In Vitro MR Imaging of Regulated Gene Expression

Alfke, Heiko; Stöppler, Hubert; Nocken, Frank; Heverhagen, Johannes T.; Kleb, Beate; Czubayko, Frank; Klose, K. J.

doi:10.1148/radiol.2282012006

Cited by 62 publications

(43 citation statements)

References 16 publications

(18 reference statements)

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“…Previous agents developed for MRI analysis of enzymatic activity include substrates for h-galactosidase (34), proteases (33,35), and ironbinding proteins, such as tyrosinase (36), the transferrin receptor (37,38), and ferritin (39). Some of these agents exploit the change in relaxivity that occurs on enzymatic activity, affecting the interaction of water molecules with the contrast material.…”

Section: Discussionmentioning

confidence: 99%

Magnetic Resonance Imaging Visualization of Hyaluronidase in Ovarian Carcinoma

et al. 2005

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Hyaluronan, a high molecular weight, negatively charged polysaccharide, is a major constituent of the extracellular matrix. High molecular weight hyaluronan is antiangiogenic, but its degradation by hyaluronidase generates proangiogenic breakdown products. Thus, by expression of hyaluronidase, cancer cells can tilt the angiogenic balance of their microenvironment. Indeed, hyaluronidase-mediated breakdown of hyaluronan correlates with aggressiveness and invasiveness of ovarian cancer metastasis and with tumor angiogenesis. The goal of this work was to develop a novel smart contrast material for detection of hyaluronidase activity by magnetic resonance imaging (MRI). Gadolinium-diethylenetriaminepentaacetic acid (GdDTPA) covalently linked to hyaluronan on the surface of agarose beads showed attenuated relaxivity. Hyaluronidase, either purified from bovine testes or secreted by ES-2 and OVCAR-3 human epithelial ovarian carcinoma cells, activated the hyaluronan-GdDTPA-beads by rapidly altering the R 1 and R 2 relaxation rates. The change in relaxation rates was consistent with the different levels of biologically active hyaluronidase secreted by those cells. Hyaluronan-GdDTPAbeads were further used for demonstration of MRI detection of hyaluronidase activity in the proximity of s.c. ES-2 ovarian carcinoma tumors in nude mice. Thus, hyaluronan-GdDTPAbeads could allow noninvasive molecular imaging of hyaluronidase-mediated tilt of the peritumor angiogenic balance. (Cancer Res 2005; 65(22): 10316-23)

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Section: Discussionmentioning

confidence: 99%

Magnetic Resonance Imaging Visualization of Hyaluronidase in Ovarian Carcinoma

et al. 2005

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“…Tyrosinase plays a role in melanin biosynthesis, and melanin has a high affinity for iron, as evidenced by ironinduced T1 hyperintensities. Changes in the MRI signals of tyrosinase-expressing cells have been detected in vitro (24,25). Ferritin is another metalloprotein that serves as an iron reservoir in vivo, and a rat glioma xenograft expressing the ferritin gene under the control of an inducible tetracycline promoter was found to clearly exhibit reduced T1 and T2 (26).…”

Section: Mrimentioning

confidence: 99%

Molecular-Genetic Imaging Based on Reporter Gene Expression

Kang¹,

Chung²

2008

J Nucl Med

205

178

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Molecular imaging includes proteomic, metabolic, cellular biologic process, and genetic imaging. In a narrow sense, molecular imaging means genetic imaging and can be called moleculargenetic imaging. Imaging reporter genes play a leading role in molecular-genetic imaging. There are 3 major methods of molecular-genetic imaging, based on optical, MRI, and nuclear medicine modalities. For each of these modalities, various reporter genes and probes have been developed, and these have resulted in successful transitions from bench to bedside applications. Each of these imaging modalities has its unique advantages and disadvantages. Fluorescent and bioluminescent optical imaging modalities are simple, less expensive, more convenient, and more user friendly than other imaging modalities. Another advantage, especially of bioluminescence imaging, is its ability to detect low levels of gene expression. MRI has the advantage of high spatial resolution, whereas nuclear medicine methods are highly sensitive and allow data from small-animal imaging studies to be translated to clinical practice. Moreover, multimodality imaging reporter genes will allow us to choose the imaging technologies that are most appropriate for the biologic problem at hand and facilitate the clinical application of reporter gene technologies. Reporter genes can be used to visualize the levels of expression of particular exogenous and endogenous genes and several intracellular biologic phenomena, including specific signal transduction pathways, nuclear receptor activities, and protein-protein interactions. This technique provides a straightforward means of monitoring tumor mass and can visualize the in vivo distributions of target cells, such as immune cells and stem cells. Molecular imaging has gradually evolved into an important tool for drug discovery and development, and transgenic mice with an imaging reporter gene can be useful during drug and stem cell therapy development. Moreover, instrumentation improvements, the identification of novel targets and genes, and imaging probe developments suggest that molecular-genetic imaging is likely to play an increasingly important role in the diagnosis and therapy of cancer.

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“…In fact, increased signal intensity on T 1 WI has been reported in transfected cells overexpressing tyrosinase gene when cultured with iron-and holotransferrin-enriched medium. 39 Chemical exchange saturation transfer is a new method of generating MR contrast that relies on the chemical exchange of protons of solutes with bulk water, which reduces MR imaging signal intensity. 40 Gilad and associates 41ˆr st described a lysine-rich protein (LRP) gene, a CEST-based reporter gene, detecting LRP-expressing xenografts in mouse brain.…”

Section: Mr Imaging Reporter Genesmentioning

confidence: 99%

Molecular MR Imaging of Cancer Gene Therapy: Ferritin Transgene Reporter Takes the Stage

2010

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Molecular imaging using magnetic resonance (MR) imaging has been actively investigated and made rapid progress in the past decade. Applied to cancer gene therapy, the technique's high spatial resolution allows evaluation of gene delivery into target tissues. Because noninvasive monitoring of the duration, location, and magnitude of transgene expression in tumor tissues or cells provides useful information for assessing therapeutic e‹cacy and optimizing protocols, molecular imaging is expected to become a critical step in the success of cancer gene therapy in the near future. We present a brief overview of the current status of molecular MR imaging, especially in vivo reporter gene imaging using ferritin and other reporters, discuss its application to cancer gene therapy, and present our research of MR imaging detection of electroporation-mediated cancer gene therapy using the ferritin reporter gene.

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In Vitro MR Imaging of Regulated Gene Expression

Cited by 62 publications

References 16 publications

Magnetic Resonance Imaging Visualization of Hyaluronidase in Ovarian Carcinoma

Magnetic Resonance Imaging Visualization of Hyaluronidase in Ovarian Carcinoma

Molecular-Genetic Imaging Based on Reporter Gene Expression

Molecular MR Imaging of Cancer Gene Therapy: Ferritin Transgene Reporter Takes the Stage

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