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镓标记环肽放射性药物的合成、生物学评价及初步临床研究——一种用于非小细胞肺癌过度表达整合素受体的早期诊断显像剂

Radiosynthesis, Biological Evaluation, and Preclinical Study of a Ga-Labeled Cyclic RGD Peptide as an Early Diagnostic Agent for Overexpressed Integrin Receptors in Non-Small-Cell Lung Cancer.

机构信息

Department of Radiopharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran.

出版信息

Contrast Media Mol Imaging. 2020 Mar 31;2020:8421657. doi: 10.1155/2020/8421657. eCollection 2020.


DOI:10.1155/2020/8421657
PMID:32292304
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7153000/
Abstract

The integrin receptors have high expression on proliferating growing tumor cells of different origins including non-small-cell lung cancer. RGD-containing peptides target the extracellular domain of integrin receptors. This specific targeting makes these short sequences a suitable nominee for theranostic application. DOTA-E(cRGDfK) was radiolabeled with Ga efficiently. The and stability was examined in different buffer systems. Metabolic stability was assessed in mice urine. specific binding, cellular uptake, and internalization were determined. The tumor-targeting potential of [Ga]Ga-DOTA-E(cRGDfK) in a lung cancer mouse model was studied. Besides, the very early diagnostic potential of the Ga-labeled RGD peptide was evaluated. The acquisition and reconstruction of the PET-CT image data were also carried out. Radiochemical and radionuclide purity for [Ga]Ga-DOTA-E(cRGDfK) was >%98 and >%99, respectively. Radiotracer showed high , , and metabolic stability which was determined by ITLC. The dissociation constant ( ) of [Ga]Ga-DOTA-E(cRGDfK) was 15.28 nM. On average, more than 95% of the radioactivity was specific binding (internalized + surface-bound) to A549 cells. Biodistribution data showed that radiolabeled peptides were accumulated significantly in A549 tumor and excreted rapidly by the renal system. Tumor uptake peaks were at 1-hour postinjection for [Ga]Ga-DOTA-E(cRGDfK). The tumor was clearly visualized in all images. [Ga]Ga-DOTA-E(cRGDfK) can be used as a peptide-based imaging agent allowing very early detection of different cancers overexpressing integrin receptors and can be a potential candidate in clinical peptide-based imaging for lung cancer.

摘要

整合素受体在不同来源的增殖生长肿瘤细胞上高表达,包括非小细胞肺癌。含有 RGD 的肽靶向整合素受体的细胞外结构域。这种特异性靶向使这些短序列成为治疗诊断应用的合适候选者。DOTA-E(cRGDfK) 可以有效地用 Ga 放射性标记。在不同的缓冲系统中检查 和 稳定性。在小鼠尿液中评估代谢稳定性。测定了 的特异性结合、细胞摄取和内化。研究了 [Ga]Ga-DOTA-E(cRGDfK) 在肺癌小鼠模型中的肿瘤靶向潜力。此外,还评估了 Ga 标记的 RGD 肽的早期诊断潜力。还进行了 PET-CT 图像数据的采集和重建。[Ga]Ga-DOTA-E(cRGDfK) 的放射化学和放射性核素纯度分别为>%98 和 >%99。放射性示踪剂显示出高的 、 、代谢稳定性,这是通过 ITLC 确定的。[Ga]Ga-DOTA-E(cRGDfK) 的解离常数( )为 15.28 nM。平均而言,超过 95%的放射性是与 A549 细胞的特异性结合(内化+表面结合)。生物分布数据表明,放射性标记的肽在 A549 肿瘤中显著积聚,并通过肾脏系统快速排泄。放射性标记物的肿瘤摄取峰值出现在 [Ga]Ga-DOTA-E(cRGDfK) 注射后 1 小时。肿瘤在所有图像中均清晰可见。[Ga]Ga-DOTA-E(cRGDfK) 可用作基于肽的成像剂,允许过表达 的不同癌症的早期检测,并且可以成为肺癌基于肽的临床成像的潜在候选者。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d13/7153000/122daf43fa95/CMMI2020-8421657.011.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d13/7153000/8c8f916e613d/CMMI2020-8421657.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d13/7153000/6dcd53f3a5a7/CMMI2020-8421657.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d13/7153000/996d7cefbc63/CMMI2020-8421657.006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d13/7153000/301387d44f05/CMMI2020-8421657.007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d13/7153000/ea7ffec671a7/CMMI2020-8421657.008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d13/7153000/d8471b633526/CMMI2020-8421657.009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d13/7153000/cf88dc7899ca/CMMI2020-8421657.010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d13/7153000/122daf43fa95/CMMI2020-8421657.011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d13/7153000/484ddb350491/CMMI2020-8421657.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d13/7153000/4a5c406ddc22/CMMI2020-8421657.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d13/7153000/34ae27c13e11/CMMI2020-8421657.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d13/7153000/8c8f916e613d/CMMI2020-8421657.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d13/7153000/6dcd53f3a5a7/CMMI2020-8421657.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d13/7153000/996d7cefbc63/CMMI2020-8421657.006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d13/7153000/301387d44f05/CMMI2020-8421657.007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d13/7153000/ea7ffec671a7/CMMI2020-8421657.008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d13/7153000/d8471b633526/CMMI2020-8421657.009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d13/7153000/cf88dc7899ca/CMMI2020-8421657.010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d13/7153000/122daf43fa95/CMMI2020-8421657.011.jpg

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