文章基本信息

标题：Development of the Fibronectin–Mimetic Peptide KSSPHSRN(SG)₅RGDSP as a Novel Radioprobe for Molecular Imaging of the Cancer Biomarker α₅β₁ Integrin
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作者：Zhao-Hui Jin ; Takako Furukawa ; Katsushi Kumata 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2015
卷号：38
期号：11
页码：1722-1731
DOI：10.1248/bpb.b15-00344
出版社：The Pharmaceutical Society of Japan
摘要：α₅β₁ Integrin, a fibronectin receptor, is becoming a pertinent therapeutic target and a promising prognostic biomarker for cancer patients. The aim of this study was to functionalize an α₅β₁-specific fibronectin–mimetic peptide sequence KSSPHSRN(SG)₅RGDSP (called PR_b) as a positron emission tomography (PET) probe. PR_b was modified by addition of a β-alanine residue, conjugated with 2- S -(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid ( p -SCN-Bn-NOTA), and radiolabeled with ¹⁸F based on the chelation of ¹⁸F-aluminum fluoride. A control probe was produced by glycine to alanine substitution in the RGD motif of PR_b. Cell binding and blocking assays, autoradiographic evaluation of tissue binding and blocking, dynamic PET scans, and a biodistribution study were conducted using cell lines and murine tumor models with determined expression levels of α₅β₁ and other related integrins. ¹⁸F-PR_b was produced with a labeling yield of 22.3±1.9% based on ¹⁸F-F⁻, a radiochemical purity of >99%, and a specific activity of 30–70 GBq/µmol; it exhibited α₅β₁-binding activity and specificity in vitro , ex vivo , and in vivo , and had a rapid blood clearance and a predominant renal excretion pathway. In vivo α₅β₁-positive tumors could be clearly visualized by ¹⁸F-PR_b PET imaging. Both imaging and biodistribution studies suggested higher uptake of ¹⁸F-PR_b in α₅β₁-positive tumors than in α₅β₁-negative tumors and higher α₅β₁-positive tumor uptake of ¹⁸F-PR_b than the control probe. In contrast, there was no significant difference seen in the contralateral muscle uptake. A PET radioprobe, ¹⁸F-PR_b, was developed de novo and potentially can be used for noninvasive detection of α₅β₁ expression in tumors.