Synthesis of molecularly imprinted polymers based on nitrogen-doped carbon dots for specific detection of chlortetracycline by reversed phase microemulsion method.

Among the tetracycline antibiotics, chlortetracycline (CTC) is the most frequently used antibiotic except for tetracycline (TC) for enhancing the ability of the organism to fight bacterial infections. The poor metabolism and degradability of CTC can cause serious health effects. Most studies have focused on the detection and analysis of TC, and research on CTC is relatively scarce. This is because the structures of CTC and TC and oxytetracycline (OTC) are extremely similar, and even indistinguishable. In this study, CTC was used as a template molecule and a molecularly imprinted layer was coated on the surface of highly fluorescent N-CDs using a reversed-phase microemulsion method to form N-CDs@MIPs. It was possible to specifically identify CTC without the influence of TC and OTC, which are extremely similar in structure. By comparing with the non-imprinted polymer (N-CDs@NIPs), it exhibited high sensitivity and selectivity with an imprinting factor of 2.02. And it was used in the determination of CTC in milk with recoveries and relative standard deviations of 96.7%-109.8% and 0.64%-3.27%, respectively, with high accuracy and precision. The specificity of the measurement is excellent compared with other assays, and it is a valid and reliable assay.

Synthesis of fluorescent probe based on molecularly imprinted polymers on nitrogen-doped carbon dots for determination of tobramycin in milk.

Tobramycin (TOB) plays a considerable role in combating milk spoilage and preventing disease in dairy cows. However, overuse of TOB can lead to nephrotoxicity, ototoxicity, neuromuscular blockade, and hypersensitivity reactions. Here, nitrogen-doped carbon dots (N-CDs) were prepared with ethylenediamine and citric acid, then molecularly imprinted layers were obtained by imprinting of surface on the N-CDs to prepare Nitrogen-doped carbon dot-based molecularly imprinted polymers (N-CDs@MIPs). The fluorescence emission spectrum of this probe showed a linear enhancement with the TOB concentration in the 1-12 µM. Meanwhile, a detection limit of 99.2 nM was obtained. This probe was not affected by the structural analogs of the TOB and can show high sensitivity and selectivity compared to non-imprinted polymers (N-CDs@NIPs). Therefore, it can be successfully used for the trace analysis of TOB in milk with advantages over other reported techniques such as liquid chromatography coupled with tandem mass spectrometry or various aptamer sensors.

Proton pump inhibitor-enhanced nanocatalytic ferroptosis induction for stimuli-responsive dual-modal molecular imaging guided cancer radiosensitization.

Although radiotherapeutic efficiency has been revealed to be positively correlated with ferroptosis, the neutral/alkaline cytoplasm pH value of tumor cells remains an intrinsic challenge for efficient Fenton/Fenton-like reaction-based ferroptosis induction. Herein, PEGylated hollow mesoporous organosilica nanotheranostics (HMON)-GOx@MnO2 nanoparticles (HGMP NPs) were designed as a ferroptosis inducer, which could specifically release Mn2+ in tumor cells to activate the Fenton-like reaction for ferroptosis induction. Proton pump inhibitors (PPIs) were synchronously administered for cytoplasm pH level regulation by inhibiting V-H+-ATPases activity, enhancing Fenton-like reaction-based ferroptosis induction. Moreover, reactive oxygen species production was facilitated via the glucose oxidase triggered cascade catalytic reaction by utilizing intracellular ß-D-glucose for H2O2 self-supply and generation of additional cytoplasm H+. The PPI enhanced ferroptosis inducing nanosystem effectively inhibited tumor growth both in vitro and in vivo for tumor-specific ferroptosis induction and radiotherapy sensitization, suggesting that PPI administration could be an efficient adjuvant to reinforce Fenton/Fenton-like reaction-based ferroptosis induction for radiosensitization. STATEMENT OF SIGNIFICANCE: The cytoplasm pH value of tumor cells is typically neutral to alkaline, which is higher than that of the Fenton/Fenton-like reaction desired acidic environments, hindering its efficiency. In this study, PEGylated hollow mesoporous organosilica nanotheranostics (HMON)-GOx@MnO2 nanoparticles were synthesized as a ferroptosis inducer, which could specifically release Mn2+ via depleting glutathione and then activate the Fenton-like reaction in the tumor microenvironment. The glucose oxidase was applied for H2O2 self-supply and addition of cytoplasm H+ to further boost the Fenton-like reaction. We found that proton pump inhibitors (PPIs) increased intracellular acidification by inhibiting the activity of V-H+-ATPases to enhance the Fenton reaction-based ferroptosis induction, suggesting PPIs administration could be a feasible strategy to reinforce ferroptosis induction for radiosensitization.

Rapid synthesis of 'yolk-shell'-like nanosystem for MR molecular and chemo-radio sensitization.

Though amounts of attempts about nanomedicine for chemo-radiotherapy have been made, more efficient strategies for chemo-radio therapy enhancement still need to be studied and perfected. Herein, a 'yolk-shell'-like nanostructure (Bi2S3@mBixMnyOz nanosystem) was facilely constructed by directly using radiosensitizer Bi2S3 nanorods (NRs) as a partial sacrificial template. Then, the chemotherapeutic drug doxorubicin (DOX) loaded PEGylated Bi2S3@mBixMnyOz nanosystem (PBmB-DOX) was constructed, which could realize tumor microenvironment (TME)-responsive drug release for chemotherapy sensitivity enhancement. And the Bi2S3 NRs core could deposit more radiant energy to improve the radiotherapy sensitivity. Meanwhile, the compounds shell could catalyze H2O2 to generate O2, so as to alleviate tumor hypoxia for further chemo-radio therapy sensitization enhancement. More importantly, ferroptosis was participated in the process of PBmB-induced therapy via glutathione (GSH)-depletion mediated GPX4 inactivation, together with Mn ions induced chemodynamic therapy (Fenton-like reaction), which made additional contributions to increase the therapeutic efficacy. Last but not least, the GSH-stimulated degradation of compounds shell could contribute to self-enhanced T1-MR imaging activation, which allowed on-demand tumor diagnosis. In this work, the synthetic strategy that directly using Bi2S3 NRs as a partial sacrificial template to rapidly synthesize the 'yolk-shell'-like nanostructure for nanomedical application has rarely been reported before. And the in vitro and in vivo results suggest that our 'yolk-shell'-like PBmB-DOX nanosystem holds great promise to regulate TME for tumor-specific diagnosis and synergistic therapy.

Functionalized Au@Cu-Sb-S Nanoparticles for Spectral CT/Photoacoustic Imaging-Guided Synergetic Photo-Radiotherapy in Breast Cancer.

BACKGROUND: Radiotherapy (RT) is clinically well-established cancer treatment. However, radioresistance remains a significant issue associated with failure of RT. Phototherapy-induced radiosensitization has recently attracted attention in translational cancer research. METHODS: Cu-Sb-S nanoparticles (NPs) coated with ultra-small Au nanocrystals (Au@Cu-Sb-S) were synthesized and characterized. The biosafety profiles, absorption of near-infrared (NIR) laser and radiation-enhancing effect of the NPs were evaluated. In vitro and in vivo spectral computed tomography (CT) imaging and photoacoustic (PA) imaging were performed in 4T1 breast cancer-bearing mice. The synergetic radio-phototherapy was assessed by in vivo tumor inhibition studies. RESULTS: Au@Cu-Sb-S NPs were prepared by in situ growth of Au NCs on the surface of Cu-Sb-S NPs. The cell viability experiments showed that the combination of Au@Cu-Sb-S+NIR+RT was significantly more cytotoxic to tumor cells than the other treatments at concentrations above 25 ppm Sb. In vitro and in vivo spectral CT imaging demonstrated that the X-ray attenuation ability of Au@Cu-Sb-S NPs was superior to that of the clinically used Iodine, particularly at lower KeV levels. Au@Cu-Sb-S NPs showed a concentration-dependent and remarkable PA signal brightening effect. In vivo tumor inhibition studies showed that the prepared Au@Cu-Sb-S NPs significantly suppressed tumor growth in 4T1 breast cancer-bearing mice treated with NIR laser irradiation and an intermediate X-ray dose (4 Gy). CONCLUSION: These results indicate that Au@Cu-Sb-S integrated with spectral CT, PA imaging, and phototherapy-enhanced radiosensitization is a promising multifunctional theranostic nanoplatform for clinical applications.

Noninvasively visualize the expression of LAPTM4B protein using a novel 18F-labeled peptide PET probe in hepatocellular carcinoma.

OBJECTIVE: Lysosomal protein transmembrane 4 beta (LAPTM4B) is selectively expressed in hepatocellular carcinoma (HCC) cells and thus a potential biomarker for diagnosing HCC. In this study, we designed a novel 18F-labeled PET probe to non-invasively visualize LAPTM4B expression in mouse model of HCC tumor. METHODS: A PET targeting tracer named [18F]FP-LAP2H was radio-synthesized using a LAPTM4B targeting peptide, LAP2H, coupled with 4-nitrophenyl-2-[18F]fluoropropionate ([18F]NFP). Radio-stability, cell uptake, micro PET/CT imaging and ex vivo biodistribution were performed for determining its stability, cell binding specificity, and tumor targeting in vivo. RESULTS: [18F]FP-LAP2H was successfully synthesized with radiochemical yields of 6-14% (decay-corrected yield) and molar activity of 10-44 GBq/µmol. The tracer showed stable (~90%) in phosphate-buffered saline, pH 7.4, and in human serum (~80%) for 2 h. In vitro cell uptake studies indicated the radioactivity accumulation in HCC cells was LAPTM4B protein-specific. Micro PET/CT demonstrated that implanted LAPTM4B positive HepG2 and BEL7402 tumors could be clearly visualized. The ex vivo biodistribution studies demonstrated that the tumor/liver ratio were 1.80 ± 0.65 and 2.09 ± 0.68 in implanted HepG2 and BEL7402 tumors respectively. Negative control and blocking experiments revealed that the radioactivity uptake in the HCC tumor was LAPTM4B protein-specific. CONCLUSIONS: [18F]FP-LAP2H appears to be a potential PET tracer for imaging LAPTM4B-positive HCC tumor. Further endeavors need to do to improve tumor/liver ratio.

[18F-FDG PET/CT manifestations of massive type active pulmonary tuberculosis and its differentiation from lung cancer].

OBJECTIVE: To investigate 18F-FDG PET/CT manifestations of massive type active tuberculosis and lung cancer and the differential diagnosis of the two diseases based on 18F-FDG PET/CT findings. METHODS: We retrospectively collected the data from 74 patients with active tuberculosis and 64 patients with lung cancer, whose lesions presented as solid masses on CT. The demographic and clinical data of the patients, 18F-FDG PET characteristics including SUVmax, 18F-FDG uptake (higher than mediastinal blood pool or not), radioactive defect within the lesion, and the CT findings including the lesion size, signs of cavity, vacuoles, lobulation, smooth border, and mediastinal/lung window ratio (M/L ratio) of the lesions were analyzed. Univariate and multivariate analyses were used to compare the variables between the two groups, and a logistic regression model was established for differentiation of the two diseases. The diagnostic efficiency was evaluated by area under the receiver-operating characteristic (ROC) curve analysis. RESULTS: No significant differences were found in the quantitative index (SUVmax >2.5 or not) or in the qualitative index (uptake of lesion higher than mediastinal blood pool or not) in PET between massive type active tuberculosis and lung cancer (P>0.05). Univariate analysis revealed that SUVmax, 18F-FDG uptake of the lesion, age, lesion size, signs of cavity, or M/L ratio were not significantly different (P>0.05), but gender, signs of radioactive defect, vacuoles, smooth border and lobulation were significantly different (P < 0.05) between the two diseases. Multivariate analysis showed that gender, signs of radioactive defect, smooth border and lobulation of the lesion were independent factors for discrimination of the two diseases (P < 0.05). A risk prediction model for active tuberculosis was established based on logistic regression analysis: P=1/(1+e-x), X=-0.530+1.978×gender+3.343×radioactive defect +2.846×smooth border-2.116×lobulation. For diagnosis of active tuberculosis, the sensitivity, specificity, accuracy, positive predictive value and negative predictive value of this model were 78.4%, 92.2%, 84.8%, 92.1%, and 78.7%, respectively. CONCLUSIONS: The combined analysis of gender, signs of radioactive defect, smooth border and lobulation of the lesions is useful for discriminating massive type active tuberculosis from lung cancer in the majority of the patients, whereas 18F-FDG uptake alone has only limited value for a differential diagnosis.

Synthesis and Evaluation of 18F-Labeled Peptide for Gonadotropin-Releasing Hormone Receptor Imaging.

The gonadotropin-releasing hormone (GnRH) receptor is overexpressed in the majority of tumors of the human reproductive system. The purpose of this study was to develop an 18F-labeled peptide for tumor GnRH receptor imaging. In this study, the GnRH (pGlu1-His2-Trp3-Ser4-Tyr5-Gly6-Leu7-Arg8-Pro9-Gly10-NH2) peptide analogues FP-d-Lys6-GnRH (FP = 2-fluoropropanoyl) and NOTA-P-d-Lys6-GnRH (P = ethylene glycol) were designed and synthesized. The IC50 values of FP-d-Lys6-GnRH and NOTA-P-d-Lys6-GnRH were 2.0 nM and 56.2 nM, respectively. 4-Nitrophenyl-2-[18F]fluoropropionate was conjugated to the ε-amino group of the d-lysine side chain of d-Lys6-GnRH to yield the new tracer [18F]FP-d-Lys6-GnRH with a decay-corrected yield of 8 ± 3% and a specific activity of 20-100 GBq/µmol (n=6). Cell uptake studies of [18F]FP-d-Lys6-GnRH in GnRH receptor-positive PC-3 cells and GnRH receptor-negative CHO-K1 cells indicated receptor-specific accumulation. Biodistribution and PET studies in nude mice bearing PC-3 xenografted tumors showed that [18F]FP-d-Lys6-GnRH was localized in tumors with a higher uptake than in surrounding muscle and heart tissues. Furthermore, the metabolic stability of [18F]FP-d-Lys6-GnRH was determined in mouse blood and PC-3 tumor homogenates at 1 h after tracer injection. The presented results indicated a potential of the novel tracer [18F]FP-d-Lys6-GnRH for tumor GnRH receptor imaging.

Utility of Maximum Standard Uptake Value as a Predictor for Differentiating the Invasiveness of T1 Stage Pulmonary Adenocarcinoma.

BACKGROUND: The present study was performed to investigate the maximum standardized uptake value (SUVmax) in 2-[fluorine-18]-fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) to preoperatively distinguish invasive from less-invasive pulmonary adenocarcinoma. PATIENTS AND METHODS: A total of 106 patients with resectable pulmonary adenocarcinoma (≤ 3 cm) who had undergone whole-body 18F-FDG PET/CT were enrolled. The SUVmax, diameter, and consolidation/tumor (C/T) ratio of the lung tumors were measured with 18F-FDG PET/CT and regional thin-section CT. RESULTS: Of the 106 patients, 32 had adenocarcinoma in situ (AIS), 13 had minimally invasive adenocarcinoma (MIA), and 61 had invasive adenocarcinoma (IAC). IAC lesions showed greater uptake of 18F-FDG, a larger tumor diameter, and greater C/T ratios than AIS and MIA (P < .001 for all). A multivariate analysis revealed that only the SUVmax, tumor diameter, and C/T ratio were independent risk factors for tumor invasiveness (P < .05 for all). The best cutoff values for the prediction of invasiveness were 2.15 for the SUVmax, 1.36 cm for the tumor diameter, and 0.36 for the C/T ratio. The SUVmax, tumor diameter, and C/T ratio showed similar predictive sensitivity (83.6%, 82.0%, and 88.5%, respectively). However, the SUVmax showed a greater predictive specificity than the C/T ratio (93.3% vs. 73.3%, respectively; P = .011) but similar to that of the tumor diameter. The predictive sensitivity and specificity were not improved using the 3 combined parameters compared with SUVmax alone. CONCLUSION: The present study has demonstrated that the SUVmax is a good preoperative predictor for the invasiveness of pulmonary adenocarcinoma (≤ 3 cm). It will help surgeons plan low invasive treatment of preinvasive tumors.

Prognostic value of 18F-fluorodeoxyglucose PET parameters and inflammation in patients with nasopharyngeal carcinoma.

The aim of the present study was to investigate the association between positron emission tomography (PET) parameters and peripheral inflammatory markers, and assess their prognostic value in nasopharyngeal carcinoma (NPC). A total of 121 patients with non-disseminated NPC were recruited. Pretreatment maximum standardized uptake values (SUVmax) of PET and peripheral inflammatory factors (leukocyte, neutrophil and monocyte counts) were recorded. Kaplan-Meier and multivariate analyses were used to identify predictors for progression-free survival (PFS), overall survival (OS), distant metastasis-free survival (DMFS) and locoregional recurrence-free survival (LRFS). The results of the present study revealed that SUVmax at the primary tumor was positively correlated with leukocytes (P=0.025), neutrophils (P=0.009) and monocytes (P=0.043). SUVmax at regional lymph nodes (SUVmax-N) was significantly associated with monocytes (P=0.024). Kaplan-Meier analysis demonstrated that SUVmax-N (>10.15) significantly predicted PFS (P=0.004) and DMFS (P=0.003). In addition, neutrophils (>5.18) were significantly associated with PFS (P=0.001), DMFS (P=0.013) and LRFS (P<0.001). Multivariate analysis revealed that SUVmax-N and neutrophils retained independent prognostic significance for PFS (SUVmax-N, P=0.026; and neutrophils, P=0.033) and DMFS (SUVmax-N, P=0.026; and neutrophils, P=0.032). Furthermore, patients with SUVmax-N ≤10.15 and neutrophils ≤5.18 had significantly improved prognosis in PFS (96.4 vs. 58.5%, P<0.001), OS (95.7 vs. 81.1%, P=0.044), DMFS (96.4 vs. 67.0%, P<0.001) and LRFS (100 vs. 90.2%, P=0.036) compared with those with SUVmax-N >10.15 or neutrophils >5.18. In conclusion, SUVmax may be significantly associated with cancer-associated inflammation. SUVmax-N and neutrophils were independent prognostic indicators for PFS and DMFS. Combined assessment of SUVmax-N and neutrophils may lead to refinement of risk stratification in NPC.

[Combined use of thin-section CT and 18F-FDG PET/CT for characterization of solitary pulmonary nodules].

OBJECTIVE: To investigate whether fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) combined with thin-section CT improves the diagnostic performance for solitary pulmonary nodules (SPNs). METHODS: A total of 267 patients underwent examinations with 18F-FDG PET/CT and thin-section CT for evaluating the SPNs with undetermined nature, which was further confirmed by pathological examination or clinical follow-up. The performance of two diagnostic criteria based on findings in PET/CT alone (Criterion 1) and in PET/CT combined with thin-section CT (Criterion 2) were compared. RESULTS: Thin-section CT provided greater diagnostic information for SPNs in 84.2% of the patients. Compared with Criterion 1, the diagnosis based on Criterion 2 significantly increased the diagnostic sensitivity (80.4% vs 91%, P<0.01) and accuracy (76.4% vs 87.2%, P<0.01) for lung cancer. The lesion size and the CT features including lobulation, air bronchogram, and feeding vessel, but not SUVmax, were all helpful for characterizing non-solid SPNs. Thin-section CT rectified diagnostic errors in 50% (20/40) of the cancerous lesions, which had been diagnosed as benign by PET due to their low metabolism. For non-solid SPNs, Criterion 2 showed a significantly higher diagnostic sensitivity than Criterion 1 (90.0% vs 40.0%, P=0.000) but their diagnostic specificity were comparable (75.2% vs 58.3%, P=0.667). For solid nodules, the use of thin-section CT resulted in no significant improvement in the diagnostic performance (P<0.05). CONCLUSION: The combination of PET/CT and thin-section CT creates a synergistic effect for the characterization of SPNs, especially non-solid nodules.

Whole-body 18F-FDG PET/CT for M staging in the patient with newly diagnosed nasopharyngeal carcinoma: Who needs?

OBJECTIVE: Although whole-body fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) (18F-FDG PET/CT) is commonly used for M staging of newly diagnosed nasopharyngeal carcinoma (NPC), some patients may not benefit from this procedure. The present study investigated which patients require this modality for M staging. METHODS: Whole-body 18F FDG PET/CT results and clinical data were collected for 264 patients with newly diagnosed NPC. The relationships between distant metastasis and age, gender, pathological type, lesion size, SUVmax-T, T staging, N staging, SUVmax-N and Epstein-Barr virus (EBV) quantity were retrospectively analysed to identify factors associated with increased risk. RESULTS: Of the 264 patients, only 37 (14.0%) were diagnosed with distant metastasis. Using multiple logistic regression analysis, EBV-positivity (OR=13.1; 95% CI:1.61,106.80), N staging (OR=3.05; 95% CI:1.41,6.63) and T staging (OR=2.16; 95% CI:1.10, 4.24) were significantly related to distant metastasis (all P<0.05). EBV DNA levels≥9000copies/ml, N3 stage and T4 stage were identified as high risk factors. A low risk of distant metastasis was found in patients with 0-1 risk factors and in those with 2 specific risk factors, T3/T4 and N2/N3 staging. Patients with EBV DNA levels ≥9000copies/ml and N3 or T4 staging and those with 3 risk factors had a medium or high risk, with a much higher incidence of distant metastasis (χ2=29.896, P=0.000), and needed a whole-body 18F FDG PET/CT for M staging. CONCLUSIONS: Due to the low incidence of distant metastasis, only patients with medium or high risk need to undergo a whole-body scan.

18F-FDG super bone marrow uptake: A highly potent indicator for the malignant infiltration.

The present study was performed to investigate whether the markedly 2-deoxy-2-(fluorine-18) fluoro-D-glucose (F-FDG) uptake in the bone marrow (BM) is a presentation of malignant infiltration (MI).Super bone marrow uptake (super BMU) was used to name the markedly F-FDG uptake on BM, which was similar to or higher than that of the brain. From April 2008 to December 2015, 31 patients with such presentation were retrospectively reviewed. The F-FDG uptake was semiquantified using SUVmax and BM to cerebellum (BM/C) ratio. The origin of super BMU was diagnosed by pathology. Some blood parameters, as well as fever, were also collected and analyzed. For comparison, 106 patients with mildly and moderately uptake in BM and 20 healthy subjects were selected as the control group.Bone marrow MI was diagnosed in 93.5% (29/31) patients with super BMU, which mostly originated from acute leukemia and highly aggressive lymphoma. The super BMU group had markedly higher F-FDG uptake in the BM than those of mildly and moderately uptake, and the control subjects (all P = 0.000) and the BM/C ratio reached a high of 1.24 ±â€Š0.36. The incidence of bone marrow MI in the super BMU group was markedly higher than that of mildly and moderately uptake (93.5% vs 36.8%, P = 0.000). Based on the receiver operating characteristic analysis, when cut-off values of BM/C and SUVmax were set at 0.835 and 6.560, the diagnostic specificity for bone marrow MI reached the high levels of 91.4% and 95.7%, respectively. In 15 patients with bone marrow MI, the extra-BM malignant lesions were simultaneously detected by F-FDG PET/CT. The liver and the nasal cavity involvements were only found in the patients with lymphoma, but not in those with leukemia. A decrease of leukocyte, hemoglobin, and platelet counts was noted in 48.4%, 86.2%, and 51.5% of patients with bone marrow MI, respectively.The present study revealed that super BMU was a highly potent indicator for the bone marrow MI.