LAT1 靶向 PET 示踪剂在 C6 神经胶质瘤和 MIA PaCa-2 大鼠异种移植模型中的分布与肿瘤血流无关。
Distribution of LAT1-targeting PET tracer was independent of the tumor blood flow in rat xenograft models of C6 glioma and MIA PaCa-2.
机构信息
Department of Nuclear Medicine and Tracer Kinetics, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Medical Imaging Center for Translational Research, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
出版信息
Ann Nucl Med. 2019 Jun;33(6):394-403. doi: 10.1007/s12149-019-01346-9. Epub 2019 Feb 28.
OBJECTIVE
L-type amino acid transporter 1 (LAT1) is strongly expressed on the cell membrane in various types of human cancer cells, while being minimally expressed in normal or inflammatory tissues. Therefore, LAT1-targeting PET tracers have been developed for cancer-specific imaging. The purpose of this study was to study the distribution of two LAT1-targeting PET tracers, L-4-borono-2-F-fluoro-phenylalanine (F-FBPA) and L-3-F-alpha-methyl tyrosine (F-FAMT), in relation to the tumor blood flow, using rat xenograft models.
METHODS
Rat tumor xenograft models of C6 glioma (n = 4; tumors = 8) and MIA PaCa-2 (pancreatic cancer) (n = 4; tumors = 6) were used. The expressions of LAT1 and CD98hc were evaluated by both immunofluorescence staining and western blot analysis. Dynamic PET was performed after injection of F-FAMT or F-FBPA (scan duration = 70 min) following O-water PET (scan duration = 10 min). The PET data were subjected to kinetic analyses, and the K, k, and total distribution volume (V) were calculated using the one-tissue compartment model. The accumulation of the LAT1 tracers was expressed in terms of their V. Tumor blood flow (TBF) was represented by the K value in O-water PET.
RESULTS
LAT1/CD98hc expression was confirmed in both xenografts by immunofluorescence staining. Western blot analysis showed higher functional expression of LAT1 in the C6 glioma cells as compared to the MIA PaCa-2 cells (C6 glioma/MIA PaCa-2 relative expression ratio = 1.70). The V values of both F-FBPA and F-FAMT were significantly higher in the C6 glioma xenografts than in the MIA PaCa-2 xenografts (C6 glioma: 2.27 ± 0.35 and 2.03 ± 0.23, respectively; MIA PaCa-2: 1.28 ± 0.26 and 1.35 ± 0.15, respectively). Meanwhile, there was no significant correlation of the V value of either F-FBPA or F-FAMT with the TBF, in either the C6 glioma or the MIA PaCa-2 xenografts.
CONCLUSIONS
This study revealed that total distribution volumes of the LAT1-targeting PET tracers F-FBPA and F-FAMT were independent of the tumor blood flow and might reflect the functional expression levels of LAT1 in the C6 glioma and MIA PaCa-2 xenograft models.
目的
L 型氨基酸转运蛋白 1（LAT1）在各种类型的人类癌细胞的细胞膜上强烈表达，而在正常或炎症组织中则很少表达。因此，已经开发了针对 LAT1 的 PET 示踪剂用于癌症特异性成像。本研究旨在使用大鼠异种移植模型研究两种针对 LAT1 的 PET 示踪剂 L-4-硼基-2-F-氟苯丙氨酸（F-FBPA）和 L-3-F-α-甲基酪氨酸（F-FAMT）的分布与肿瘤血流的关系。
方法
使用 C6 神经胶质瘤（n=4；肿瘤=8）和 MIA PaCa-2（胰腺癌）（n=4；肿瘤=6）大鼠肿瘤异种移植模型。通过免疫荧光染色和 Western blot 分析评估 LAT1 和 CD98hc 的表达。在 O-水 PET（扫描持续时间=10 分钟）后注射 F-FAMT 或 F-FBPA（扫描持续时间=70 分钟）后进行动态 PET。使用单室模型对 PET 数据进行动力学分析，并计算 K、k 和总分布容积（V）。LAT1 示踪剂的积累用 V 表示。肿瘤血流（TBF）用 O-水 PET 中的 K 值表示。
结果
免疫荧光染色证实了两种异种移植中的 LAT1/CD98hc 表达。Western blot 分析显示 C6 神经胶质瘤细胞中 LAT1 的功能表达高于 MIA PaCa-2 细胞（C6 神经胶质瘤/MIA PaCa-2 相对表达比=1.70）。F-FBPA 和 F-FAMT 的 V 值在 C6 神经胶质瘤异种移植中均显著高于 MIA PaCa-2 异种移植（C6 神经胶质瘤：2.27±0.35 和 2.03±0.23；MIA PaCa-2：1.28±0.26 和 1.35±0.15）。同时，在 C6 神经胶质瘤或 MIA PaCa-2 异种移植中，F-FBPA 或 F-FAMT 的 V 值均与 TBF 无显著相关性。
结论
本研究表明，针对 LAT1 的 PET 示踪剂 F-FBPA 和 F-FAMT 的总分布容积与肿瘤血流无关，可能反映了 C6 神经胶质瘤和 MIA PaCa-2 异种移植模型中 LAT1 的功能表达水平。
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