Sun Xianlei, Gao Duo, Gao Liquan, Zhang Chenran, Yu Xinhe, Jia Bing, Wang Fan, Liu Zhaofei
1. Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China;
1. Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China; ; 2. Interdisciplinary Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Theranostics. 2015 Feb 27;5(6):597-608. doi: 10.7150/thno.11546. eCollection 2015.
Significant evidence has indicated that tumor-associated macrophages (TAMs) play a critical role in the proliferation, invasion, angiogenesis, and metastasis of a variety of human carcinomas. In this study, we investigated whether near-infrared fluorescence (NIRF) imaging using a macrophage mannose receptor (MMR; CD206)-targeting agent could be used to noninvasively visualize and quantify changes in TAMs in vivo. The CD206-targeting NIRF agent, Dye-anti-CD206, was prepared and characterized in vitro and in vivo. By using NIRF imaging, we were able to noninvasively image tumor-infiltrating macrophages in the 4T1 mouse breast cancer model. Importantly, longitudinal NIRF imaging revealed the depletion of macrophages in response to zoledronic acid (ZA) treatment. However, ZA alone did not lead to the inhibition of 4T1 tumor growth. We therefore combined anti-macrophage ZA therapy and tumor cytotoxic docetaxel (DTX) therapy in the mouse model. The results demonstrated that this combination strategy could significantly inhibit tumor growth as well as tumor metastasis to the lungs. Based on these findings, we concluded that CD206-targeted molecular imaging can sensitively detect the dynamic changes in tumor-infiltrating macrophages, and that the combination of macrophage depletion and cytotoxic therapy is a promising strategy for the effective treatment of solid tumors.
大量证据表明，肿瘤相关巨噬细胞（TAM）在多种人类癌症的增殖、侵袭、血管生成和转移中起关键作用。在本研究中，我们调查了使用靶向巨噬细胞甘露糖受体（MMR；CD206）的试剂进行近红外荧光（NIRF）成像是否可用于在体内非侵入性地可视化和量化TAM的变化。制备了靶向CD206的NIRF试剂Dye-anti-CD206，并在体外和体内对其进行了表征。通过使用NIRF成像，我们能够在4T1小鼠乳腺癌模型中对肿瘤浸润巨噬细胞进行非侵入性成像。重要的是，纵向NIRF成像显示了唑来膦酸（ZA）治疗后巨噬细胞的减少。然而，单独使用ZA并未导致4T1肿瘤生长受到抑制。因此，我们在小鼠模型中将抗巨噬细胞ZA疗法与肿瘤细胞毒性多西他赛（DTX）疗法相结合。结果表明，这种联合策略可显著抑制肿瘤生长以及肿瘤向肺部的转移。基于这些发现，我们得出结论，靶向CD206的分子成像可灵敏地检测肿瘤浸润巨噬细胞的动态变化，并且巨噬细胞清除与细胞毒性疗法相结合是有效治疗实体瘤的一种有前景的策略。
