| 蒋金泉,李丹,刘特立,夏雷,徐晓霞,郭晓轶,朱华,杨志.构建肿瘤免疫治疗PD-L1靶向PET分子探针68Ga-NOTA-WL12及生物学观察[J].中国医学影像技术,2021,37(1):8~12 |
| 构建肿瘤免疫治疗PD-L1靶向PET分子探针68Ga-NOTA-WL12及生物学观察 |
| Preparation of PET molecular probe 68Ga-NOTA-WL12 targeting PD-L1 for tumor immunotherapy |
| 投稿时间：2019-09-10 修订日期：2020-09-09 |
| DOI：10.13929/j.issn.1003-3289.2021.01.002 |
| 中文关键词: 免疫抑制剂 正电子发射断层显像 体层摄影术,X线计算机 分子探针技术 |
| 英文关键词:immunosuppressive agents positron-emission tomography tomography, X-ray computed molecular probe techniques |
| 基金项目:国家自然科学基金（81401467、81731592）。 |
| 作者 | 单位 | E-mail | | 蒋金泉 | 德阳市人民医院放射科, 四川 德阳 618000
北京大学肿瘤医院暨北京市肿瘤防治研究所核医学科, 恶性肿瘤发病机制及转化研究教育部重点实验室, 北京 100142 | | | 李丹 | 北京大学肿瘤医院暨北京市肿瘤防治研究所核医学科, 恶性肿瘤发病机制及转化研究教育部重点实验室, 北京 100142 | | | 刘特立 | 北京大学肿瘤医院暨北京市肿瘤防治研究所核医学科, 恶性肿瘤发病机制及转化研究教育部重点实验室, 北京 100142 | | | 夏雷 | 北京大学肿瘤医院暨北京市肿瘤防治研究所核医学科, 恶性肿瘤发病机制及转化研究教育部重点实验室, 北京 100142 | | | 徐晓霞 | 北京大学肿瘤医院暨北京市肿瘤防治研究所核医学科, 恶性肿瘤发病机制及转化研究教育部重点实验室, 北京 100142 | | | 郭晓轶 | 北京大学肿瘤医院暨北京市肿瘤防治研究所核医学科, 恶性肿瘤发病机制及转化研究教育部重点实验室, 北京 100142 | | | 朱华 | 北京大学肿瘤医院暨北京市肿瘤防治研究所核医学科, 恶性肿瘤发病机制及转化研究教育部重点实验室, 北京 100142 | zhuhuananjing@163.com | | 杨志 | 北京大学肿瘤医院暨北京市肿瘤防治研究所核医学科, 恶性肿瘤发病机制及转化研究教育部重点实验室, 北京 100142 | |
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| 中文摘要: |
| 目的 构建程序性细胞死亡受体1（PD-1）靶向68Ga-NOTA-WL12分子探针，观察其生物分布，评价可否用于检测肿瘤PD-L1表达。方法 在60℃、pH 4.5条件下，以放射性核素68Ga标记多肽分子NOTA-WL12，利用放射性薄层色谱扫描仪（Radio-TLC）测定反应产物标记率。以活化C18柱对原始反应产物进行纯化并获得终产物，分析其放射化学纯度。以0.9%生理盐水及5%人血白蛋白（HSA）分析该分子探针的体外稳定性，并以脂水分布实验观察其分布。向正常雌性昆明鼠体内注射1.11 MBq 68Ga-NOTA-WL12，分别于其后5、30、60、120及240 min观察其体内分布。建立PD-1配体（PD-L1）表达阳性CHO-hPD-L1肿瘤模型和PD-L1表达阴性MDA-MB-231肿瘤模型，以小动物PET/CT显像观察该分子探针在体分布代谢，评价其可否用于检测肿瘤病灶内PD-L1表达。对CHO-hPD-L1肿瘤模型鼠行共注射阻断实验，观察肿瘤病灶摄取。结果 68Ga-NOTA-WL12分子探针标记率>95%，放射化学纯度>98%，体外稳定性良好；生物分布观察及PET/CT显像显示其主要通过肝肾代谢，肝肾存在非特异性摄取。注射后肿瘤病灶分子探针摄取先逐渐增高，后明显降低。结论 68Ga-NOTA-WL12体外稳定性良好，并能特异性地在小鼠模型PD-L1阳性肿瘤组织中浓聚。 |
| 英文摘要: |
| Objective To construct a programmed death 1 (PD-1) targeted 68Ga-NOTA-WL12 molecular probe, and to observe its biological distribution and the ability to detect tumor PD-L1. Methods Under the condition of 60℃ and pH4.5, NOTA-WL12 was labeled by radionuclide 68Ga, and the labeling rate of the reaction product was determined with Radio-TLC. Then the crude product was purified by pre-activated C18 column, the final product was obtained, and the radiochemical purity of the final product was analyzed. 68Ga-NOTA-WL12 of 1.11 MBq was injected into Kunming mice through tail vein, and the in vivo distribution of the radiotracer was observed after 5, 30, 60, 120 and 240 min, respectively. CHO-hPD-L1 tumor models with positive PD-L1 expression and MDA-MB-231 tumor models with negative PD-L1 expression were established. PET/CT was used to image the animal models at multiple time points to explore the distribution and metabolism of this molecular probe and the detection of PD-L1 in tumor lesions. Co-injection blocking experiment was carried out in CHO-hPD-L1 tumor model mice to observe the uptake of the radiotracer in the tumor. Results The labeling rate of 68Ga-NOTA-WL12 radiotracer was more than 95%, the radiochemical purity was over 98%, and the in vitro stability was good. The radiotracer was metabolized mainly through the liver and kidney, and non-specific high uptake appeared in the liver and kidney. Within 240 min, the uptake of molecular probes in tumor lesions first increased gradually, then decreased significantly. Conclusion 68Ga was convenient to label peptide NOTA-WL12, and the obtained 68Ga-NOTA-WL12 had good stability in vitro. The molecular probe could be specifically concentrated in tumor tissue in rat models with positive expression of PD-L1. |
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