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评价二聚体-cRGD 肽在糖尿病小鼠外周血管生成靶向 PET-CT 成像中的应用。

Evaluation of a dimeric-cRGD peptide for targeted PET-CT imaging of peripheral angiogenesis in diabetic mice.

机构信息

Beckman Institute for Advanced Science and Technology, Urbana, IL, USA.

Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.

出版信息

Sci Rep. 2018 Mar 29;8(1):5401. doi: 10.1038/s41598-018-23372-9.


DOI:10.1038/s41598-018-23372-9
PMID:29599497
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5876368/
Abstract

The α  β integrin plays an important role in many physiological functions and pathological disorders. α  β is minimally expressed in normal quiescent endothelial cells, but significantly upregulated during neovascularization. In this study, we evaluated a Cu-labeled dimeric cRGD tracer targeted at α  β integrin and report its applicability to assess peripheral angiogenesis in diabetes mellitus (DM). We established a murine model of type-1 DM characterized by elevated glucose, glycated serum protein (GSP), and glycated hemoglobin A1c (HbA1c). We demonstrated that our imaging probe is specific to α  β integrin under both normo- and hyperglycemic conditions. We found that the analysis of in vivo PET-CT images correlated well with gamma well counting (GWC). Both GWC and PET-CT imaging demonstrated increased uptake of Cu-NOTA-PEG4-cRGD in the ischemic hindlimb in contrast to non-ischemic control. GWC of the distal ischemic tissue from DM mice showed significantly lower probe accumulation than in non-DM mice. The immunofluorescence staining of the ischemic tissues showed a 3-fold reduction in CD31 and 4-fold reduction in the α  β expression in DM vs. non-DM animals. In conclusion, we successfully demonstrated that diabetes-associated reductions in peripheral angiogenesis can be non-invasively detected with PET-CT imaging using targeted dimeric-cRGD probe.

摘要

αβ 整联蛋白在许多生理功能和病理紊乱中起着重要作用。αβ 在正常静止的内皮细胞中表达很少,但在新血管生成过程中显著上调。在这项研究中,我们评估了一种针对 αβ 整联蛋白的 Cu 标记二聚体 cRGD 示踪剂,并报告了其在评估糖尿病(DM)外周血管生成中的适用性。我们建立了一种 1 型糖尿病的小鼠模型,其特征是血糖、糖化血清蛋白(GSP)和糖化血红蛋白 A1c(HbA1c)升高。我们证明,我们的成像探针在正常血糖和高血糖条件下均特异性针对 αβ 整联蛋白。我们发现,体内 PET-CT 图像分析与伽马井计数(GWC)密切相关。GWC 和 PET-CT 成像均显示,与非缺血对照相比,缺血后肢对 Cu-NOTA-PEG4-cRGD 的摄取增加。与非糖尿病小鼠相比,糖尿病小鼠缺血组织的 GWC 显示探针积累明显降低。缺血组织的免疫荧光染色显示,与非糖尿病动物相比,CD31 减少了 3 倍,αβ 表达减少了 4 倍。总之,我们成功地证明了使用靶向二聚体-cRGD 探针的 PET-CT 成像可以非侵入性地检测到与糖尿病相关的外周血管生成减少。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41b8/5876368/639eb0bd9145/41598_2018_23372_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41b8/5876368/4966e0e0c7f8/41598_2018_23372_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41b8/5876368/05180cf4697c/41598_2018_23372_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41b8/5876368/3f70286d33dc/41598_2018_23372_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41b8/5876368/0433d7e8d553/41598_2018_23372_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41b8/5876368/43722c5e89a1/41598_2018_23372_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41b8/5876368/d14a26e7fa1c/41598_2018_23372_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41b8/5876368/82392275fa2d/41598_2018_23372_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41b8/5876368/639eb0bd9145/41598_2018_23372_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41b8/5876368/4966e0e0c7f8/41598_2018_23372_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41b8/5876368/05180cf4697c/41598_2018_23372_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41b8/5876368/3f70286d33dc/41598_2018_23372_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41b8/5876368/0433d7e8d553/41598_2018_23372_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41b8/5876368/43722c5e89a1/41598_2018_23372_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41b8/5876368/d14a26e7fa1c/41598_2018_23372_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41b8/5876368/82392275fa2d/41598_2018_23372_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41b8/5876368/639eb0bd9145/41598_2018_23372_Fig8_HTML.jpg

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本文引用的文献

[1]
Synthesis, Chemical Characterization and Multiscale Biological Evaluation of a Dimeric-cRGD Peptide for Targeted Imaging of α β Integrin Activity.

Sci Rep. 2017-6-9

[2]
Analytical evaluation of the Diazyme glycated serum protein assay on the siemens ADVIA 1800: comparison of results against HbA1c for diagnosis and management of diabetes.

J Diabetes Sci Technol. 2015-3

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PLoS One. 2014-10-22

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J Nucl Med. 2012-4-12

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Theranostics. 2011-1-17

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Nucl Med Biol. 2010-7-24

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