您现在的位置是：首页 》 发表论文

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.

Abstract:

To assess the potential utility of an integrin α_vβ₃-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.

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.

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 α_vβ₃, α_vβ₅, 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 α_vβ₃ and α_vβ₅, 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

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 α_vβ₃ and gastrin-releasing peptide receptor (GRPR). The receptor-positive group was further divided into 3 subgroups (GRPR(+)/α_vβ₃ (+), GRPR(+)/α_vβ₃ (-), and α_vβ₃ (+)/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.

    "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.

Doi: 10.7150/thno.14792.

    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

    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.

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

    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.

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

Received: 30 April 2015

Accepted: 30 November 2015

Published online: 06 January 2016