Department of Nuclear Medicine and Minnan PET Center, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, China.
Department of Radiation Oncology, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, China.
Mol Pharm. 2024 Jul 1;21(7):3684-3692. doi: 10.1021/acs.molpharmaceut.4c00405. Epub 2024 Jun 20.
Early detection of pulmonary fibrosis is a critical yet insufficiently met clinical necessity. This study evaluated the effectiveness of FAPI-LM3, a Ga-radiolabeled heterobivalent molecular probe that targets fibroblast activating protein (FAP) and somatostatin receptor 2 (SSTR2), in the early detection of pulmonary fibrosis, leveraging its potential for early disease identification. A bleomycin-induced early pulmonary fibrosis model was established in C57BL/6 mice for 7 days. FAP and SSTR2 expression levels were quantitatively assessed in human idiopathic pulmonary fibrosis lung tissue samples and bleomycin-treated mouse lung tissues by using western blotting, real-time quantitative PCR (RT-qPCR), and immunofluorescence techniques. The diagnostic performance of FAPI-LM3 was investigated by synthesizing monomeric radiotracers Ga-FAPI-46 and Ga-DOTA-LM3 alongside the heterobivalent probe Ga-FAPI-LM3. These imaging radiopharmaceuticals were used in small-animal PET to compare their uptake in fibrotic and normal lung tissues. Results indicated significant upregulation of FAP and SSTR2 at both RNA and protein levels in fibrotic lung tissues compared with that in normal controls. PET imaging demonstrated significantly enhanced uptake of the Ga-FAPI-LM3 probe in fibrotic lung tissues, with superior visual effects compared to monomeric tracers. At 60 min postinjection, early stage fibrotic tissues (day 7) demonstrated low-to-medium uptake of monomeric probes, including Ga-DOTA-LM3 (0.45 ± 0.04% ID/g) and Ga-FAPI-46 (0.78 ± 0.09% ID/g), whereas the uptake of the heterobivalent probe Ga-FAPI-LM3 (1.90 ± 0.10% ID/g) was significantly higher in fibrotic lesions than in normal lung tissue. Blockade experiments confirmed the specificity of Ga-FAPI-LM3 uptake, which was attributed to synergistic targeting of FAP and SSTR2. This study demonstrates the potential of Ga-FAPI-LM3 for early pulmonary fibrosis detection via molecular imaging, offering significant benefits over monomeric tracers Ga-FAPI-46 and Ga-DOTA-LM3. This strategy offers new possibilities for noninvasive and precise early detection of pulmonary fibrosis.
早期发现肺纤维化是一项至关重要但尚未得到充分满足的临床需求。本研究评估了 FAPI-LM3 的有效性，FAPI-LM3 是一种 Ga 放射性标记的双价分子探针，靶向成纤维细胞激活蛋白 (FAP) 和生长抑素受体 2 (SSTR2)，利用其早期疾病识别的潜力，用于早期检测肺纤维化。在 C57BL/6 小鼠中建立了博来霉素诱导的早期肺纤维化模型，持续 7 天。通过 Western blot、实时定量 PCR (RT-qPCR) 和免疫荧光技术，定量评估了人特发性肺纤维化肺组织样本和博来霉素处理的小鼠肺组织中 FAP 和 SSTR2 的表达水平。通过合成单体放射性示踪剂 Ga-FAPI-46 和 Ga-DOTA-LM3 以及双价探针 Ga-FAPI-LM3，研究了 FAPI-LM3 的诊断性能。这些成像放射性药物用于小动物 PET 比较它们在纤维化和正常肺组织中的摄取。结果表明，纤维化肺组织中 FAP 和 SSTR2 的 RNA 和蛋白质水平均显著上调，与正常对照组相比。PET 成像显示，Ga-FAPI-LM3 探针在纤维化肺组织中的摄取明显增强，与单体示踪剂相比具有更好的视觉效果。在注射后 60 分钟，早期纤维化组织（第 7 天）摄取单体探针，包括 Ga-DOTA-LM3（0.45±0.04% ID/g）和 Ga-FAPI-46（0.78±0.09% ID/g），而双价探针 Ga-FAPI-LM3（1.90±0.10% ID/g）在纤维化病变中的摄取明显高于正常肺组织。阻断实验证实了 Ga-FAPI-LM3 摄取的特异性，这归因于 FAP 和 SSTR2 的协同靶向。本研究通过分子成像证明了 Ga-FAPI-LM3 用于早期肺纤维化检测的潜力，与单体示踪剂 Ga-FAPI-46 和 Ga-DOTA-LM3 相比具有显著优势。该策略为肺纤维化的非侵入性和精确早期检测提供了新的可能性。
