Liposomal Treatment of Experimental Arthritis Can Be Monitored Noninvasively with a Radiolabeled Anti-Fibroblast Activation Protein Antibody
Liposomal Treatment of Experimental Arthritis Can Be Monitored Noninvasively with a Radiolabeled Anti-Fibroblast Activation Protein Antibody
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DOI：
10.2967/jnumed.116.177931
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发表时间：
2017-01-01
影响因子：
9.3
通讯作者：
Boerman, Otto C.
中科院分区：
文献类型：
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作者：
van der Geest, Tessa;Laverman, Peter;Boerman, Otto C.
类风湿性关节炎是一种慢性自身免疫性疾病，导致滑膜炎症。成纤维细胞激活蛋白(FAP)在关节炎关节中由成纤维样滑膜细胞过度表达。抗FAP抗体的放射免疫成像可用于监测治疗反应，从而实现量身定制的治疗策略和治疗结果。本研究的目的是评估放射性标记的抗FAP抗体是否可以用于监测含有强的松龙磷酸盐(PLP-LCL)的长循环脂质体(PLP-LCL)对小鼠关节炎模型的治疗效果。方法：建立雄性DBA/1J小鼠胶原性关节炎(CIA)模型。给小鼠单次注射PLP-LCL(10 mg/kg)或空白LCL作为对照。分别于治疗后2、5、9d注射99m标记的琥珀酰亚胺-烟酰胺(TC-99m-S-HYNIC)标记的抗FAP抗体28H1，24 h后采集SPECT和CT图像。对所有关节的~(99m)Tc-S-HYNIC-28H1摄取进行量化，并与关节炎大体评分进行相关分析。结果：PLP-LCL对CIA大鼠关节肿胀有明显抑制作用。仅在治疗后1天，关节炎的宏观评分就下降了50%。在治疗后第5天和第9天，评分进一步下降，仅为初始评分的10%。相比之下，在注射空LCL后第9天，未治疗的小鼠的宏观关节炎评分增加了600%。~(99m)TC-S-HYNIC-28H1在非炎症关节的摄取百分率为1.5%~严重炎症关节的摄取百分率为22.6%。放射性标记28H1在炎症关节中的摄取(注射剂量百分比)与关节炎评分相关(Spearman p，0.77；P<；0.0001)。此外，~(99)MTC-S-HYNIC-28H1的摄取在治疗后第9天略有增加，但肉眼看不到，提示SPECT/CT显像可能比肉眼关节炎评分方法更敏感。结论：99m-S-HYNIC28H1SPECT/CT显像可特异性监测治疗反应，示踪剂蓄积与炎症程度相关。此外，SPECT/CT成像可能比宏观关节炎评分方法更敏感。本研究表明，SPECT/CT结合(TCS)-TC-99m-HYNIC-28H1可用于无创性监测小鼠CIA的病程。
Rheumatoid arthritis is a chronic autoimmune disorder resulting in synovial inflammation. Fibroblast activation protein (FAP) is overexpressed by fibroblastlike synoviocytes in arthritic joints. Radioimmunoimaging with an anti-FAP antibody might be used to monitor the response to therapy, thus enabling tailored therapy strategies and therapeutic outcomes. The aim of this study was to assess whether a radiolabeled anti-FAP antibody could be used to monitor the efficacy of treatment with long-circulating liposomes (LCL) containing prednisolone phosphate (PLP-LCL) in a mouse model of arthritis. Methods: Collagen-induced arthritis (CIA) was induced in male DBA/1J mice. Mice were treated with a single injection (10 mg/kg) of PLP-LCL or empty LCL as a control. SPECT and CT images were acquired 24 h after injection of Tc-99m-labeled succinimidyl-hydrazinonicotinamide (Tc-99m-S-HYNIC) conjugated anti-FAP antibody 28H1 at 2, 5, and 9 d after treatment. The uptake of Tc-99m-S-HYNIC-28H1 in all joints was quantified and correlated with macroscopic arthritis scores. Results: Treatment of CIA with PLP-LCL significantly suppressed joint swelling. At just 1 d after treatment, the macroscopic arthritis scores had decreased by 50%. Scores decreased further, to only 10% of the initial scores, at 5 and 9 d after treatment. In contrast, macroscopic arthritis scores had increased up to 600% in untreated mice at 9 d after the injection of empty LCL. Tc-99m-S-HYNIC-28H1 uptake ranged from 1.5 percentage injected dose per gram in noninflamed joints to 22.6 percentage injected dose per gram in severely inflamed joints. The uptake of radiolabeled 28H1 in inflamed joints (percentage injected dose) correlated with the arthritis score (Spearman p, 0.77; P < 0.0001). Moreover, the uptake of (99)mTc-S-HYNIC-28H1 was slightly increased at 9 d after therapy but was not seen macroscopically, indicating that SPECT/CT imaging might be more sensitive than the macroscopic arthritis scoring method. Conclusion: SPECT/CT imaging with Tc-99m-S-HYNIC28H1 specifically monitored the response to therapy, and tracer accumulation correlated with the severity of inflammation. In addition, SPECT/CT imaging was potentially more sensitive than the macroscopic arthritis scoring method. This study showed that SPECT/CT with (TcS)-Tc-99m-HYNIC-28H1 could be used to noninvasively monitor the course of CIA in mice.