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纤维蛋白结合环肽 F-iCREKA 的合成及临床前评价：与对照线性肽的比较

Synthesis and Preclinical Evaluation of the Fibrin-Binding Cyclic Peptide F-iCREKA: Comparison with Its Contrasted Linear Peptide.

机构信息

PET Center, Nanfang Hospital, Southern Medical University, Guangzhou, China.

PET/CT Center, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

出版信息

Contrast Media Mol Imaging. 2019 Jun 27;2019:6315954. doi: 10.1155/2019/6315954. eCollection 2019.

DOI:10.1155/2019/6315954
PMID:31346326
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6620859/
Abstract

PURPOSE

Cys-Arg-Glu-Lys-Ala (CREKA) is a pentapeptide which can target fibrin-fibronectin complexes. Our previous study has built a probe called iCREKA which was based on CREKA and has proved the feasibility and specificity of iCREKA by the fluorescence experiment. The purpose of this study is to achieve the F-labeled iCREKA and make preclinical evaluation of the F-iCREKA with comparison of its contrasted linear peptide (LP).

METHODS

CREKA, LP, and iCREKA were labeled by the AlF labeling method, respectively. These F-labeled peptides were evaluated by the radiochemistry, binding affinity, in vitro stability, in vivo stability, micro-PET imaging, and biodistribution tests.

RESULTS

F-NOTA-iCREKA was stable both in vitro and in vivo. However, F-NOTA-CREKA and F-NOTA-LP were both unstable. The FITC or F-labeled iCREKA could be abundantly discovered only in matrix metalloproteinases- (MMPs-) 2/9 highly expressed U87MG cells, while the FITC or F-labeled LP could also be abundantly discovered in MMP-2/9 lowly expressed Caov3 cells. Biodistribution and micropositron emission tomography (PET) imaging revealed that the U87MG xenografts showed a higher uptake of F-NOTA-iCREKA than F-NOTA-LP while the Caov3 xenografts showed very low uptake of both F-NOTA-iCREKA and F-NOTA-LP. The tumor-to-muscle (T/M) ratio of F-NOTA-iCREKA (9.93 ± 0.42) was obviously higher than F-NOTA-LP (2.69 ± 0.35) in U87MG xenografts.

CONCLUSIONS

The novel CREKA-based probe F-NOTA-iCREKA could get a high uptake in U87MG cells and high T/M ratio in U87MG mice. It was more stable and specific than the F-NOTA-LP.

摘要

目的

Cys-Arg-Glu-Lys-Ala（CREKA）是一种五肽，可靶向纤维蛋白-纤维连接蛋白复合物。我们之前的研究构建了一种基于 CREKA 的探针 iCREKA，并通过荧光实验证明了 iCREKA 的可行性和特异性。本研究的目的是获得 F 标记的 iCREKA，并通过比较其对比线性肽（LP）来对 F-iCREKA 进行临床前评估。

方法

分别用 AlF 标记法标记 CREKA、LP 和 iCREKA。通过放射化学、结合亲和力、体外稳定性、体内稳定性、微 PET 成像和生物分布试验对这些 F 标记的肽进行评估。

结果

F-NOTA-iCREKA 在体外和体内均稳定。然而，F-NOTA-CREKA 和 F-NOTA-LP 均不稳定。FITC 或 F 标记的 iCREKA 只能在基质金属蛋白酶-（MMPs-）2/9 高表达的 U87MG 细胞中大量发现，而 FITC 或 F 标记的 LP 也可以在 MMP-2/9 低表达的 Caov3 细胞中大量发现。生物分布和微正电子发射断层扫描（PET）成像显示，F-NOTA-iCREKA 对 U87MG 异种移植瘤的摄取率高于 F-NOTA-LP，而 Caov3 异种移植瘤对 F-NOTA-iCREKA 和 F-NOTA-LP 的摄取率均非常低。F-NOTA-iCREKA（9.93±0.42）在 U87MG 异种移植瘤中的肿瘤与肌肉（T/M）比值明显高于 F-NOTA-LP（2.69±0.35）。

结论

新型基于 CREKA 的探针 F-NOTA-iCREKA 可在 U87MG 细胞中获得高摄取率，并在 U87MG 小鼠中获得高 T/M 比值。它比 F-NOTA-LP 更稳定、更特异。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0545/6620859/745d8a2afce3/CMMI2019-6315954.006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0545/6620859/a6690f2a3260/CMMI2019-6315954.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0545/6620859/030ea8b555c7/CMMI2019-6315954.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0545/6620859/023e6e37acf2/CMMI2019-6315954.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0545/6620859/60403c035bab/CMMI2019-6315954.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0545/6620859/700da13601b9/CMMI2019-6315954.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0545/6620859/745d8a2afce3/CMMI2019-6315954.006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0545/6620859/a6690f2a3260/CMMI2019-6315954.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0545/6620859/030ea8b555c7/CMMI2019-6315954.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0545/6620859/023e6e37acf2/CMMI2019-6315954.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0545/6620859/60403c035bab/CMMI2019-6315954.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0545/6620859/700da13601b9/CMMI2019-6315954.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0545/6620859/745d8a2afce3/CMMI2019-6315954.006.jpg

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