Evaluation of chemotherapy response in VX2 rabbit lung cancer with 18F-labeled C2A domain of synaptotagmin I.
Evaluation of chemotherapy response in VX2 rabbit lung cancer with 18F-labeled C2A domain of synaptotagmin I.
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使用突触结合蛋白 I 的 18F 标记的 C2A 结构域评估 VX2 兔肺癌的化疗反应。
DOI：
10.2967/jnumed.110.081588
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发表时间：
2011-04
期刊：
影响因子：
--
通讯作者：
Suzuki K
中科院分区：
文献类型：
--
作者：
Wang F;Fang W;Zhang MR;Zhao M;Liu B;Wang Z;Hua Z;Yang M;Kumata K;Hatori A;Yamasaki T;Yanamoto K;Suzuki K
突触结合蛋白I的C2 A结构域可以通过与暴露的阴离子磷脂结合来靶向凋亡细胞。本研究的目的是合成和开发18F标记的C2 A-谷胱甘肽-S-转移酶（GST）作为分子成像探针，用于检测VX 2兔肺癌细胞凋亡和评估紫杉醇化疗的反应。18F-C2 A-GST是通过用N-琥珀酰亚胺基4- 18F-氟苯甲酸酯（18F-SFB）标记C2 A-GST制备的。18F-C2 A-GST经高效液相色谱和十二烷基硫酸钠聚丙烯酰胺凝胶电泳证实。使用喜树碱诱导的Jurkat细胞在体外验证18F-C2 A-GST对凋亡的结合。通过解剖法和小动物PET测定18F-C2 A-GST在小鼠中的生物分布。单剂量紫杉醇用于诱导携带VX 2肿瘤的兔（n = 6）中的细胞凋亡，2只未治疗的VX 2兔作为对照。治疗前及治疗后72 h行18F-C2 A-GST PET检查，治疗前行18F-FDG PET/CT检查。为了确认细胞凋亡的存在，分析肿瘤组织并测量活化的半胱天冬酶-3。获得放射化学纯度大于95%的18F-C2 A-GST，并且在配制后稳定4 h。18F-C2 A-GST特异性结合凋亡细胞。在小鼠体内的生物分布表明，18F-C2 A-GST主要从肾脏排泄，并迅速从血液和非特异性器官中清除。治疗后肿瘤区域的18F-C2 A-GST高摄取，而在18F-FDG-avid病灶的肿瘤中，治疗前未发现明显的摄取。治疗后最大标准摄取值为0.47 ± 0.28，明显高于对照组（0.009 ± 0.001; P < 0.001）。凋亡指数治疗组为79.81% ± 8.73%，明显高于对照组（5.03% ± 0.81%，P < 0.001）。紫杉醇治疗后caspase-3活性升高至69.55% ± 16.27%，显著高于对照组（12.26% ± 5.39%，P < 0.001）。18F-C2 A-GST可与18F-SFB偶联合成，并具有良好的生物分布。我们的研究结果表明，18F-C2 A-GST的化疗后早期检测凋亡的VX 2肺癌模型，可以模拟人肺癌的发生，发展和进展的可行性。
The C2A domain of synaptotagmin I can target apoptotic cells by binding to exposed anionic phospholipids. The goal of this study was to synthesize and develop 18F-labeled C2A-gluta-thione-S-transferase (GST) as a molecular imaging probe for the detection of apoptosis and to assess the response of paclitaxel chemotherapy in VX2 rabbit lung cancer. 18F-C2A-GST was prepared by labeling C2A-GST with N-succinimidyl 4-18F-fluorobenzoate (18F-SFB). 18F-C2A-GST was confirmed by high-performance liquid chromatography and sodium dodecyl sulfate polyacrylamide gel electrophoresis. The binding of 18F-C2A-GST toward apoptosis was validated in vitro using camptothecin-induced Jurkat cells. Biodistribution of 18F-C2A-GST was determined in mice by a dissection method and small-animal PET. Single-dose paclitaxel was used to induce apoptosis in rabbits bearing VX2 tumors (n = 6), and 2 VX2 rabbits without treatment served as control. 18F-C2A-GST PET was performed before and at 72 h after therapy, and 18F-FDG PET/CT was also performed before treatment. To confirm the presence of apoptosis, tumor tissue was analyzed and activated caspase-3 was measured. 18F-C2A-GST was obtained with more than 95% radiochemical purity and was stable for 4 h after formulation. 18F-C2A-GST bound apoptotic cells specifically. Biodistribution in mice showed that 18F-C2A-GST mainly excreted from the kidneys and rapidly cleared from blood and nonspecific organs. High focal uptake of 18F-C2A-GST in the tumor area was determined after therapy, whereas no significant uptake before therapy was found in the tumor with 18F-FDG–avid foci. The maximum standardized uptake value after therapy was 0.47 ± 0.28, significantly higher than that in the control (0.009 ± 0.001; P < 0.001). The apoptotic index was 79.81% ± 8.73% in the therapy group, significantly higher than that in the control (5.03% ± 0.81%; P < 0.001). Activated caspase-3 after paclitaxel treatment increased to 69.55% ± 16.27% and was significantly higher than that in the control (12.26% ± 5.39%; P < 0.001). 18F-C2A-GST was easily synthesized by conjugation with 18F-SFB and manifested a favorable biodistribution. Our results demonstrated the feasibility of 18F-C2A-GST for the early detection of apoptosis after chemotherapy in a VX2 lung cancer model that could imitate the human lung cancer initiation, development, and progress.
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