Foss Catherine A, Wildes Flonné, Mezzanzanica Delia, Podo Franca, Hung Chien-Fu, Yadav Santosh, Vidaver Marie-France Penet
Department of Radiology and Radiological Science, The Russell H. Morgan, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Center for Infection and Inflammation Imaging Research, Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, USA.
EJNMMI Res. 2024 Nov 29;14(1):121. doi: 10.1186/s13550-024-01157-8.
Tumor-Associated Macrophages (TAMs) play a critical role in the pathogenesis and progression of ovarian cancer, a lethal gynecologic malignancy. [I]iodo-DPA-713 is a PET radiotracer that is selectively trapped within reactive macrophages. We have employed this radioligand here as well as a fluorescent analog to image TAMs associated with primary tumors, secondary pulmonary metastases and gastrointestinal tract-associated macrophages, associated with ascites accumulation in a syngeneic mouse model of metastatic ovarian cancer. Intact female C57BL/6 mice were engrafted with ID8-Defb29-VEGF tumor pieces. One month after engraftment, the mice were selected for positive bioluminescence to show primary and secondary tumor burden and were then scanned by PET/MRI with [I]iodo-DPA-713, observing a 24 h uptake time. PET data were overlayed with T-weighted MRI data to facilitate PET uptake tissue identity. Additionally, mice were imaged ex vivo using Near IR Fluorescence (NIRF), capturing the uptake and sequestration of DPA-713-IRDye800CW, a fluorescent analog of the radioligand used here. Additionally, cell culture uptake of DPA-713-IRDye680LT in ID8-DEFb29-VEGF, IOSE hTERT and RAW264.7 cells was conducted to measure tracer uptake in ovarian cancer cells, ovarian epithelial cells and macrophage.
PET/MRI data show an intense ring of radiotracer uptake surrounding primary tumors. PET uptake is also associated with lung metastases, but not healthy lung. Mice displaying ascites also display PET uptake along the gastrointestinal tract while sham-operated mice show minimal gastrointestinal uptake. All mice show specific kidney uptake. Mice imaged by NIRF confirmed TAMs uptake mostly at the rim of primary tumors while 1 mm secondary tumors in the lungs displayed robust, homogeneous uptake of the radio- and fluorescent analog. Ex vivo biodistribution of [I]iodo-DPA-713 showed that contralateral ovaries in middle-stage disease had the highest probe uptake with tissues sampled in mid- and late-stage disease showing increasing uptake.
[I]iodo-DPA-713 and DPA-713-IRDye800CW sensitively identify and locate TAMs in a syngeneic mouse model of metastatic ovarian cancer.
肿瘤相关巨噬细胞（TAM）在卵巢癌（一种致命的妇科恶性肿瘤）的发病机制和进展中起关键作用。[I]碘代-DPA-713是一种PET放射性示踪剂，可选择性地滞留在反应性巨噬细胞内。我们在此使用了这种放射性配体以及一种荧光类似物，对同基因转移性卵巢癌小鼠模型中与原发性肿瘤、继发性肺转移灶相关的TAM以及与腹水积聚相关的胃肠道相关巨噬细胞进行成像。将完整的雌性C57BL/6小鼠植入ID8-Defb29-VEGF肿瘤块。植入后一个月，选择小鼠进行阳性生物发光检测以显示原发性和继发性肿瘤负荷，然后用[I]碘代-DPA-713进行PET/MRI扫描，摄取时间为24小时。将PET数据与T加权MRI数据叠加，以方便确定PET摄取组织的身份。此外，使用近红外荧光（NIRF）对小鼠进行离体成像，捕获DPA-713-IRDye800CW（此处使用的放射性配体的荧光类似物）的摄取和滞留情况。此外，还进行了ID8-DEFb29-VEGF、IOSE hTERT和RAW264.7细胞对DPA-713-IRDye680LT的细胞培养摄取实验，以测量卵巢癌细胞、卵巢上皮细胞和巨噬细胞对示踪剂的摄取。
PET/MRI数据显示原发性肿瘤周围有强烈的放射性示踪剂摄取环。PET摄取也与肺转移有关，但与健康肺无关。出现腹水 的小鼠在胃肠道也有PET摄取，而假手术小鼠的胃肠道摄取极少。所有小鼠的肾脏均有特异性摄取。通过NIRF成像的小鼠证实，TAM主要在原发性肿瘤边缘摄取，而肺部1毫米的继发性肿瘤对放射性和荧光类似物均有强烈、均匀的摄取。[I]碘代-DPA-713的离体生物分布显示，中期疾病的对侧卵巢探针摄取最高，中晚期疾病采集的组织摄取增加。
[I]碘代-DPA-713和DPA-713-IRDye800CW可在同基因转移性卵巢癌小鼠模型中灵敏地识别和定位TAM。
