Preclinical Development and First-in-Human Imaging of the Integrin α(v)β(6) with [(18)F]α(v)β(6)-Binding Peptide in Metastatic Carcinoma.
Preclinical Development and First-in-Human Imaging of the Integrin α(v)β(6) with [(18)F]α(v)β(6)-Binding Peptide in Metastatic Carcinoma.
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DOI：
10.1158/1078-0432.ccr-18-2665
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发表时间：
2019-02-15
期刊：
影响因子：
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通讯作者：
Sutcliffe JL
中科院分区：
文献类型：
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作者：
Hausner SH;Bold RJ;Cheuy LY;Chew HK;Daly ME;Davis RA;Foster CC;Kim EJ;Sutcliffe JL
本研究旨在开发和评价整合素αvβ6结合肽(αvβ6-BP)用于多种恶性肿瘤的正电子发射断层扫描无创成像的可能性。用固相法制备了αvβ6-BP多肽，并用4-[18F]氟苯甲酸进行放射性标记。体外试验包括使用成对的αvβ6表达细胞系和αvβ6空细胞系进行的ELISA法、血清稳定性和细胞结合研究。体内评价(PET/CT，生物分布和放射自显影)在小鼠模型中进行相同的配对αvβ6表达和αvβ6-空细胞异种移植。在转移性肺癌、结肠癌、乳腺癌或胰腺癌患者中进行了首例人类PET/CT成像研究。[18F]αvβ6-BP在体外对整合素具有良好的亲和力和选择性(IC50(αvβ6)=1.2nM vsIC50(αβ3)>；10μM)，并具有快速的靶向特异性细胞结合和内化(分别为72.5±0.9%和52.5±1.8%)。在小鼠模型中保留了良好的肿瘤亲和力和选择性，游离的[18F]αvβ6-BP排泄迅速，主要通过肾脏。在患者中，[18F]αvβ6-BP耐受性良好，没有明显的副作用。PET图像显示[18F]αvβ6-BP在原发灶和转移灶中均有显著摄取，包括脑、骨、肝和肺转移灶。在这项首例人类研究中展示的[18F]αvβ6-BP正电子发射计算机断层扫描的临床效果对广泛的恶性肿瘤是直接的。
The study was undertaken to develop and evaluate the potential of an integrin αvβ6-binding peptide (αvβ6-BP) for noninvasive imaging of a diverse range of malignancies with positron emission tomography (PET). The peptide αvβ6-BP was prepared on solid phase and radiolabeled with 4-[18F]fluorobenzoic acid. In vitro testing included ELISA, serum stability, and cell binding studies using a paired αvβ6-expressing and αvβ6-null cell lines. In vivo evaluation (PET/CT, biodistribution and autoradiography) was performed in a mouse model bearing the same paired αvβ6-expressing and αvβ6-null cell xenografts. A first-in-human PET/CT imaging study was performed in patients with metastatic lung, colon, breast or pancreatic cancer. [18F]αvβ6-BP displayed excellent affinity and selectivity for the integrin in vitro (IC50(αvβ6) = 1.2 nM vsIC50(α β3) >10 μM) in addition to rapid target-specific cell binding and internalization (72.5±0.9% binding and 52.5±1.8% respectively). Favorable tumor affinity and selectivity were retained in the mouse model and excretion of unbound [18F]αvβ6-BP was rapid, primarily via the kidneys. In patients, [18F]αvβ6-BP was well tolerated without noticeable adverse side effects. PET images showed significant uptake of [18F]αvβ6-BP in both the primary lesion and metastases, including metastasis to brain, bone, liver and lung. The clinical impact of [18F]αvβ6-BP PET imaging demonstrated in this first-in-human study is immediate for a broad spectrum of malignancies.