Liu Zhenfeng, Wen Guanghua, Huang Yuqiao, Dong Yanzhao, Wang Zewei, Alhaskawi Ahmad, Zhang Shuyi, Wang GuoLin, Ye Qianni, Zhou Haiying, Lu Hui, Dong Mengjie
Department of Nuclear Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Department of Nuclear Medicine, Shenzhen Longhua District Central Hospital, Shenzhen, China.
Front Oncol. 2023 May 22;13:1126721. doi: 10.3389/fonc.2023.1126721. eCollection 2023.
The cell adhesion molecule (CAM) N-cadherin has become an important target for tumor therapy. The N-cadherin antagonist, ADH-1, exerts significant antitumor activity against N-cadherin-expressing cancers.
In this study, [F]AlF-NOTA-ADH-1 was radiosynthesized. An in vitro cell binding test was performed, and the biodistribution and micro-PET imaging of the probe targeting N-cadherin were also studied in vivo.
Radiolabeling of ADH-1 with [F]AlF achieved a yield of up to 30% (not decay-corrected) with a radiochemical purity of >97%. The cell uptake study showed that Cy3-ADH-1 binds to SW480 cells but weakly binds to BXPC3 cells in the same concentration range. The biodistribution results demonstrated that [F]AlF-NOTA-ADH-1 had a good tumor/muscle ratio (8.70±2.68) in patient-derived xenograft (PDX) tumor xenografts but a lower tumor/muscle ratio (1.91±0.69) in SW480 tumor xenografts and lowest tumor/muscle ratio (0.96±0.32) in BXPC3 tumor xenografts at 1 h post-injection (p.i.) These findings were in accordance with the immunohistochemistry results. The micro PET imaging results revealed good [18F]AlF-NOTA-ADH-1 tumor uptake in pancreatic cancer PDX xenografts with strong positive N-calcium expression, while lower tumor uptake in SW480 xenografts with positive expression of N-cadherin, and significantly lower tumor uptake in BXPC3 xenografts with low expression of N-cadherin, which was consistent with the biodistribution and immunohistochemistry results. The N-cadherin-specific binding of [18F]AlF-NOTA-ADH-1 was further verified by a blocking experiment involving coinjection of a non radiolabeled ADH-1 peptide, resulting in a significant reduction in tumor uptake in PDX xenografts and SW480 tumor.
[F]AlF-NOTA-ADH-1 was successfully radiosynthesized, and Cy3-ADH-1 showed favorable N-cadherin-specific targeting ability by in vitro data. The biodistribution and microPET imaging of the probe further showed that [18F]AlF-NOTA-ADH-1 could discern different expressions of N-cadherin in tumors. Collectively, the findings demonstrated the potential of [F]AlF-NOTA-ADH-1 as a PET imaging probe for non-invasive evaluation of the N-cadherin expression in tumors.
细胞黏附分子（CAM）N-钙黏蛋白已成为肿瘤治疗的重要靶点。N-钙黏蛋白拮抗剂ADH-1对表达N-钙黏蛋白的癌症具有显著的抗肿瘤活性。
在本研究中，合成了[F]AlF-NOTA-ADH-1。进行了体外细胞结合试验，并在体内研究了靶向N-钙黏蛋白的探针的生物分布和微型PET成像。
用[F]AlF对ADH-1进行放射性标记，产率高达30%（未进行衰变校正），放射化学纯度>97%。细胞摄取研究表明，在相同浓度范围内，Cy3-ADH-1与SW480细胞结合，但与BXPC3细胞的结合较弱。生物分布结果表明，在注射后1小时，[F]AlF-NOTA-ADH-1在患者来源的异种移植（PDX）肿瘤异种移植物中的肿瘤/肌肉比良好（8.70±2.68），但在SW480肿瘤异种移植物中的肿瘤/肌肉比更低（1.91±0.69），在BXPC3肿瘤异种移植物中的肿瘤/肌肉比最低（0.96±0.32）。这些发现与免疫组织化学结果一致。微型PET成像结果显示，在N-钙黏蛋白表达强阳性的胰腺癌PDX异种移植物中，[18F]AlF-NOTA-ADH-1对肿瘤的摄取良好，而在N-钙黏蛋白表达阳性的SW480异种移植物中肿瘤摄取较低，在N-钙黏蛋白表达低的BXPC3异种移植物中肿瘤摄取显著更低，这与生物分布和免疫组织化学结果一致。通过共注射未标记的ADH-1肽的阻断实验进一步验证了[18F]AlF-NOTA-ADH-1与N-钙黏蛋白的特异性结合，结果导致PDX异种移植物和SW480肿瘤中的肿瘤摄取显著降低。
成功合成了[F]AlF-NOTA-ADH-1，体外数据表明Cy3-ADH-1具有良好的N-钙黏蛋白特异性靶向能力。该探针的生物分布和微型PET成像进一步表明，[18F]AlF-NOTA-ADH-1可以区分肿瘤中N-钙黏蛋白的不同表达。总的来说，这些发现证明了[F]AlF-NOTA-ADH-1作为PET成像探针用于无创评估肿瘤中N-钙黏蛋白表达的潜力。
