection rate for patients with a raised PSA level after radical prostatectomy even in patients with extremely low PSA level (eg. PSA level ≤0.5 ng/mL), which was essential for further clinical management for PCa patients.

FAPI-04 PET/CT Using [18F]AlF Labeling Strategy: Automatic Synthesis, Quality Control, and In Vivo Assessment in Patient.

68Ga labeled FAPI is the current standard for FAPI-PET, but its batch activity is limited. [18F]AlF-NOTA-FAPI-04 is a promising alternative combining the advantages of a chelator-based radiolabeling method with the unique properties of fluorine-18. The objective of this study was to develop a quick automatic method for synthesis of [18F]AlF-NOTA-FAPI-04 using a AllinOne synthesis system, and perform PET imaging with [18F]AlF-NOTA-FAPI-04 on patients. [18F]AlF-NOTA-FAPI-04 was produced, and its quality control was conducted by HPLC equipped with a radioactive detector. [18F]AlF-NOTA-FAPI-04 PET/CT imaging was performed in normal BALB/c mice (n = 3) and 4T1 breast cancer models (n = 3) to determine its biodistribution. Then [18F]AlF-NOTA-FAPI-04 and 18F-fluorodeoxyglucose (FDG) PET/CT imaging were performed in an invasive ductal carcinoma patient (female, 54 years old). The synthesis time of [18F]AlF-NOTA-FAPI-04 was about 25 min, and the radiochemical yield was 26.4 ± 1.5% (attenuation correction, n = 10). The radiochemical purity was above 99.0% and was above 98.0% after 6 h. The product was colorless transparent solution with pH value of 7.0-7.5, and the specific activity was 49.41 ± 3.19 GBq/µmol. PET/CT imaging in mice showed that physiological uptake of [18F]AlF-NOTA-FAPI-04 was mainly in the biliary system and bladder, and [18F]AlF-NOTA-FAPI-04 highly concentrated in tumor xenografts. PET/CT imaging in the patient showed that [18F]AlF-NOTA-FAPI-04 obtained high tumor background ratio (TBR) value of 8.44 in segment V and VI, while TBR value was 2.55 by 18F-FDG. [18F]AlF-NOTA-FAPI-04 could be synthesized with high radiochemical yield and batch production by AllinOne module and show excellent diagnosis performance in cancer patients.

Quick Automatic Synthesis of Solvent-Free 16α-[18F] Fluoroestradiol: Comparison of Kryptofix 222 and Tetrabutylammonium Bicarbonate.

Estrogen receptor (ER) expression level of human breast cancer often reflects the stage of disease and is usually monitored by immunohistochemical staining in vitro. The preferable non-invasive and real-time diagnosis in vivo is more accessible by PET scan using 16α-[18F]FES. The objective of this study was to develop a quick automatic method for synthesis of solvent-free 16α-[18F]FES using a CFN-MPS-200 synthesis system and compare the catalytic efficiency of two phase transfer catalysts, Kryptofix 222/K2CO3 (K222/K2CO3) and tetrabutylammonium hydrogen carbonate (TBA·HCO3). In this method, phase transfer catalysts K222/K2CO3 and TBA·HCO3 were used, respectively. The intermediate products were both hydrolyzed with hydrochloric acid and neutralized with sodium bicarbonate. The crude product was purified with semi-preparative HPLC, and the solvent was removed by rotary evaporation. The effects of radiofluorination temperature and time on the synthesis were also investigated. Radiochemical purity of solvent-free product was above 99% and the decay-corrected radiochemical yield of 16α-[18F]FES was obtained in 48.7 ± 0.95% (catalyzed by K222/K2CO3, n = 4) and 46.7 ± 0.77% (catalyzed by TBA·HCO3, n = 4, respectively). The solvent-free 16α-[18F]FES was studied in clinically diagnosed breast cancer patients, and FES-PET results were compared with pathology diagnosis results to validate the diagnosis value of 16α-[18F]FES. The new method was more reliable, efficient, and time-saving. There was no significant difference in catalytic activity between K222/K2CO3 and TBA·HCO3.

Research Progress of Chloroquine and Hydroxychloroquine on the COVID-19 and Their Potential Risks in Clinic Use.

In December 2019, a severe outbreak of a novel coronavirus (COVID-19) occurred in the whole world, posing a great threat to people's health. With the outbreak and development of the epidemic, how to improve the cure rate, find effective drugs against this virus, has been the most urgent problem. Chloroquine (CQ) was verified effective against COVID-19 in vitro. As CQ's analogue, hydroxychloroquine (HCQ) was also reminded as a potential candidate for treating COVID-19. This review summarizes the latest clinical trials of CQ and HCQ against COVID-19 and its therapeutic regimen in China aiming to share their current usage to the whole world and provide insight into its appropriate future use in the treatment of COVID-19. Through searching the CNKI and Wangfang databases in Chinese language and PubMed, EMBASE, and Ovid databases in English language to identify published reports with the keywords including "coronavirus/COVID, chloroquine, hyroxychloroquine" in alone or combined, we found out the potential preclinical or clinical evidence for using CQ and HCQ against COVID-19. Consequently, we also searched the website of Chinese Clinical Trial Registry (http://www.chictr.org.cn/) till the day on 27th, June, 2020. This review found that there are 23 programs aimed to treat the different phases under COVID-19 pipeline in clinic with CQ and HCQ, totally. The inclusion criteria, exclusion criteria and therapeutic regimen were all shared to consult. Among them, seven have been canceled due to lack of patients or other objective factors. There are two trials have completed, which the potential relationship between usage and adverse reactions was discussed emphatically. Through literature research, we suggested that paid close attention to retinal toxicity and ophthalmologic adverse symptom of CQ and HCQ. And the outcome of HCQ in clinic shows better than CQ especially in protective effect with low dosage.

Trichostatin A reverses epithelial-mesenchymal transition and attenuates invasion and migration in MCF-7 breast cancer cells.

Breast cancer remains one of the leading causes of mortality in women, and epithelial-mesenchymal transition (EMT) serves an indispensable role in the invasion and migration of breast cancer cells. As a representative of classical histone deacetylase inhibitors (HDACIs), trichostatin A (TSA) has been demonstrated to reverse EMT in certain types of non-tumor cells and tumor cells. In the present study, the invasive and migratory abilities of MCF-7 cells were examined following treatment with TSA. TSA-induced changes in the expression of an epithelial biomarker epithelial cadherin (E-cadherin), a mesenchymal biomarker (vimentin), and a transcription factor [zinc finger protein SNAI2 (SLUG)] were also investigated. Transwell invasion and migration assays, and wound healing assays, revealed that the invasive and migratory abilities of MCF-7 cells were suppressed significantly upon treatment with TSA. Treatment with TSA led to an increased expression level of E-cadherin, and decreased expression of vimentin and, in MCF-7 cells. The overexpression of SLUG decreased the expression level of E-cadherin, but increased vimentin expression, and upon treatment with TSA, these effects were reversed. Additionally, SLUG knockdown also led to upregulation of E-cadherin expression, downregulation of vimentin expression, and suppression of the invasion and migration of MCF-7 cells. Taken together, these results suggest that TSA is able to reverse EMT via suppressing SLUG and attenuate the invasion and migration of MCF-7 cells in vitro, thereby providing a potential avenue for chemotherapeutic intervention in the treatment of breast cancer.

Intra-Individual Comparison of 18F-PSMA-1007 and 18F-FDG PET/CT in the Evaluation of Patients With Prostate Cancer.

PURPOSE: 18F labelled PSMA-1007 presents promising results in detecting prostate cancer (PC), while some pitfalls exists meanwhile. An intra-individual comparison of 18F-FDG and 18F-PSMA-1007 in patients with prostate cancer were aimed to be performed in the present study. Then, the pitfalls of 18F-PSMA-1007 PET/CT in imaging of patients with prostate cancer were analyzed. METHODS AND MATERIAL: 21 prostate cancer patients underwent 18F-PSMA-1007 PET/CT as well as 18F-FDG PET/CT before treatment. All positive lesions were noticed in both 18F-PSMA-1007 PET/CT and 18F-FDG PET/CT, then differentiated PC metastasis from benign lesions. the SUVmax, SUVmean and TBR of lesions, up to 10 metastases and 10 benign lesions per patients were recorded (5 for bone, 5 for soft tissue metastasis ). The distribution of positive lesions were analyzed for two imaging. Detection rates, SUVmax, SUVmean and TBR in 18F-PSMA-1007 PET/CT and 18F-FDG PET/CT were compared, respectively. The optimal cut-off values of SUVmax, SUVmean for metastases vs. benign lesions was found through areas under ROC in 18F-PSMA-1007. RESULTS: The detection rates of primary lesions in 18F-PSMA-1007 PET/CT was higher than that of 18F-FDG PET/CT(100% (21/21) vs. 67%(14/21)). For extra- prostatic lesions, 18F-PSMA-1007 PET/CT revealed 124 positive lesions, 49(49/124, 40%) attributed to a benign origin; 18F-FDG PET/CT revealed 68 positive lesions, 14(14/68, 21%) attributed to a benign origin. The SUVmax, SUVmean, TBR of primary tumor in 18F-PSMA-1007 PET/CT was higher than that in 18F-FDG PET/CT (15.20 vs. 4.20 for SUVmax; 8.70 vs. 2.80 for SUVmean; 24.92 vs. 4.82 for TBR, respectively); The SUVmax, SUVmean, TBR of metastases in 18F-PSMA-1007 PET/CT was higher than that in 18F-FDG PET/CT (10.72 vs. 4.42 for SUVmax; 6.67 vs. 2.59 for SUVmean; The TBR of metastases was 13.3 vs. 7.91). For 18F-FDG PET/CT, the SUVmax, SUVmean in metastases was higher than that in benign lesions (4.42 vs. 3.04 for SUVmax, 2.59 vs. 1.75 for SUVmean, respectively). Similarly, for 18F-PSMA-1007 PET/CT, the SUVmax, SUVmean in metastases was significantly higher than that in benign lesions(10.72 vs. 3.14 for SUVmax, 6.67 vs. 1.91 for SUVmean, respectively), ROC suggested that SUVmax=7.71, SUVmean=5.35 might be the optimal cut-off values for metastases vs. benign lesions. CONCLUSION: The pilot study suggested that 18F-PSMA-1007 showed superiority over 18F-FDG because its high detecting rate of PC lesions and excellent tumor uptake. While non-tumor uptake in 18F-PSMA-1007 may lead to misdiagnosis, recognizing these pitfalls and careful analysis can improve the accuracy of diagnosis.

Lactosylated N-Alkyl polyethylenimine coated iron oxide nanoparticles induced autophagy in mouse dendritic cells.

Dendritic cell (DC)-based vaccines have shown promising therapeutic results in cancer and some immune disorders. It is critical to track in vivo migration behaviours of DCs and monitor the whole process dynamically and non-invasively. Superparamagnetic iron oxide (SPIO) nanoparticles are chosen for DC labelling under magnetic resonance imaging (MRI) because of their proven biosafety as contrast agents. However, when used for cell labelling, sensitive biological indicators such as cell autophagy may be helpful to better understand the process and improve the probe design. Here, lactosylated N-Alkyl polyethylenimine coated SPIO nanoparticles are used for DC labelling. This probe shows satisfactory cell labelling efficiency and low cytotoxicity. In this study, autophagy was used as a key factor to understand how DCs react to nanoparticles after labelling. Our results demonstrate that the nanoparticles can induce protective autophagy in DCs, as inhibition of the autophagy flux could lead to cell death. Meanwhile, the nanoparticles induced autophagy could promote DC maturation which is an essential process for its migration and antigen presentation. Autophagy induced DC maturation is known to enhance the vaccine functions of DCs, therefore, our results suggest that beyond the MRI tracking ability, this probe might enhance therapeutic immune activation as well.

Albumin-based nanoparticles loaded with hydrophobic gadolinium chelates as T1-T2 dual-mode contrast agents for accurate liver tumor imaging.

Magnetic resonance contrast agents with T1-T2 dual mode contrast capability have attracted considerable interest because they offer complementary and synergistic diagnostic information, leading to high imaging sensitivity and accurate diagnosis. Here, we reported a facile strategy to construct albumin based nanoparticles loaded with hydrophobic gadolinium chelates by hydrophobic interaction for magnetic resonance imaging (MRI). We synthesized a glycyrrhetinic acid-containing Gd-DOTA derivative (GGD) and loaded GGD molecules into BSA nanoparticles to form GGD-BSA nanoparticles (GGD-BSA NPs). The large size and porous structure endow GGD-BSA NPs with geometrical confinement, which restricts the tumbling of GGD and the diffusion of surrounding water molecules. As a result, GGD-BSA NPs exhibit ultrahigh T1 and T2 relaxivities, which are approximately 8-fold higher than those of gadolinium-based clinical contrast agents at 0.5 T. Besides, due to the intrinsic properties of their components, GGD-BSA NPs show good biocompatibility in vitro and in vivo, which warrants their great potential in clinical translation. Furthermore, GGD-BSA NPs show remarkable sensitivity in noninvasive detection of liver tumors by self-confirmed T1-T2 dual-mode contrast-enhanced MRI. All of these merits make GGD-BSA NPs a potential candidate for fruitful biomedical and preclinical applications.

Reduction of polyethylenimine-coated iron oxide nanoparticles induced autophagy and cytotoxicity by lactosylation.

Superparamagnetic iron oxide (SPIO) nanoparticles are excellent magnetic resonance contrast agents and surface engineering can expand their applications. When covered with amphiphilic alkyl-polyethyleneimine (PEI), the modified SPIO nanoparticles can be used as MRI visible gene/drug delivery carriers and cell tracking probes. However, the positively charged amines of PEI can also cause cytotoxicity and restricts their further applications. In this study, we used lactose to modify amphiphilic low molecular weight polyethylenimine (C12-PEI2K) at different lactosylation degree. It was found that the N-alkyl-PEI-lactobionic acid wrapped SPIO nanocomposites show better cell viability without compromising their labelling efficacy as well as MR imaging capability in RAW 264.7 cells, comparing to the unsubstituted ones. Besides, we found the PEI induced cell autophagy can be reduced via lactose modification, indicating the increased cell viability might rely on down-regulating autophagy. Thus, our findings provide a new approach to overcome the toxicity of PEI wrapped SPIO nanocomposites by lactose modification.