A Whole-Body Dual-Modality Radionuclide Optical Strategy for Preclinical Imaging of Metastasis and Heterogeneous Treatment Response in Different Microenvironments
A Whole-Body Dual-Modality Radionuclide Optical Strategy for Preclinical Imaging of Metastasis and Heterogeneous Treatment Response in Different Microenvironments
复制标题
DOI：
10.2967/jnumed.113.127480
复制
发表时间：
2014-04-01
影响因子：
9.3
通讯作者：
Mullen, Greg E. D.
中科院分区：
文献类型：
--
作者：
Fruhwirth, Gilbert O.;Diocou, Seckou;Mullen, Greg E. D.
在体内对自发性癌细胞转移或对药物治疗的异质性肿瘤反应进行成像是难以实现的。其目标是为此目的开发一种新的高灵敏度和可靠的临床前纵向体内成像模型，从而促进抗癌疗法或分子成像剂的发现和验证。研究方法：该策略基于稳定表达与红色荧光蛋白融合的人钠碘同向转运体（NIS）的乳腺癌细胞，从而允许放射性核素和荧光成像。使用全身nano-SPECT/CT与（TcO 4-）-Tc-99 m，我们遵循原发性肿瘤生长和自发转移的依托泊苷治疗的存在或不存在。NIS成像用于将小至单个淋巴结（LN）的器官分类为转移阳性或阴性，并通过共聚焦荧光显微镜证实结果。依托泊苷的治疗效果通过离体抗半胱氨酸蛋白酶3染色和荧光显微镜证实。结果如下：在该临床前模型中，我们发现NIS成像策略在检测小肿瘤（肿瘤-血液比高18.5倍）和转移（LN，3.6倍）的能力方面优于最先进的F-18-FDG成像，因为靠近转移部位的器官中的对比度提高（心脏和肾脏中的标准化摄取值分别低12倍和8.5倍）。我们应用该模型评估新辅助依托泊苷的治疗反应，发现自发转移检测得到一致和可靠的改善。重要的是，我们还发现不同微环境中的肿瘤细胞对依托泊苷治疗的反应是异质性的，这只能通过基于NIS的策略来确定，而不能通过F-18-FDG成像来确定。结论：我们开发了一种新的临床前纵向体内癌细胞跟踪策略，其灵敏度和可靠性高于F-18-FDG PET，并将其应用于在存在或不存在遗传毒性应激治疗的情况下跟踪自发和远处转移。重要的是，该模型提供了足够的灵敏度和动态范围，以允许在各种微环境中的异质性治疗反应的可靠评估。
Imaging spontaneous cancer cell metastasis or heterogeneous tumor responses to drug treatment in vivo is difficult to achieve. The goal was to develop a new highly sensitive and reliable preclinical longitudinal in vivo imaging model for this purpose, thereby facilitating discovery and validation of anticancer therapies or molecular imaging agents. Methods: The strategy is based on breast cancer cells stably expressing the human sodium iodide symporter (NIS) fused to a red fluorescent protein, thereby permitting radionuclide and fluorescence imaging. Using whole-body nano-SPECT/CT with (TcO4-)-Tc-99m, we followed primary tumor growth and spontaneous metastasis in the presence or absence of etoposide treatment. NIS imaging was used to classify organs as small as individual lymph nodes (LNs) to be positive or negative for metastasis, and results were confirmed by confocal fluorescence microscopy. Etoposide treatment efficacy was proven by ex vivo anticaspase 3 staining and fluorescence microscopy. Results: In this preclinical model, we found that the NIS imaging strategy outperformed stateof- the-art F-18-FDG imaging in its ability to detect small tumors (18.5-fold-better tumor-to-blood ratio) and metastases (LN, 3.6-fold) because of improved contrast in organs close to metastatic sites (12- and 8.5-fold-lower standardized uptake value in the heart and kidney, respectively). We applied the model to assess the treatment response to the neoadjuvant etoposide and found a consistent and reliable improvement in spontaneous metastasis detection. Importantly, we also found that tumor cells in different microenvironments responded in a heterogeneous manner to etoposide treatment, which could be determined only by the NIS-based strategy and not by F-18-FDG imaging. Conclusion: We developed a new strategy for preclinical longitudinal in vivo cancer cell tracking with greater sensitivity and reliability than F-18-FDG PET and applied it to track spontaneous and distant metastasis in the presence or absence of genotoxic stress therapy. Importantly, the model provides sufficient sensitivity and dynamic range to permit the reliable assessment of heterogeneous treatment responses in various microenvironments.