^18F-阿法肽荷瘤裸鼠模型显像与药代动力学研究

Preclinical microPET imaging in tumor-bearing nude mice and pharmacokinetic studies of ^18F-Alfatide Ⅱ

目的探讨^18F-阿法肽(^18F-Alfatide Ⅱ)在不同荷瘤裸鼠模型中的显像及Beagle犬中的药代动力学性能。方法取BALB/c裸鼠24只,分别制备皮下荷瘤裸鼠模型(肺癌A549和神经胶质瘤U87MG)、原位肺癌模型(A549)和原位乳腺癌模型(MDA-MB-231)各6只。于4种荷瘤裸鼠模型中行^18F-Alfatide Ⅱ与^18F-脱氧葡萄糖(FDG)对比显像;于A549皮下荷瘤裸鼠模型中行^18F-Alfatide Ⅱ阻断实验、生物分布实验及在不同生长周期肿瘤中的显像研究;于Beagle犬(6只)及CD-1小鼠(9只)中行药代动力学实验。采用两样本t检验分析数据。结果与^18F-FDG相比,^18F-Alfatide Ⅱ在A549、U87MG皮下肿瘤及A549原位肺癌(肿瘤/心脏比值,4.50±1.17与0.95±0.31;t=4.125,P<0.01)、MDA-MB-231原位乳腺癌(肿瘤/肌肉比值,6.60±1.53与0.92±0.43;t=3.984,P<0.01)荷瘤裸鼠模型中有更好的显像质量。预先注射阻断剂环(精氨酸-甘氨酸-天冬氨酸-D-酪氨酸-赖氨酸多肽[c(RGDyk)]后,A549肿瘤对^18F-Alfatide Ⅱ的摄取降低了75%。^18F-Alfatide Ⅱ在Beagle犬血液中快速清除,半衰期为(57.34±11.69) min。^18F-Alfatide Ⅱ以原药形式从体内快速清除,给药后4 h内,(69.24±6.82)%的给药剂量通过尿液排出。结论^18F-Alfatide Ⅱ在A549、MDA-MB-231、U87MG肿瘤显像的靶/非靶比值高于^18F-FDG,可显著提高显像质量,且药代动力学性能优良。

Methods BALB/c nude mice (n=24) were used for subcutaneous tumor models (A549 and U87MG), orthotopic lung cancer models (A549) and orthotopic breast cancer models (MDA-MB-231)(n=6 in each group).^18F-Alfatide Ⅱ and ^18F-fluorodeoxyglucose (FDG) microPET/CT images were compared in the 4 types of tumor-bearing nude mice models.^18F-Alfatide Ⅱ blocking experiment, biodistribution experiment and imaging studies in tumors of different growth cycles were performed in A549 subcutaneous tumor-bearing nude mice models. Pharmacokinetic experiments were carried out in Beagle dogs (n=6) and CD-1 mice (n=9). Two-sample t test was used to analyze the data. Results Compared with ^18F-FDG,^18F-Alfatide Ⅱ microPET/CT images showed better imaging quality and contrast in subcutaneous A549, U87MG tumors and orthotopic A549 (tumor/heart: 4.50±1.17 vs 0.95±0.31;t=4.125, P<0.01), orthotopic MDA-MB-231 (tumor/muscle: 6.60±1.53 vs 0.92±0.43;t=3.984, P<0.01) transplantation nude mice models.^18F-Alfatide Ⅱ could specifically target A549 tumors, and the tumor uptake of ^18F-Alfatide Ⅱ was reduced by about 75% after pre-injection with cyclo(Arg-Gly-Asp-D-Tyr-Lys)(c(RGDyk)).^18F-Alfatide Ⅱ was rapidly cleared from the blood of Beagle dogs (t1/2 was (57.34±11.69) min). It was cleared in the form of prototype drug and (69.24±6.82)% of cumulative dose was excreted through the urine within 4 h after administration. Conclusions ^18F-Alfatide Ⅱ shows a higher target/non-target ratio than ^18F-FDG in the imaging of A549, MDA-MB-231 and U87MG tumor-bearing nude mice models, which is more conducive to the diagnosis of tumor.^18F-Alfatide Ⅱ has excellent pharmacokinetic properties.