68Ga⁃DOTA⁃K⁃PEG2⁃(K⁃FA)2靶向卵巢癌及其腹腔转移灶显像的实验研究
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国家自然科学基金青年基金项目(81301247);南京市杰出青年基金项目(JQX14009);江苏省“科教强卫工程”青年医学人才(QNRC2016075);2019高层次卫生人才“六个一工程” 拔尖人才项目(LGY2019005)


Experimental study on 68Ga⁃DOTA⁃K⁃PEG2⁃(K⁃FA)2 targeted imaging of ovarian cancer and peritoneal metastases
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    摘要:

    目的:制备68Ga-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸-赖氨酸-聚乙二醇-赖氨酸叶酸二聚体[68Ga-DOTA-K-PEG2-(K-FA)2,简称68Ga-DOTA-2P-FA2],并研究其用于卵巢癌及腹腔转移灶靶向显像的价值。方法:合成68Ga-DOTA-2P-FA2并考察其体外理化特性,构建皮下荷人卵巢癌(SKOV3)及其腹腔转移灶裸鼠模型。设立叶酸受体阻断组、荷人肺癌(A549:叶酸受体表达阴性)裸鼠阴性对照组及空白对照组。考察68Ga-DOTA-2P-FA2体内生物学分布,皮下荷瘤鼠在显像剂尾静脉给药后120 min行microPET检查、腹腔转移荷瘤鼠在显像剂尾静脉给药后60 min行microPET-CT显像。结果:68Ga-DOTA-2P-FA2放射化学纯度为(96.30±1.28)%,体外稳定性好,叶酸受体亲合实验IC50为17.1 nmol/L,辛醇/水分配系数(lg P)为-1.89。尾静脉注射后120 min,卵巢癌皮下肿瘤放射性摄取达到峰值,可被过量叶酸有效阻断,其在血液、心及肺中清除迅速,肝脏摄取少,主要通过肾脏排泄,培美曲赛预注射有效加快其在肾脏的排泄。microPET显像提示皮下卵巢癌肿瘤放射性摄取明显高于叶酸受体阻断组和阴性对照组。microPET-CT显像提示腹腔转移灶放射性摄取明显高于空白对照组。结论:68Ga-DOTA-2P-FA2能靶向聚集在叶酸受体高表达的肿瘤部位,是卵巢癌及其腹腔转移灶显像的良好显像剂。

    Abstract:

    Objective:This study aims to prepare 68Ga-DOTA-K-PEG2-(K-FA)2(68Ga-DOTA-2P-FA2)and investigate the value of 68Ga-DOTA-2P-FA2 for targeted imaging of ovarian cancer and peritoneal metastasis. Methods:Characteristics of 68Ga-DOTA-2P-FA2 was investigated in vitro after its preparation. A nude mouse model of subcutaneous human ovarian cancer(SKOV3)and its peritoneal metastasis was established to investigate the biodistribution of 68Ga-DOTA-2P-FA2 in vivo. The receptor blocking group,the negative control group of human lung cancer(A549)and blank control group were set up. The microPET imaging was performed at 120 min(in mice bearing subcutaneous tumor xenograft)and microPET-CT imaging was performed at 60 min(in mice bearing peritoneal metastases)after tail vein administration. Results:68Ga-DOTA-2P-FA2 was stable in vitro with radiochemical purity of (96.30±1.28)%. Folate receptor affinity(IC50)was 17.1 nmol/L. Octanol/water partition coefficient(lg P)was -1.89. Radioactivity uptake of subcutaneous ovarian cancer reached a peak at 120 min after tail vein injection,which could be effectively blocked by overdose free folic acid. It could be removed rapidly in blood,heart and lung,generating a low uptake in liver,and mainly excreted through kidney. Pre-injection of pemetrexed could effectively accelerate the excretion of radioactivity in kidney. MicroPET imaging showed radioactivity uptake of subcutaneous ovarian cancer was significantly higher than that of folate receptor blocking group and that of the negative control group. The radioactivity uptake of peritoneal metastases was significantly higher than that of blank control detected by microPET-CT. Conclusion:68Ga-DOTA-2P-FA2,which accumulated in tumor sites with high expression of folate receptor,was a good imaging agent for ovarian cancer and peritoneal metastases.

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蒋翠萍,赵 宇,刘子君,施雪松,付晶晶,王 峰,邵国强.68Ga⁃DOTA⁃K⁃PEG2⁃(K⁃FA)2靶向卵巢癌及其腹腔转移灶显像的实验研究[J].南京医科大学学报(自然科学版),2020,(3):348-354

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  • 收稿日期:2018-12-27
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  • 在线发布日期: 2020-03-30
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