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授权专利(12项目):
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2008  (7 / Total 98 )

  • 1
    He W, Liu Z, Liu D, Jia B, Wang F*, Cui Y*. Preliminary in vitro Biological Evaluation of Novel O6-benzylguanine Derivative-precursors of PET Tracers for the DNA Repair Protein AGT. Journal of Chinese Pharmaceutical Sciences, 2008, 17:70-74.

    Novel radiolabeled O6-benzylguanine (O6-BG) derivatives, 2-amino-6-O-[11C]-[(methoxymethyl)benzyloxy]-9-methyl purines ([11C]p-O6-AMMP, 1a; [11C]m-O6-AMMP, 1b; [11C]o-O6-AMMP, 1c), 2-amino-6-O-benzyloxy-9-[11C]-[(methoxycarbonyl)methyl]purine ([11C]ABMMP, 2), and 2-amino-6-O-benzyloxy-9-[11C]-[(4′-methoxycarbonyl)benzyl]purine ([11C]ABMBP, 3), have been synthesized for evaluation as new potential positron emission tomography (PET) imaging agents for the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) in breast cancer. The appropriate precursors for radiolabeling were obtained in two to three steps from starting material 2-amino-6-chloropurine with moderate to excellent chemical yields. Tracers were prepared by O-[11C]methylation of hydroxymethyl or acid precursors using [11C]methyl triflate. Pure target compounds were isolated by solid-phase extraction (SPE) purification procedure in 45–65% radiochemical yields (decay corrected to end of bombardment), and a synthesis time of 20–25 min. The activity of unlabeled standard samples of 1–3 was evaluated via an in vitro AGT oligonucleotide assay. Preliminary findings from biological assay indicate the synthesized analogs have similar strong inhibitory effectiveness on AGT in comparison with the parent compound O6-BG. The results warrant further evaluation of these radiotracers as new potential PET imaging agents for the DNA repair protein AGT in breast cancer in vivo.

     

  • 2
    Zhang L, Jia B, Hu C, Wang F*, Cui Y*. Synthesis and Preliminary Biological Evaluation of the Derivatives of O6-benzylguanine as Inactivators of O6-alkylguanine-DNA Alkyltransferase. Chinese Chem Lett. 2008, 19:801-804.
  • 3
    Liu Z, Wang F, Chen X. Integrin αvβ3 Targeted Cancer Therapy. Drug Develop Res. 2008, 69:329-339.

    Abstract

    Anti-angiogenesis is a promising strategy for the treatment of cancer. Integrins, consisting of two noncovalently bound transmembrane alpha and beta subunits, are an important molecular family involved in tumor angiogenesis. The blockade of integrin signaling has been demonstrated to be efficient to inhibit tumor growth, angiogenesis, and metastasis. Among all the integrins, alpha(v)beta(3) seems to be the most important one during tumor angiogenesis. The inhibition of integrin alpha(v)beta(3) signaling with antibodies, peptides, peptidomimetics, and other antagonists has great potential in the treatment of cancer. In addition, integrin alpha(v)beta(3) is highly expressed on activated endothelial cells, new-born vessels as well as some tumor cells, but is not present in resting endothelial cells and most normal organ systems, making it a suitable target for anti-angiogenic therapy. In this article we will review the role of integrin alpha(v)beta(3) in angiogenesis, present recent progress in the use of integrin alpha(v)beta(3) antagonists and integrin-targeted delivery systems as potential cancer therapeutics, and discuss future perspectives.

    http://dx.doi.org/10.1002/ddr.20265

  • 4
    He Q, Liu Z, Jia B, Li X, Shi J, Zhang J, Lan F, Yang Z, Liu Y, Shen L*, Wang F*. In vivo Gamma Imaging of the Secondary Tumors of Transplanted Human Fetal Striatum Neural Stem Cells-derived Primary Tumor Cells. NeuroReport. 2008, 19(10):1009-1014.

    Abstract

    This study describes γ-imaging of the secondary tumors from the transplanted human fetal striatum neural stem cells-derived primary tumor cells in nude mice. The subcutaneous primary tumors were detected to express integrin αvβ3, and the corresponding cells were isolated and enriched in vitro, then transplanted to the nude mice. The technetium-99m-labeled Arg-Gly-Asp peptide, with high affinity to integrin αvβ3, was prepared for biodistribution and γ-imaging. The secondary tumors were readily visualized at 1-h postinjection, and the tumor uptake of radiotracer was similar to that of positive control animals transplanted with U87MG human glioma cells. The tumor specificity of radiotracer was demonstrated by blocking experiment. We concluded that γ-imaging is a promising approach in imaging the tumorigenesis of transplanted stem cells in vivo.

    http://dx.doi.org/10.1097/WNR.0b013e328303c020

  • 5
    Veeravagu A, Liu Z, Niu G, Chen K, Jia B, Cai W, Jin C, Hsu A, Connolly A, Tse V, Wang F*, Chen X*. Integrin-αvβ3 Targeted Radioimmunotherapy of Glioblastoma Multiforme. Clin Cancer Res. 2008, 14(22):7330-7339.

    Purpose: Abegrin is a monoclonal antibody to human integrin αVβ3, a cell adhesion molecule highly expressed on actively angiogenic endothelium and glioblastoma multiforme tumor cells. The purpose of this study was to evaluate the efficacy of a novel90Y-Abegrin radioimmunotherapeutic agent in murine xenograft glioblastoma models with noninvasive in vivo molecular imaging modalities.

    Experimental Design: A s.c. U87MG human glioblastoma xenograft model was used to determine maximum tolerated dose (MTD), biodistribution, dose response, and efficacy of90Y-Abegrin. Antitumor efficacy was also characterized in an orthotopic U87MG and in a HT-29 colorectal cancer model, a low integrin-expressing carcinoma. Small-animal positron emission tomography imaging was used to correlate histologic findings of treatment efficacy.

    Results: MTD and dose response analysis revealed 200 μCi per mouse as appropriate treatment dose with hepatic clearance and no organ toxicity. 90Y-Abegrin–treated U87MG tumor mice showed partial regression of tumor volume, with increased tumor volumes in 90Y-IgG, Abegrin, and saline groups. 18F-FDG imaging revealed a reduction of cell proliferation and metabolic activity whereas 18F-FLT reflected decreased DNA synthesis in the 90Y-Abegrin group. Ki67 analysis showed reduced proliferative index and quantitative terminal deoxynucleotidyl transferase dUTP nick-end labeling–positive analysis revealed increased DNA fragmentation and apoptosis in 90Y-Abegrin animals. CD31 and 4′,6-diamidino-2-phenylindole staining showed increased vascular fragmentation and dysmorphic vessel structure in 90Y-Abegrin animals only. Orthotopic U87MG tumors treated with 90Y-Abegrin displayed reduced tumor volume. HT-29 tumors showed no significant difference among the various groups.

    Conclusion: Radioimmunotherapy with 90Y-labeled Abegrin may prove promising in the treatment of highly vascular, invasive, and heterogeneous malignant brain tumors.

    http://dx.doi.org/10.1158/1078-0432.CCR-08-0797

  • 6
    Shi J, Jia B, Liu Z, Yang Z, Yu Z, Chen K, Chen X, Liu S*, Wang F* . 99mTc-Labeled Bombesin(7-14)NH2 with Favorable Properties for SPECT Imaging of Colon Cancer. Bioconjugate Chem. 2008, 19(6):1170-1178.

    In this report, we present the synthesis and evaluation of the 99mTc-labeled β-Ala-BN(7−14)NH2 (ABN = β-Ala-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2) as a new radiotracer for tumor imaging in the BALB/c nude mice bearing HT-29 human colon cancer xenografts. The gastrin releasing peptide receptor binding affinity of ABN and HYNIC-ABN (6-hydrazinonicotinamide) was assessed via a competitive displacement of 125I-[Tyr4]BBN bound to the PC-3 human prostate carcinoma cells. The IC50 values were calculated to be 24 ± 2 nM and 38 ± 1 nM for ABN and HYNIC-ABN, respectively. HYNIC is the bifunctional coupling agent for 99mTc-labeling, while tricine and TPPTS (trisodium triphenylphosphine-3,3′,3′′-trisulfonate) are used as coligands to prepare the ternary ligand complex [99mTc(HYNIC-ABN)(tricine)(TPPTS)] in very high yield and high specific activity. Because of its high hydrophilicity (log P = −2.39 ± 0.06), [99mTc(HYNIC-ABN)(tricine)(TPPS)] was excreted mainly through the renal route with little radioactivity accumulation in the liver, lungs, stomach, and gastrointestinal tract. The tumor uptake at 30 min postinjection (p.i.) was 1.59 ± 0.23%ID/g with a steady tumor washout over the 4 h study period. As a result, it had the best T/B ratios in the blood (2.37 ± 0.68), liver (1.69 ± 0.41), and muscle (11.17 ± 3.32) at 1 h p.i. Most of the injected radioactivity was found in the urine sample at 1 h p.i., and there was no intact [99mTc(HYNIC-ABN)(tricine)(TPPTS)] detectable in the urine, kidney, and liver samples. Its metabolic instability may contribute to its rapid clearance from the liver, lungs, and stomach. Despite the steady radioactivity washout, the tumors could be clearly visualized in planar images of the BALB/c nude mice bearing the HT-29 human colon xenografts at 1 and 4 h p.i. The favorable excretion kinetics from the liver, lungs, stomach, and gastrointestinal tract makes [99mTc(HYNIC-ABN)(tricine)(TPPTS)] a promising SPECT radiotracer for imaging colon cancer.

    http://dx.doi.org/10.1021/bc700471z

  • 7
    Jia B, Liu Z, Shi J, Yu Z, Yang Z, Zhao H, He Z, Liu S*, Wang F*. Linker Effects on Biological Properties of 111In-Labeled DTPA Conjugates of a Cyclic RGDfK Dimer. Bioconjugate Chem. 2008, 19(1):201-210.

    Abstract

    In this report, we present in vitro and in vivo evaluation of three 111 In-labeled DTPA conjugates of a cyclic RGDfK dimer: DTPA-Bn-SU016 (SU016 = E[c(RGDfK)] 2; DTPA-Bn = 2-( p-isothioureidobenzyl)diethylenetriaminepentaacetic acid), DTPA-Bn-E-SU016 ( E = glutamic acid) and DTPA-Bn-Cys-SU016 (Cys = cysteic acid). The integrin alpha vbeta 3 binding affinities of SU016, DTPA-Bn-SU016, DTPA-Bn-E-SU016, and DTPA-Bn-Cys-SU016 were determined to be 5.0 +/- 0.7 nM, 7.9 +/- 0.6 nM, 5.8 +/- 0.6 nM, and 6.9 +/- 0.9 nM, respectively, against 125 I-c(RGDyK) in binding to integrin alpha vbeta3, suggesting that E or Cys residue has little effect on the integrin alpha vbeta3 affinity of E[c(RGDfK)] 2. It was also found that the 111 In-labeling efficiency of DTPA-Bn-SU016 and DTPA-Bn-E-SU016 is 3-5 times better than that of DOTA analogues due to fast chelation kinetics and high-yield 111 In-labeling under mild conditions (e.g., room temperature). Biodistribution studies were performed using BALB/c nude mice bearing U87MG human glioma xenografts. 111 In-DTPA-Bn-SU016, 111 In-DTPA-Bn-E-SU016, and 111 In-DTPA-Bn-Cys-SU016 all displayed rapid blood clearance. Their tumor uptake was comparable between 0.5 and 4 h postinjection (p.i.) within experimental error. 111 In-DTPA-Bn-E-SU016 had a significantly lower ( p < 0.01) kidney uptake than 111 In-DTPA-Bn-SU016 and 111 In-DTPA-Bn-Cys-SU016. The liver uptake of 111 In-DTPA-Bn-SU016 was 1.69 +/- 0.18% ID/g at 24 h p.i., while the liver uptake values of 111 In-DTPA-Bn-E-SU016 and 111 In-DTPA-Bn-Cys-SU016 were 0.55 +/- 0.11% ID/g and 0.79 +/- 0.15% ID/g at 24 h p.i., respectively. Among the three 111 In radiotracers evaluated in this study, 111 In-DTPA-Bn-E-SU016 has the lowest liver and kidney uptake and the best tumor/liver and tumor/kidney ratios. Results from metabolism studies indicated that there is little metabolism (<10%) for three 111 In radiotracers at 1 h p.i. Imaging data showed that tumors can be clearly visualized at 4 h p.i. with good contrast in the tumor-bearing mice administered with 111 In-DTPA-Bn-E-SU016. It is concluded that using a glutamic acid linker can significantly improve excretion kinetics of the 111 In-labeled E[c(RGDfK)] 2 from liver and kidneys.

    http://dx.doi.org/10.1021/bc7002988

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