Targeted in vivo imaging of integrin alphavbeta6 with an improved radiotracer and its relevance in a pancreatic tumor model.
Targeted in vivo imaging of integrin alphavbeta6 with an improved radiotracer and its relevance in a pancreatic tumor model.
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DOI：
10.1158/0008-5472.can-08-4410
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发表时间：
2009-07-15
期刊：
影响因子：
11.2
通讯作者：
Sutcliffe JL
中科院分区：
文献类型：
--
作者：
Hausner SH;Abbey CK;Bold RJ;Gagnon MK;Marik J;Marshall JF;Stanecki CE;Sutcliffe JL
细胞表面受体αvβ6是上皮特异性的，其表达受到严格调控;在成人组织中含量低或检测不到，但已显示在许多不同的癌症中增加，包括胰腺癌、宫颈癌、肺癌和结肠癌。研究已将αvβ6描述为与生存不良相关的预后生物标志物。我们最近证明了使用肽[18 F] FBA-A20 FMDV 2通过PET在体内成像αvβ6的可行性。在这里，我们描述了改进的αvβ6显像剂，并在内源性αvβ6表达的小鼠模型中测试其疗效。经修饰的化合物保持对αvβ6的高亲和力和超过相关整联蛋白的>1000倍选择性（通过ELISA），并且在基于细胞的测定中显示显著改善的αvβ6依赖性结合（>60%结合vs <10%[18F] FBA-A20 FMDV 2）。使用黑色素瘤细胞系（转导的αvβ6-表达）或BxPC-3人胰腺癌细胞系（内源性αvβ6-表达）的体内研究显示，修饰的化合物显示出显著改善的肿瘤保留。这沿着非特异性结合活性的良好清除，特别是对于新的放射性示踪剂[18 F] FBA-PEG 28-A20 FMDV 2，导致PET成像的改善。肿瘤/胰腺和肿瘤/血液生物分布比在4小时分别达到>23：1和>47：1。值得注意的是，[18 F] FBA-PEG 28-A20 FMDV 2在BxPC-3肿瘤成像中上级[18 F]-氟脱氧葡萄糖（[18 F]FDG）。胰腺导管腺癌是高度转移性的，目前使用非侵入性成像进行可切除性的术前评估成功率有限，大多数患者在手术时已经转移。这些肿瘤表达αvβ6的事实表明，该探针具有体内检测这种恶性肿瘤的显著潜力，因此对患者护理和治疗具有重要意义。
The cell surface receptor αvβ6 is epithelial-specific and its expression is tightly regulated; it is low or undetectable in adult tissues but has been shown to be increased in many different cancers, including pancreatic, cervical, lung, and colon cancer. Studies have described αvβ6 as prognostic biomarker linked to poor survival. We have recently demonstrated the feasibility of imaging αvβ6 in vivo by PET using the peptide [18F]FBA-A20FMDV2. Here we describe improved αvβ6 imaging agents and test their efficacy in a mouse model with endogenous αvβ6-expression. The modified compounds maintained high affinity for αvβ6 and >1000-fold selectivity over related integrins (by ELISA), and demonstrated significantly improved, αvβ6-dependent binding in cell-based assays (>60% binding vs <10% for [18F]FBA-A20FMDV2). In vivo studies using either a melanoma cell line (transduced αvβ6-expression) or the BxPC-3 human pancreatic carcinoma cell line (endogenous αvβ6-expression) revealed that the modified compounds showed significantly improved tumor retention. This, along with good clearance of nonspecifically bound activity, particularly for the new radiotracer [18F]FBA-PEG28-A20FMDV2, resulted in improved PET-imaging. Tumor/pancreas and tumor/blood biodistribution-ratios of >23:1 and >47:1, respectively, were achieved at 4 h. Significantly, [18F]FBA-PEG28-A20FMDV2 was superior to [18F]-fluorodeoxyglucose ([18F]FDG) in imaging the BxPC-3 tumors. Pancreatic ductal adenocarcinoma is highly metastatic and current preoperative evaluation of resectability using non-invasive imaging has limited success, with most patients having metastases at time of surgery. The fact that these tumors express αvβ6 suggests that this probe has significant potential for the in vivo detection of this malignancy, thus having important implications for patient care and therapy.