使用[F]氟聚乙二醇叶酸和正电子发射断层扫描对关节炎大鼠抗叶酸治疗进行体内监测。

In-vivo monitoring of anti-folate therapy in arthritic rats using [F]fluoro-PEG-folate and positron emission tomography.

作者信息

Chandrupatla Durga M S H, Jansen Gerrit, Vos Ricardo, Verlaan Mariska, Chen Qingshou, Low Philip S, Windhorst Albert D, Lammertsma Adriaan A, van der Laken Conny J, Molthoff Carla F M

机构信息

Amsterdam Rheumatology and Immunology Center, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.

Department of Radiology & Nuclear Medicine, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.

出版信息

Arthritis Res Ther. 2017 May 31;19(1):114. doi: 10.1186/s13075-017-1325-x.

BACKGROUND

Folate receptor β (FRβ) is involved in facilitating cellular uptake of folates and anti-folates (such as methotrexate (MTX)). In rheumatoid arthritis, FRβ is expressed on synovial macrophages and recently has been explored as a biomarker for imaging in arthritic rats using the folate-based positron emission tomography (PET) tracer [F]fluoro-PEG-folate. The purpose of this study was to examine whether this folate tracer can also be used to monitor therapeutic efficacy of MTX in arthritic rats.

METHODS

Arthritic rats received either no treatment or MTX therapy (1 mg/kg, either 2× or 4×). Healthy rats did not receive any arthritic induction or therapy. [F]fluoro-PEG-folate PET-CT scans (60 min) were performed before and after MTX therapy. Following PET, the ex-vivo tissue distribution of radioactivity was determined in excised knees and multiple tissues. Synovial macrophage infiltration in knee sections was quantified by immunohistochemistry using ED1 and ED2 antibodies.

RESULTS

PET scans clearly visualized increased uptake of [F]fluoro-PEG-folate in arthritic knees compared with contralateral knees. Significantly lower standard uptake values (1.5-fold, p < 0.01) were observed in arthritic knees of both MTX-treated groups after therapy, approximating the levels seen in healthy rats. Consistently, ex-vivo tissue distribution demonstrated a 2-4-fold lower tracer uptake in the arthritic knee of 2× and 4× MTX-treated rats, respectively, compared with control rats. These results were corroborated with significantly reduced (2-4-fold, p < 0.01) ED1-positive and ED2-positive synovial macrophages in arthritic knees of the MTX-treated rats compared with those of the control rats.

CONCLUSION

This study in arthritic rats underscores the potential and usefulness of [F]fluoro-PEG-folate PET as a therapeutic monitoring tool of MTX therapy and potentially other anti-folate treatment of arthritis.

背景

叶酸受体β（FRβ）参与促进细胞对叶酸和抗叶酸药物（如甲氨蝶呤（MTX））的摄取。在类风湿性关节炎中，FRβ在滑膜巨噬细胞上表达，最近已被探索作为使用基于叶酸的正电子发射断层扫描（PET）示踪剂[F]氟-聚乙二醇-叶酸对关节炎大鼠进行成像的生物标志物。本研究的目的是检查这种叶酸示踪剂是否也可用于监测MTX在关节炎大鼠中的治疗效果。

方法

关节炎大鼠不接受治疗或接受MTX治疗（1mg/kg，2次或4次）。健康大鼠未接受任何关节炎诱导或治疗。在MTX治疗前后进行[F]氟-聚乙二醇-叶酸PET-CT扫描（60分钟）。PET检查后，测定切除的膝盖和多个组织中放射性的体外组织分布。使用ED1和ED2抗体通过免疫组织化学对膝盖切片中的滑膜巨噬细胞浸润进行定量。

结果

PET扫描清楚地显示，与对侧膝盖相比，关节炎膝盖中[F]氟-聚乙二醇-叶酸的摄取增加。治疗后，两个MTX治疗组的关节炎膝盖中的标准摄取值均显著降低（1.5倍，p<0.01），接近健康大鼠中的水平。一致地，体外组织分布显示，与对照大鼠相比，2倍和4倍MTX治疗大鼠的关节炎膝盖中的示踪剂摄取分别降低2-4倍。这些结果得到了证实，与对照大鼠相比，MTX治疗大鼠的关节炎膝盖中ED1阳性和ED2阳性滑膜巨噬细胞显著减少（2-4倍，p<0.01）。