Evaluation of Chemotherapy Response in VX2 Rabbit Lung Cancer with 18F-Labeled C2A Domain of Synaptotagmin I

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 F-18-labeled C2A-glutathione-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. Methods: F-18-C2A-GST was prepared by labeling C2A-GST with N-succinimidyl 4-F-18-fluorobenzoate (F-18-SFB). F-18-C2A-GST was confirmed by high-performance liquid chromatography and sodium dodecyl sulfate polyacrylamide gel electrophoresis. The binding of F-18-C2A-GST toward apoptosis was validated in vitro using camptothecin-induced Jurkat cells. Biodistribution of F-18-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 5 6), and 2 VX2 rabbits without treatment served as control. F-18-C2A-GST PET was performed before and at 72 h after therapy, and F-18-FDG PET/CT was also performed before treatment. To confirm the presence of apoptosis, tumor tissue was analyzed and activated caspase-3 was measured. Results: F-18-C2A-GST was obtained with more than 95% radiochemical purity and was stable for 4 h after formulation. F-18-C2A-GST bound apoptotic cells specifically. Biodistribution in mice showed that F-18-C2A-GST mainly excreted from the kidneys and rapidly cleared from blood and nonspecific organs. High focal uptake of F-18-C2A-GST in the tumor area was determined after therapy, whereas no significant uptake before therapy was found in the tumor with F-18-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). Conclusion: F-18-C2A-GST was easily synthesized by conjugation with F-18-SFB and manifested a favorable biodistribution. Our results demonstrated the feasibility of F-18-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.