A new method for imaging the tumor human vascular endothelial growth factor 165 (VEGF 165) is presented. A magnetic resonance imaging (MRI) probe was prepared by crosslinking ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles to the aptamer for tumor vascular endothelial growth factor 165 (VEGF165-aptamer). The molecular probe was evaluated for its in vitro and in vivo activities toward VEGF165. Enzyme-linked immunosorbent assay showed that the VEGF165-aptamer-USPIO nanoparticles conjugate specifically binds to VEGF165 in vitro. A cell proliferation test showed that VEGF165-aptamer-USPIO seems to block the proliferation of human umbilical vein endothelial cells induced by free VEGF165, suggesting that VEGF165 is an effective target of this molecular probe. In xenograft mice carrying liver cancer that expresses VEGF165, T2-weighted imaging of the tumor displayed marked negative enhancement 3 h after the intravenous administration of VEGF165-aptamer-USPIO. The enhancement disappeared 6 h after administration of the probe. These results suggest the targeted imaging effect of VEGF165-aptamer-USPIO probe in vivo for VEGF165-expressing tumors. This is the first report of a targeted MRI molecular probe based on USPIO and VEGF165-aptamer.
In the in vitro studies, the MRI results of BEL-7402 cells treated with VGd showed significantly higher T1 signal-to-noise ratio than that of both the competitive group, namely, those treated with VGd and VEGF 125-136 and the control group, a scramble peptide conjugated to Gd(III) (SGd). In vivo, when xenografts of BEL-7402 cells were established in mice and then VGd or SGd were injected via tail vein, MRI showed that the tumour signal from VGd initially decreased from 5 to 120 min and then it increased at 120 min post injection. The peak signal was observed at 120 min after injection. In contrast, no distinct peak was observed for SGd. These findings indicate that VGd can target VEGFR2, highly expressed by BEL-7402 cells, enabling targeting MRI with high efficacy to be achieved both in vitro and in vivo.
Background. Lung cancer continues to be a burden worldwide with an estimated 2.09 million new cases of lung cancer and 1.76 million deaths in 2018. MicroRNAs (miRs) are key regulators of gene expression and show their oncogenic or antioncogenic role in human cancers including lung cancer. In this study, we test the hypothesis that miR-34c-5p functions as a candidate antioncomiR in lung adenocarcinoma by targeting NUF2. Methods. The expression pattern of miR-34c-5p and NUF2 was evaluated in 202 biopsy specimens from patients with lung adenocarcinoma and 176 biopsy specimens from patients with benign lung diseases. Interaction between miR-34c-5p and NUF2 was verified by the luciferase-based assay. Cell viability and invasion assays were carried out in cultured A549 cells treated with miR-34c-5p mimic, inhibitor, and siRNA against NUF2. Results. NUF2 was highly expressed in lung adenocarcinoma samples and related to the differentiation degree, TNM stage, and presence of lymph node metastasis (LNM). Patients with NUF2 overexpression had reduced overall survival (OS) and disease-free survival (DFS) compared to patients with underexpression. Cox multivariate analysis revealed that high expression of NUF2, advanced TNM stage, well/moderate differentiation, and existence of LNM were unfavorable prognostic factors. siRNA-mediated knockdown of NUF2 inhibits A549 cell viability and invasion. miR-34c-5p was expressed at a poor level in lung adenocarcinoma samples and related to the differentiation degree, TNM stage, and presence of LNM. miR-34c-5p underexpression contributes to reduced OS and DFS, which was demonstrated as an unfavorable prognostic factor by Cox multivariate analysis. siRNA-mediated knockdown of NUF2 could ablate miR-34c-5p inhibition-mediated effects on A549 cells. Conclusion. Our results prove the hypothesis that miR-34c-5p could suppress lung adenocarcinoma progression by binding to the NUF2 gene. The study is a significant step towards extending our understanding of the mode of miRNA regulation in lung adenocarcinoma.
Development of imaging methods that can detect target molecules will be of great significance for non-invasive molecular diagnosis. Vascular endothelial growth factor receptor-2 (VEGFR-2) is a broadly expressed target, and VEGFR-2-specific agents have been used in biological therapy. In this study, amine-reactive coupling was used to label the polypeptide VEGF125–136 with a Gd(DOTA) complex to create a magnetic resonance contrast agent, VEGF125–136-Gd, which binds to VEGFR-2. Using T1-weighted magnetic resonance imaging, we explored the tumor cell-targeting ability of VEGF125–136-Gd and its enhancement of T1-weighted image intensity using human hepatoma (HepG2) cells and found that the signal-to-noise ratio (SNR) increased commensurately with the concentration of VEGF125–136-Gd. At a concentration of 2 mM, the SNR produced by VEGF125–136-Gd was 5.4-fold higher than that produced by a Gd-labelled non-targeting polypeptide (NTPP-Gd) control. We also evaluated the tumor-targeting efficiency of VEGF125–136-Gd in nude mice injected with human hepatoma (HepG2) cells. Preliminary in vivo imaging of VEGFR-2 in tumor tissue revealed a targeting peak 60 min post administration of VEGF125–136-Gd, the intensity of which was 23% higher than the SNR of NTPP-Gd at the same time point. Our findings may help lay the foundation for clinical applications of VEGF125–136-Gd in targeted imaging.
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