使用 18F-DPA-714 和 18F-Alfatide II 进行肌肉炎症的纵向 PET 成像及与肿瘤的鉴别。
Longitudinal PET imaging of muscular inflammation using 18F-DPA-714 and 18F-Alfatide II and differentiation with tumors.
机构信息
1. Department of Nuclear Medicine, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, China. ; 2. Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, USA.
2. Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, USA.
出版信息
Theranostics. 2014 Feb 26;4(5):546-55. doi: 10.7150/thno.8159. eCollection 2014.
AIM
(18)F-DPA-714 is a PET tracer that recognizes macrophage translocator protein (TSPO), and (18)F-Alfatide II ((18)F-AlF-NOTA-E[PEG4-c(RGDfk)]2) is specific for integrin αvβ3. This study aims to apply these two tracers for longitudinal PET imaging of muscular inflammation, and evaluate the value of (18)F-DPA-714 in differentiating inflammation from tumor.
METHODS
RAW264.7 mouse macrophage cells were used for cell uptake analysis of (18)F-DPA-714. A mouse hind limb muscular inflammation model was established by intramuscular injection of turpentine oil. For the inflammation model, PET imaging was performed at different days using (18)F-DPA-714 and (18)F-Alfatide II. The specificity of the imaging probes was tested by co- or pre-injection of PK11195 or unlabeled RGD (Arg-Gly-Asp) peptide. PET imaging using (18)F-DPA-714 was performed in A549, HT29, U87MG, INS-1, and 4T1 xenograft models. Immunofluorescence staining was performed to evaluate infiltrated macrophages and angiogenesis in inflammation and/or tumors.
RESULTS
Uptake of (18)F-DPA-714 in RAW264.7 cells was 45.5% at 1 h after incubation, and could be blocked by PK11195. PET imaging showed increased (18)F-DPA-714 and (18)F-Alfatide II uptake at inflammatory muscles. Peak uptake of (18)F-DPA-714 was seen on day 6 (4.02 ± 0.64 %ID/g), and peak uptake of (18)F-Alfatide II was shown on day 12 (1.87 ± 0.35 %ID/g) at 1 h p.i.. Tracer uptakes could be inhibited by PK11195 for (18)F-DPA-714 or cold RGD for (18)F-Alfatide II. Moreover, macrophage depletion with liposomal clodronate also reduced the local accumulation of both tracers. A549, HT29, U87MG, INS-1, and 4T1 tumor uptakes of (18)F-DPA-714 (0.46 ± 0.28, 0.91 ± 0.08, 1.69 ± 0.67, 1.13 ± 0.33, 1.22 ± 0.55 %ID/g at 1 h p.i., respectively) were significantly lower than inflammation uptake (All P < 0.05).
CONCLUSION
PET imaging using (18)F-DPA-714 as a TSPO targeting tracer could evaluate the dynamics of macrophage activation and infiltration in different stages of inflammatory diseases. The concomitant longitudinal PET imaging with both (18)F-DPA-714 and (18)F-Alfatide II matched the causal relationship between macrophage infiltration and angiogenesis. Moreover, we found (18)F-DPA-714 uptake in several types of tumors is significantly lower than that in inflammatory muscles, suggesting (18)F-DPA-714 PET has the potential for better differentiation of tumor and non-tumor inflammation.
目的
（18）F-DPA-714 是一种识别巨噬细胞转位蛋白（TSPO）的 PET 示踪剂，（18）F-Alfatide II（（18）F-AlF-NOTA-E[PEG4-c（RGDfk）]2）特异性结合整合素 αvβ3。本研究旨在应用这两种示踪剂进行肌肉炎症的纵向 PET 成像，并评估（18）F-DPA-714 区分炎症与肿瘤的价值。
方法
采用 RAW264.7 小鼠巨噬细胞进行（18）F-DPA-714 的细胞摄取分析。通过肌肉内注射松节油建立小鼠后肢肌肉炎症模型。对于炎症模型，在不同时间点使用（18）F-DPA-714 和（18）F-Alfatide II 进行 PET 成像。通过共注射或预注射 PK11195 或未标记的 RGD（精氨酸-甘氨酸-天冬氨酸）肽来测试成像探针的特异性。在 A549、HT29、U87MG、INS-1 和 4T1 异种移植模型中进行（18）F-DPA-714 的 PET 成像。进行免疫荧光染色以评估炎症和/或肿瘤中浸润的巨噬细胞和血管生成。
结果
（18）F-DPA-714 在 RAW264.7 细胞孵育 1 小时后的摄取率为 45.5%，可被 PK11195 阻断。PET 成像显示炎症肌肉中（18）F-DPA-714 和（18）F-Alfatide II 的摄取增加。（18）F-DPA-714 的摄取峰值出现在第 6 天（6 天时的摄取率为 4.02 ± 0.64 %ID/g），（18）F-Alfatide II 的摄取峰值出现在第 12 天（12 天时的摄取率为 1.87 ± 0.35 %ID/g）。PK11195 可抑制（18）F-DPA-714 的摄取，冷 RGD 可抑制（18）F-Alfatide II 的摄取。此外，用脂质体氯膦酸盐进行巨噬细胞耗竭也减少了两种示踪剂的局部积累。（18）F-DPA-714 在 A549、HT29、U87MG、INS-1 和 4T1 肿瘤中的摄取率（1 h 时分别为 0.46 ± 0.28、0.91 ± 0.08、1.69 ± 0.67、1.13 ± 0.33 和 1.22 ± 0.55 %ID/g）明显低于炎症摄取（均 P < 0.05）。
结论
使用（18）F-DPA-714 作为 TSPO 靶向示踪剂的 PET 成像可以评估不同炎症疾病阶段巨噬细胞激活和浸润的动力学。同时进行（18）F-DPA-714 和（18）F-Alfatide II 的纵向 PET 成像，匹配了巨噬细胞浸润和血管生成之间的因果关系。此外，我们发现几种类型的肿瘤中的（18）F-DPA-714 摄取明显低于炎症肌肉，提示（18）F-DPA-714 PET 具有更好地区分肿瘤和非肿瘤性炎症的潜力。
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