Li Jia, Zhang Lei, Li Wenbo, Lei Chengming, Cao Yiyi, Wang Ying, Wang Zhengjie, Pang Hua
Department of Nuclear Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
Onco Targets Ther. 2020 Jan 15;13:487-496. doi: 10.2147/OTT.S238098. eCollection 2020.
The expression of Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 1 (CITED1) is upregulated in papillary thyroid carcinoma (PTC) and mediates cell proliferation and migration. To facilitate early diagnosis and monitoring of recurrent or metastatic PTC, we designed Lu-labeled antisense peptide nucleic acid (PNA) targeting CITED1 mRNA to evaluate the therapeutic potential, while analyzing its distribution in nude mice and the characteristics withsingle-photon emission-computed tomography/computed tomography (SPECT/CT) imaging.
Lu-DOTA-anti-CITED1-PNA (Lu-asPNA) was obtained by indirect labeling. High-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC) were used to determine the labeling rate and radiochemical purity. The stability of Lu-asPNA was evaluated by TLC, and the radioactivity count was measured by a γ counter to calculate its uptake capacity in K1 cells. To analyze the distribution of Lu-asPNA in body tissues and organs of nude mice, static single-photon emission-computed tomography (SPECT) imaging and SPECT/CT image fusion were performed. Then, the therapeutic effects of probes were explored by tumor growth curves and survival analysis.
Our probe showed a radiochemical purity of 96.5±0.15% at 1 hr and specific activity of 8.7±0.53 MBq/μg. The uptake rate in the Lu-asPNA group was much higher than that in the Lu-DOTA-nonsense-PNA (Lu-nonsense-PNA) and Lu-DOTA groups (P<0.05). The biological distribution showed that the tumor/muscle ratio was at its highest at 24 h (4.98±0.34) post-inoculation, with SPECT/CT imaging showing clear tumor development. By measuring tumor volume of tumor-bearing nude mice, the Lu-asPNA group showed a significant difference in tumor size 9 days after injection (P < 0.05). Kaplan-Meier survival curves showed that the overall survival rate in the Lu-asPNA group was significantly different from those in the DOTA-anti-CITED1-PNA (asPNA) and saline groups (P = 0.002, log-rank test).
Lu-asPNA was developed successfully, showing a high labeling rate and good stability. SPECT/CT imaging demonstrated tumor growth in nude mice, which was effectively inhibited by our probe, thus prolonging survival.
富含谷氨酸/天冬氨酸的羧基末端结构域1相互作用反式激活因子（CITED1）在甲状腺乳头状癌（PTC）中表达上调，并介导细胞增殖和迁移。为便于PTC复发或转移的早期诊断及监测，我们设计了靶向CITED1 mRNA的镥标记反义肽核酸（PNA）以评估其治疗潜力，同时分析其在裸鼠体内的分布及单光子发射计算机断层扫描/计算机断层扫描（SPECT/CT）成像特征。
通过间接标记法获得镥-四氮杂环十二烷四乙酸-抗CITED1-PNA（Lu-asPNA）。采用高效液相色谱（HPLC）和薄层色谱（TLC）测定标记率和放射化学纯度。通过TLC评估Lu-asPNA的稳定性，用γ计数器测量放射性计数以计算其在K1细胞中的摄取能力。为分析Lu-asPNA在裸鼠身体组织和器官中的分布，进行静态单光子发射计算机断层扫描（SPECT）成像及SPECT/CT图像融合。然后，通过肿瘤生长曲线和生存分析探索探针的治疗效果。
我们的探针在1小时时放射化学纯度为96.5±0.15%，比活度为8.7±0.53 MBq/μg。Lu-asPNA组的摄取率远高于Lu-四氮杂环十二烷四乙酸-无义PNA（Lu-无义PNA）组和Lu-四氮杂环十二烷四乙酸组（P<0.05）。生物分布显示，接种后24小时肿瘤/肌肉比值最高（4.98±0.34），SPECT/CT成像显示肿瘤显影清晰。通过测量荷瘤裸鼠的肿瘤体积，Lu-asPNA组在注射后9天肿瘤大小有显著差异（P<0.05）。Kaplan-Meier生存曲线显示，Lu-asPNA组的总生存率与四氮杂环十二烷四乙酸-抗CITED1-PNA（asPNA）组和生理盐水组有显著差异（P = 0.002，对数秩检验）。
成功研发出Lu-asPNA，其标记率高且稳定性良好。SPECT/CT成像显示裸鼠体内肿瘤生长，我们的探针有效抑制了肿瘤生长，从而延长了生存期。
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