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2016  (10 / Total 98 )

  • 1
    Jin X, Liang N, Wang M, Meng Y, Jia B, Shi X, Li S, Luo J, Luo Y, Cui Q, Zheng K, Liu Z, Shi J, Li F, Wang F, Zhu Z.Integrin Imaging with 99mTc-3PRGD2 SPECT/CT Shows High Specificity in the Diagnosis of Lymph Node Metastasis from Non-Small Cell Lung Cancer.Radiology. 2016 Dec;281(3):958-966.

    Abstract:

    Purpose To evaluate an integrin imaging approach based on single photon emission computed tomography (SPECT)/computed tomography (CT) by using technetium 99m (99mTc)-dimeric cyclic arginine-glycine-aspartic acid (RGD) peptides with three polyethylene glycol spacers (3PRGD2) as the tracer to target the integrin αvβ3 expression in lung cancer and lymph node metastasis. Materials and Methods With ethics committee approval and written informed consent, 65 patients (41 male, 24 female; mean age, 60 years ± 11 [standard deviation]) with suspicious lung lesions were recruited with informed consent. The patients underwent both99mTc-3PRGD2 SPECT/CT and fluorine 18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT within 1 week. Finally, 65 lung lesions in 53 patients were pathologically diagnosed as non-small cell lung cancer (NSCLC) and 14 lung lesions in 12 patients were benign. Per-region analysis of lymph nodes included 248 regions with metastasis and 56 negative regions. Twenty specimens from the removed lung lesions or lymph nodes were stained with integrin αvβ3, CD34, and Ki-67 to correlate with the image findings. Receiver operating characteristic curve, z statistics, McNemar test, and χ2 analysis were used to compare the diagnostic performance of the two imaging methods. Results 99mTc-3PRGD2 SPECT/CT was found to be more specific than 18F-FDG PET/CT in the per-region diagnosis of lymph node metastasis (specificity, 94.6% vs 75.0%; P = .008) when the sensitivity of the two methods was comparable (88.3% vs 90.7%; P = .557). There was no significant difference between the two methods in the per-lesion diagnosis of lung tumor (z = 0.82, P = .410). The accumulation level of 99mTc-3PRGD2 was found in positive correlation with the integrin αvβ3expression (r = 0.84, P = .001) and microvessel density (r = 0.63, P = .011) in the tumors. Conclusion 99mTc-3PRGD2 SPECT/CT shows high specificity in the diagnosis of lymph node metastasis from NSCLC, which may benefit surgical decision making for the patients.

                                                               


    Radiology., 2016 Jul 29:150813

    DOI:10.1148/radiol.2016150813

    Publication Date(Web): Jul 29 ,
    2016 

  • 2
    Yu X, Wu Y, Liu H, Gao L, Sun X, Zhang C, Shi J, Zhao H, Jia B, Liu Z, Wang F.Small-Animal SPECT/CT of the Progression and Recovery of Rat Liver Fibrosis by Using an Integrin αvβ3-targeting Radiotracer.Radiology. 2016 May;279(2):502-12.

    Abstract:

    To assess the potential utility of an integrin αvβ3-targeting radiotracer, technetium 99m-PEG4-E[PEG4-cyclo(arginine-glycine-aspartic acid-D-phenylalanine-lysine)]2 (99mTc-3PRGD2), for single photon emission computed tomography (SPECT)/computed tomography (CT) for monitoring of the progression and prognosis of liver fibrosis in a rat model.

    .99mTc-3PRGD2 was prepared and longitudinal SPECT/CT was performed to monitor the progression (n = 8) and recovery (n = 5) of liver fibrosis induced in a rat model by means of thioacetamide (TAA) administration. The mean liver-to-background radioactivity per unit volume ratio was analyzed for comparisons between the TAA and control (saline) groups at different stages of liver fibrosis. Data were compared by using Student t and Mann-Whitney tests. Accumulation of 99mTc-3PRGD2 in the liver increased in proportion to the progression of fibrosis and TAA exposure time; accumulation levels were significantly different between the TAA and control groups as early as week 4 of TAA administration. Results of ex vivo immunofluorescence staining demonstrated the positive expression of integrin αvβ3 on the activated hepatic stellate cells, and the integrin αvβ3 levels in the liver corresponded to the results of SPECT/CT (R2= 0.75, P < .0001). 99mTc-3PRGD2 SPECT/CT was successfully used to monitor the progression and recovery of liver fibrosis and shows potential applications for noninvasive diagnosis of early stage liver fibrosis.

                                             

    Figure 3a: Blocking studies of 99mTc-3PRGD2 in rats treated with saline or TAA(a) SPECT/CT images of rats treated with saline (control) or TAA 30 minutes after intravenous injection of 99mTc-3PRGD2 (74 MBq) with or without presence of blocking dose of c(RGDfK) (cRGD) or c(RADfK) (cRAD). Images were adjusted by using the same scale for all animals. (b) Bar chart shows mean liver-to-background radioactivity per unit volume ratio. *** =P < .0001.


    Radiology, 2016 May;279(2):502-12.

    DOI:10.1148/radiol.2015150090

    Publication Date(Web):Dec 14 ,2015


  • 3
    Zhang X, Yao M, Chen M, Li L, Dong C, Hou Y, Zhao H, Jia B, Wang F. Hyaluronic Acid-Coated Silver Nanoparticles As a Nanoplatform for in Vivo Imaging Applications.ACS Appl Mater Interfaces. 2016 Oct 5;8(39):25650-25653.

    Abstract:

    An efficient chemical reduction protocol has been developed for the synthesis of hyaluronic acid-coated silver nanoparticles (HA-Ag NPs) that are spherical, ultrasmall and monodisperse. The as-synthesized HA-Ag NPs not only exhibited excellent long-term stability and low cytotoxicity but also could be used as a nanoplatform for X-ray computed tomography (CT) and single-photon emission computed tomography (SPECT) imaging after being radiolabeled with 99mTc.


                                                          


    ACS Appl Mater Interfaces.  ,2016 ,8(39):25650-25653
    DOI:10.1021/acsami.6b08166

    Publication Date(Web):Oct 5 ,2016     


  • 4
    Zhao H, Gao H, Zhai L, Liu X, Jia B, Shi J, Wang F.99mTc-HisoDGR as a Potential SPECT Probe for Orthotopic Glioma Detection via Targeting of Integrin α5β1.Bioconjug Chem. 2016 May 18;27(5):1259-66. Epub 2016 May 3.

    Abstract:

    Integrins, a large family of cell adhesion receptors, have been shown to play an important role for glioma proliferation and invasion. Several integrin receptors, including αvβ3, αvβ5, and α5β1, have generated clinical interest for glioma diagnosis and antitumor therapy. Integrin α5β1 has been highlighted as a prognostic and diagnostic marker in glioma, and its expression is correlated with a worse prognosis in high-grade glioma. However, unlike extensively studied integrins αvβ3 and αvβ5, very few integrin α5β1-specific radiotracers have been reported. Developing α5β1-specific radiotracers may provide alternative diagnosis and evaluation options in addition to well-studied αvβ3/αvβ5-specific tracers, and they may add new documents for profiling tumor progression. Here, a novel integrin α5β1-specific probe 99mTc-HisoDGR was fabricated for SPECT (single-photon emission computed tomography) imaging of glioma. To confirm its selective targeting of integrin α5β1 in vivo, the mouse models of α5β1-positive U87MG human glioma were subjected to SPECT/CT scans, and biodistribution experiments and blocking studies were performed. Small-animal SPECT/CT imaging experiments demonstrated that the tumors were clearly visualized in both subcutaneous and orthotopic glioma tumor models with clear background at 0.5, 1, and 2 h p.i. The tumor accumulation of 99mTc-HisoDGR showed significant reduction when excess cold isoDGR peptide was coinjected, suggesting that the tumor uptake was specifically mediated. Our work revealed that 99mTc-HisoDGR represented a powerful molecular probe for integrin α5β1-positive cancer imaging; moreover, it might be a promising tool for evaluating malignancy, predicting prognosis, selecting subpopulations of patients who might be sensitive to integrin α5β1-targeted drugs, and assessing and monitoring the response to integrin α5β1-targeted drugs in clinical trials.

                                                          


    Bioconjug Chem. ,2016 May 18;27(5):1259-66. 

    DOI: 10.1021/acs.bioconjchem.6b00098.

    Publication Date(Web):May 3 ,2016


     

  • 5
    Ji T, Gao S, Liu Z, Xing H, Zhao G, Ma Q.99mTc-Glu-c(RGDyK)-Bombesin SPECT Can Reduce Unnecessary Biopsy of Masses That Are BI-RADS Category 4 on Ultrasonography.J Nucl Med. 2016 Aug;57(8):1196-200.Epub 2016 Mar 24.

    Abstract:

    Masses that, on ultrasonography, are category 4 according to the Breast Imaging Reporting and Data System (BI-RADS) represent possible malignancy, and a biopsy is recommended. This study explored the value of 99mTc-Glu-c(RGDyK)-bombesin (99mTc-RGD-bombesin) in reducing unnecessary biopsy of these masses.

    Ninety women with a BI-RADS 4 mass on ultrasonography were enrolled in this study to undergo breast SPECT using 99mTc-RGD-bombesin. The images were independently interpreted using qualitative visual and semiquantitative analyses. The final diagnosis was based on histopathologic examination of surgically excised or percutaneous biopsy specimens. Fractions of the samples were immunohistochemically analyzed to evaluate expression of integrin αvβ3 and gastrin-releasing peptide receptor (GRPR). The receptor-positive group was further divided into 3 subgroups (GRPR(+)/αvβ3 (+), GRPR(+)/αvβ3 (-), and αvβ3 (+)/GRPR(-)).

    Ninety-four masses (22 malignant and 72 benign) were confirmed by histopathologic examination. On qualitative analysis, 20 of the malignant masses showed high 99mTc-RGD-bombesin accumulation and 48 of the benign masses showed no 99mTc-RGD-bombesin accumulation. The optimal cutoff for qualitative analysis was a score of 2. Semiquantitative analysis revealed that 20 of the malignant masses and 16 of the benign masses had a relatively high tumor-to-normal-tissue ratio (T/N). The optimal cutoff was a T/N of 2.26. The mean T/N was higher for malignant masses than for benign masses (3.17 ± 0.86 vs. 1.89 ± 0.71, P < 0.05). T/Ns did not differ among the 3 subgroups (P > 0.05). The areas under the receiver-operating-characteristic curves for the qualitative and semiquantitative analyses were 0.788 and 0.865, respectively, and the overall diagnostic performance did not significantly differ between these analyses (P > 0.05).

    99mTc-RGD-bombesin SPECT can differentiate benign from malignant BI-RADS 4 masses with high specificity. Further study of the application of this test to clinical breast cancer appears warranted.

                                                                                  


    J Nucl Med. 2016, 57(8), 1196-200. 

    DOI:10.2967/jnumed.115.168773.

    Publication Date(Web):Mar 24, 2016 
  • 6
    Gao L, Zhang C, Gao D, Liu H, Yu X, Lai J, Wang F, Lin J, Liu Z. Enhanced Anti-Tumor Efficacy through a Combination of Integrin αvβ6-Targeted Photodynamic Therapy and Immune Checkpoint Inhibition. Theranostics. 2016 Mar 3;6(5):627-37.


    Abstract:

        "Training" the host immune system to recognize and systemically eliminate residual tumor lesions and micrometastases is a promising strategy for cancer therapy. In this study, we investigated whether integrin αvβ6-targeted photodynamic therapy (PDT) of tumors using a phthalocyanine dye-labeled probe (termed DSAB-HK) could trigger the host immune response, and whether PDT in combination with anti-PD-1 immune checkpoint inhibition could be used for the effective therapy of primary tumors and metastases. By near-infrared fluorescence imaging, DSAB-HK was demonstrated to specifically target either subcutaneous tumors in a 4T1 mouse breast cancer model or firefly luciferase stably transfected 4T1 (4T1-fLuc) lung metastatic tumors. Upon light irradiation, PDT by DSAB-HK significantly inhibited the growth of subcutaneous 4T1 tumors, and in addition promoted the maturation of dendritic cells and their production of cytokines, which subsequently stimulated the tumor recruitment of CD8(+) cytotoxic T lymphocytes. Furthermore, DSAB-HK PDT of the first tumor followed by PD-1 blockade markedly suppressed the growth of a second subcutaneous tumor, and also slowed the growth of 4T1-fLuc lung metastasis as demonstrated by serial bioluminescence imaging. Together, our results demonstrated the synergistic effect of tumor-targeted PDT and immune checkpoint inhibition for improving anti-tumor immunity and suppressing tumor growth/metastasis.


     


    Theranostics. 2016, 6(5), 627-37

    Doi: 10.7150/thno.14792.

  • 7
    Li D, Chen Y, Wang X, Deuther-Conrad W, Chen X, Jia B, Dong C, Steinbach J, Brust P, Liu B, Jia H. (99m)Tc-Cyclopentadienyl Tricarbonyl Chelate-Labeled Compounds as Selective Sigma-2 Receptor Ligands for Tumor Imaging. J Med Chem. 2016 Feb 11;59(3):934-46.


    Abstract:

        We have designed and synthesized a series of cyclopentadienyl tricarbonyl rhenium complexes containing a 5,6-dimethoxyisoindoline or a 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline pharmacophore as σ2 receptor ligands. Rhenium compound 20a possessed low nanomolar σ2 receptor affinity (Ki = 2.97 nM) and moderate subtype selectivity (10-fold). Moreover, it showed high selectivity toward vesicular acetylcholine transporter (2374-fold), dopamine D2L receptor, NMDA receptor, opiate receptor, dopamine transporter, norepinephrine transporter, and serotonin transporter. Its corresponding radiotracer [99mTc]20b showed high uptake in a time- and dose-dependent manner in DU145 prostate cells and C6 glioma cells. In addition, this tracer exhibited high tumor uptake (5.92% ID/g at 240 min) and high tumor/blood and tumor/muscle ratios (21 and 16 at 240 min, respectively) as well as specific binding to σ receptors in nude mice bearing C6 glioma xenografts. Small animal SPECT/CT imaging of [99mTc]20b in the C6 glioma xenograft model demonstrated a clear visualization of the tumor at 180 min after injection.


    J. Med. Chem., 2016, 59 (3), pp 934–946

    DOI: 10.1021/acs.jmedchem.5b01378

    Publication Date (Web): January 7, 2016


  • 8
    Gao L, Liu H, Sun X, Gao D, Zhang C, Jia B, Zhu Z, Wang F, Liu Z. Molecular Imaging of Post-Src Inhibition Tumor Signatures for Guiding Dasatinib Combination Therapy. J Nucl Med. 2016 Feb;57(2):321-6.

    Abstract
        Noninvasive, real-time, quantitative measurement of key biomarkers associated with cancer therapeutic interventions could provide a better understanding of cancer biology. We investigated in this study whether incorporating multiple molecular imaging approaches could be used to guide dasatinib anti-Src therapy and aid in the rational design of a combination therapy regimen. Bioluminescence imaging, (18)F-FDG PET, integrin αvβ3-targeted SPECT/CT, and vascular endothelial growth factor-targeted near-infrared fluorescence imaging were performed before and after dasatinib treatment in a tumor mouse model. There was no significant difference in the bioluminescence imaging signal or (18)F-FDG tumor uptake in dasatinib-treated tumors compared with the control tumors. However, the uptake of (99m)T-3PRGD2 (integrin αvβ3-specific) and DyLight755-ranibizumab (vascular endothelial growth factor-specific) in the dasatinib-treated tumors was significantly lower than that in the control tumors. In vitro studies confirmed the antiangiogenic effects of dasatinib but indicated a lack of cytotoxicity. Dasatinib plus cytotoxic docetaxel elicited marked synergistic tumor growth inhibition in vivo. Visualization of post-Src inhibition tumor signatures through multiple imaging approaches facilitates sensitive and quantitative measurement of cancer biomarkers in vivo, thus aiding in the rational design of dasatinib combination therapy.
  • 9
    Zhang C, Gao L, Cai Y, Liu H, Gao D, Lai J, Jia B, Wang F, Liu Z. Inhibition of tumor growth and metastasis by photoimmunotherapy targeting tumor-associated macrophage in a sorafenib-resistant tumor model. Biomaterials. 2016 Jan 13;84:1-12.

    Abstract

        Tumor-associated macrophages (TAMs) play essential roles in tumor invasion and metastasis, and contribute to drug resistance. Clinical evidence suggests that TAM levels are correlated with local tumor relapse, distant metastasis, and poor prognosis in patients. In this study, we synthesized a TAM-targeted probe (IRD-αCD206) by conjugating a monoclonal anti-CD206 antibody with a near-infrared phthalocyanine dye. We then investigated the potential application of the IRD-αCD206 probe to near-infrared fluorescence (NIRF) imaging and photoimmunotherapy (PIT) of tumors resistant to treatment with the kinase inhibitor sorafenib. Sorafenib treatment had no effect on tumor growth in a 4T1 mouse model of breast cancer, but induced M2 macrophage polarization in tumors. M2 macrophage recruitment by sorafenib-treated 4T1 tumors was noninvasively visualized by in vivo NIRF imaging of IRD-αCD206. Small-animal single-photon emission computed tomography (SPECT)/CT and intratumoral microdistribution analysis indicated TAM-specific localization of the IRD-αCD206 probe in 4T1 tumors after several rounds of sorafenib treatment. Upon light irradiation, IRD-αCD206 suppressed the growth of sorafenib-resistant tumors. In vivo CT imaging and ex vivo histological analysis confirmed the inhibition of lung metastasis in mice by IRD-αCD206 PIT. These results demonstrate the utility of the IRD-αCD206 probe for TAM-targeted diagnostic imaging and treatment of tumors that are resistant to conventional therapeutics.


    http://www.sciencedirect.com/science/article/pii/S0142961216000351

    Biomaterials. 2016 Jan 13;84:1-12. doi: 10.1016/j.biomaterials.2016.01.027.

    Received: 28 November 2015

    Revised: 11 January 2016

    Accepted: 12 January 2016

    Available online: 13 January 2016


  • 10
    Dong C, Yang S, Shi J, Zhao H, Zhong L, Liu Z, Jia B, Wang F. SPECT/NIRF Dual Modality Imaging for Detection of Intraperitoneal Colon Tumor with an Avidin/Biotin Pretargeting System. Sci Rep. 2016;6:18905.


    Abstract

        We describe herein dual-modality imaging of intraperitoneal colon tumor using an avidin/biotin pretargeting system. A novel dual-modality probe, 99mTc-HYNIC-lys(Cy5.5)-PEG4-biotin, was designed, synthesized and characterized. Single-photon emission computed tomography/ computed tomography (SPECT/CT) imaging and near infrared fluorescence (NIRF) imaging were developed using intraperitoneal LS180 human colon adenocarcinoma xenografts. Following avidin preinjection for 4 hours, 99mTc-HYNIC-lys(Cy5.5)-PEG4-biotin could successfully detect colon tumors of different sizes inside the abdominal region using both modalities, and the imaging results showed no differences. Biodistribution studies demonstrated that the tumors had a very high uptake of the probe 99mTc-HYNIC-lys(Cy5.5)-PEG4-biotin (12.74 ± 1.89% ID/g at 2 h p.i.), and the clearance from blood and other normal tissues occured very fast. The low tumor uptake in the non-pretargeted mice (1.63 ± 0.50% ID/g at 2 h p.i.) and tumor cell staining results showed excellent tumor binding specificity of the pretargeting system. The ability of the novel probe to show excellent imaging quality with high tumor-to-background contrast, a high degree of binding specificity with tumors and excellent in vivo biodistribution pharmacokinetics should prove that the avidin/biotin based dual-modality pretargeting probe is a promising imaging tool during the entire period of tumor diagnosis and treatment.


    SPECT/CT imaging of 99mTc-HYNIC-lys(Cy5.5)-PEG4-biotin in nude mice bearing LS180 colon tumor. 

    (A,B) Dashed arrows mark location of LS180 tumors of large size among the liver, stomach, spleen and pancreas. (C,D,E) The solid arrows mark the location of LS180 tumors of small size along the intestine wall.


    http://www.nature.com/articles/srep18905. 

    Scientific Reports 6, Article number: 18905 (2016). doi:10.1038/srep18905

    Received: 30 April 2015

    Accepted: 30 November 2015

    Published online: 06 January 2016


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