Trafficking Macrophage Migration Using Reporter Gene Imaging with Human Sodium Iodide Symporter in Animal Models of Inflammation

Seo, Ji Hyoung; Jeon, Yong Hyun; Lee, Yong Jin; Yoon, Gil Sook; Won, Dong Il; Ha, Jeoung‐Hee; Jeong, Shin Young; Lee, Sang Woo; Ahn, Byeong‐Cheol; Lee, Jaetae

doi:10.2967/jnumed.110.077891

Cited by 45 publications

(31 citation statements)

References 24 publications

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“…NIS overexpression was also reported for several nonthyroidal cancer types including colorectal, lung, and a subset of breast cancers (13,(20)(21)(22)(23)(24), but it remains to be determined if those NIS expression levels are sufficient and consistent enough for accurate diagnosis and therapy. NIS has also been used as a reporter gene preclinically in cardiac (25), hematopoietic (26), and neural studies (27); for tracking macrophage migration (28); and for noninvasive imaging of gene therapy vectors (29,30). It has not yet been used for cancer metastasis tracking.…”

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confidence: 99%

A Whole-Body Dual-Modality Radionuclide Optical Strategy for Preclinical Imaging of Metastasis and Heterogeneous Treatment Response in Different Microenvironments

et al. 2014

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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 99m TcO 4 − , 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 18 F-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 18 F-FDG imaging. Conclusion: We developed a new strategy for preclinical longitudinal in vivo cancer cell tracking with greater sensitivity and reliability than 18 F-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.

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confidence: 99%

A Whole-Body Dual-Modality Radionuclide Optical Strategy for Preclinical Imaging of Metastasis and Heterogeneous Treatment Response in Different Microenvironments

et al. 2014

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“…3B). Although expression of sodium iodide symporter alone is sufficient to accumulate 99m Tc-pertechnetate in a cell (14,15), we found that incubation with Sn 2+ , which diffuses across the cell membrane, accumulates intracellularly, and reduces Tc 7+ , helped to retain the radioisotope.…”

Section: Resultsmentioning

confidence: 70%

Microscopic Validation of Macroscopic In Vivo Images Enabled by Same-Slide Optical and Nuclear Fusion

et al. 2014

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It is currently difficult to determine the molecular and cellular basis for radioscintigraphic signals obtained during macroscopic in vivo imaging. The field is in need of technology that helps bridge the macroscopic and microscopic regimes. To solve this problem, we developed a fiducial marker (FM) simultaneously compatible with 2-color near-infrared (NIR) fluorescence (700 and 800 nm), autoradiography, and conventional hematoxylin–eosin (HE) histology. Methods The FM was constructed from an optimized concentration of commercially available human serum albumin, 700- and 800-nm NIR fluorophores, 99mTc-pertechnetate, dimethyl sulfoxide, and glutaraldehyde. Lymphangioleiomyomatosis cells coexpressing the sodium iodide symporter and green fluorescent protein were labeled with 700-nm fluorophore and 99mTc-pertechnatate and then administered intratracheally into CD-1 mice. After in vivo SPECT imaging and ex vivo SPECT and NIR fluorescence imaging of the lungs, 30-µm frozen sections were prepared and processed for 800-nm NIR fluorophore costaining, autoradiography, and HE staining on the same slide using the FMs to coregister all datasets. Results Optimized FMs, composed of 100 µM unlabeled human serum albumin, 1 µM NIR fluorescent human serum albumin, 15% dimethyl sulfoxide, and 3% glutaraldehyde in phosphate-buffered saline (pH 7.4), were prepared within 15 min, displayed homogeneity and stability, and were visible by all imaging modalities, including HE staining. Using these FMs, tissue displaying high signal by SPECT could be dissected and analyzed on the same slide and at the microscopic level for 700-nm NIR fluorescence, 800-nm NIR fluorescence, autoradiography, and HE histopathologic staining. Conclusion When multimodal FMs are combined with a new technique for simultaneous same-slide NIR fluorescence imaging, autoradiography, and HE staining, macroscopic in vivo images can now be studied unambiguously at the microscopic level.

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“…After cells have been transfected with the symporter gene, using an adenovirus as the carrier, they can be imaged by injecting any of the isotopes of iodine or 99m Tc pertechnetate. This approach has been used recently to study the trafficking of macrophages in humans [79]. …”

Section: Cell Traffickingmentioning

confidence: 99%

Clinical Molecular Imaging with Radiotracers: Current Status

Graham

2011

Med Princ Pract

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Molecular imaging is defined as the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems. Most clinical molecular imaging is currently done using radioisotope-labeled agents to define the activity of various metabolic pathways in vivo or to determine the distribution and density of various receptors relevant to human disease. This paper briefly reviews most of the commonly used radiopharmaceuticals in nuclear medicine, as well as newer agents that are likely to become available in the near future. The metabolic pathways include those relevant to the thyroid, parathyroid, heart, brain, bones, kidneys, liver, pancreas, adrenals and tumor. The receptor systems include agents useful in evaluating movement disorders, dementia, cardiac sympathetic enervation and neoangiogenesis. Receptor systems relevant to tumors include somatostatin receptors (neuroendocrine tumors), prostate-specific membrane antigen, carbonic anhydrase IX (renal cancer), and CD-20 (lymphoma). These agents, and newer agents that are being developed, are likely to become critical in the development of personalized medicine, where it will become increasingly important to determine whether a treatment that is targeted to a specific metabolic pathway or receptor is likely to be successful.

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Trafficking Macrophage Migration Using Reporter Gene Imaging with Human Sodium Iodide Symporter in Animal Models of Inflammation

Cited by 45 publications

References 24 publications

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

Microscopic Validation of Macroscopic In Vivo Images Enabled by Same-Slide Optical and Nuclear Fusion

Clinical Molecular Imaging with Radiotracers: Current Status

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