Tissue-specific MR contrast agents

Weinmann, Hanns‐Joachim; Ebert, Wolfgang; Misselwitz, Bernd; Schmitt‐Willich, Heribert

doi:10.1016/s0720-048x(02)00332-7

Cited by 238 publications

(166 citation statements)

References 143 publications

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“…There is a great deal of interest in enhancing the utility of these tools in medicine and research through the development of molecularly-targeted MRI contrast agents. One example might be a chimeric molecule comprised of a contrast agent tethered to a molecule capable of binding to a specific protein or other biomolecular target with high affinity and specificity [4][5][6][7][8][9][10][11][12][13][14][15][16][17]. For example, we previously reported that a peptide selected from a phage display library to bind the yeast Gal80 protein can be linked to GdDOTA to create a reagent capable of imaging Gal80 protein in vitro [18,19].…”

Section: Introductionmentioning

confidence: 99%

The detection limit of a Gd3+-based T1 agent is substantially reduced when targeted to a protein microdomain

Hanaoka

Lubag

Castillo-Muzquiz³

et al. 2008

Magnetic Resonance Imaging

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Simple low MW chelates of Gd 3+ such as those currently used in clinical MR imaging are considered too insensitive for most molecular imaging applications. Here, we evaluated the detection limit of a molecularly targeted, low MW Gd 3+ -based, T 1 agent in a model where the receptor concentration was precisely known. The data demonstrate that receptors clustered together to form a microdomain of high local concentration can be imaged successfully even when the bulk concentration of the receptor is quite low. A GdDO3A-peptide identified by phage display to target the anti-FLAG antibody was synthesized, purified and characterized. T 1 weighted MR images were compared with the agent bound to antibody in bulk solution and with the agent bound to the antibody localized on agarose beads. Fluorescence competition binding assays show that the agent has a high binding affinity (K D = 150 nM) for the antibody while the fully bound relaxivity of the GdDO3A-peptide:anti-FLAG antibody in solution was a relatively modest 17 mM −1 s −1 . The agent:antibody complex was MR silent at concentrations below ~9 µM but was detectable down to 4 µM bulk concentrations when presented to antibody clustered together on the surface of agarose beads. These results provided an estimate of the detection limits for other T 1 -based agents with higher fully bound relaxivities or multimeric structures bound to clustered receptor molecules. The results demonstrate that the sensitivity of molecularly-targeted contrast agents depends on the local microdomain concentration of the target protein and the molecular relaxivity of the bound complex. A model is presented which predicts that for a molecularly targeted agent consisting of a single Gd 3+ complex with bound relaxivity of 100 mM −1 s −1 or, more reasonably, four tethered Gd 3+ complexes each having a bound relaxivity of 25 mM −1 s −1 , the detection limit of a protein microdomain is ~690 nM at 9.4T. These experimental and extrapolated detection limits are both well below current literature estimates and suggests that detection of low MW molecularly targeted T 1 agents is not an unrealistic goal.

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Section: Introductionmentioning

confidence: 99%

The detection limit of a Gd3+-based T1 agent is substantially reduced when targeted to a protein microdomain

Hanaoka

Lubag

Castillo-Muzquiz³

et al. 2008

Magnetic Resonance Imaging

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“…Detection of small liver lesions at early disease stages requires contrast agents that have a significantly improved sensitivity and a large dynamic range with reduced background water signal in tissue, as well as appropriate liver distributions and retention times for high-quality imaging. The most commonly used clinically approved T 1 -weighted liver contrast agents, gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) (Eovist, United States; Primovist, Europe; Bayer) and gadobenate dimeglumine (Gd-BOPTA) (Multihance; Bracco), have 50% and 5% hepatocyte uptake, respectively (9). They cannot detect earlystage small liver tumors and metastases (size, <0.5 mm), differentiate dysplastic nodules from HCC, or discriminate tumor thrombosis from platelet-fibrin thrombosis.…”

mentioning

confidence: 99%

Protein MRI contrast agent with unprecedented metal selectivity and sensitivity for liver cancer imaging

Xue

Yang²,

Qiao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

119

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With available MRI techniques, primary and metastatic liver cancers that are associated with high mortality rates and poor treatment responses are only diagnosed at late stages, due to the lack of highly sensitive contrast agents without Gd 3+ toxicity. We have developed a protein contrast agent (ProCA32) that exhibits high stability for Gd 3+ and a 10 11 -fold greater selectivity for Gd 3+ over Zn 2+ compared with existing contrast agents. ProCA32, modified from parvalbumin, possesses high relaxivities (r 1 /r 2 : 66.8 mmol −1 ·s −1 / 89.2 mmol −1 ·s −1 per particle). Using T 1 -and T 2 -weighted, as well as T 2 /T 1 ratio imaging, we have achieved, for the first time (to our knowledge), robust MRI detection of early liver metastases as small as ∼0.24 mm in diameter, much smaller than the current detection limit of 10-20 mm. Furthermore, ProCA32 exhibits appropriate in vivo preference for liver sinusoidal spaces and pharmacokinetics for high-quality imaging. ProCA32 will be invaluable for noninvasive early detection of primary and metastatic liver cancers as well as for monitoring treatment and guiding therapeutic interventions, including drug delivery.MRI | uveal melanoma | metastasis | contrast agents | T 2 /T 1 ratio imaging T umor metastasis is the main cause of nearly all human cancerrelated deaths. Liver is a common site for metastases of a variety of cancers, including melanoma, breast, pancreatic, and colon cancers (1, 2). For example, uveal melanoma, the most common primary intraocular tumor, has a 40% risk of metastasizing to the liver within 10 y of diagnosis of the primary tumor. Hepatic metastases, which occur in 95% of patients with uveal melanoma metastasis, result in death in almost all cases. This high death rate is related to the recognition of liver metastasis at a late clinical stage (at stage II or later in the TNM system) in which the metastatic uveal melanoma is resistant to currently available systemic chemotherapies (3, 4). The liver may also give rise to primary tumors such as hepatocellular carcinoma (HCC), which is the most common primary malignancy worldwide (5). However, currently there is no reliable way to detect primary liver cancer and hepatic metastases at early stages with high sensitivity and specificity.MRI is a widely used clinical imaging modality that provides exquisite soft-tissue contrast without using ionizing radiation (6, 7). More than 35% of MRI scans use MRI contrast agents, particularly paramagnetic gadolinium (Gd 3+ )-based contrast agents, which shorten T 1 and lead to an increase in MRI intensity (8). All clinically approved Gd 3+ -containing contrast agents are based on small chelators with relaxivity (r 1 and r 2 ) values around 4-6 mM −1 ·s −1 . Their low relaxivities severely limit the sensitivity of current MR imaging methods with respect to detection of lesions and treatment planning and monitoring. Repeat MRI scans are frequently requested for patients with ambiguous small lesions and are used as a routine follow-up modality for highrisk patients, but t...

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“…Another aim will be to establish the application of selective and non-selective contrasting agents, such as e.g. manganese, Magnevist or Gadovist (for an overview see Weinmann et al (2003)) on both living and fixed sea urchin specimens. In order to carry out our experiments using living organisms, we will look further into the application of anaesthetic substances in order to decrease movement artifacts.…”

Section: Future Perspectivesmentioning

confidence: 99%

Rheinische Friedrich‐Wilhelms‐Universität Bonn

Carr¹

2017

Geschichte Der Anorganischen Chemie

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SummaryEchinoidea (sea urchins) are a group of benthic marine invertebrates that belong to the deuterostome taxon Echinodermata. Although extensive data have been gathered on larval and adult hard-part anatomy of sea urchins, for several reasons the knowledge of echinoid soft tissue anatomy is still fragmentary. For example, published works report differences in various taxa regarding the presence or absence of prominent internal organs such as the primary siphon, the gastric caecum, or the spongy bodies.The major aim of the present study was therefore to evaluate the potential of two non-invasive imaging techniques, namely magnetic resonance imaging (MRI) and micro-computed tomography (µCT), to visualize, in combination with advanced 3D modeling protocols, internal structures of sea urchins and to apply these techniques for large-scale comparative morphological analyses. In order to significantly extend taxon sampling, valuable specimens from museum collections were selected to be included in this study.MRI proved to be ideally suited to depict internal structures of invertebrates non-invasively, especially soft tissues, at isotropic resolutions well below 100 µm. Due to the simple specimen preparation as well as straight-forward imaging protocols, a high specimen throughput could be accomplished. Based on the digital tomographic datasets, 3D models were assembled in order to visualize selected features of echinoid soft tissue anatomy. Although imaging of soft tissues was practically impossible using conventional desktop µCT equipment due to the physical properties inherent in X-ray technology, this technique was successfully employed to visualize sea urchin hard-part anatomy at isotropic resolutions below 20 µm. MRI and µCT can therefore be seen as complementary non-invasive imaging techniques, especially for echinoderm specimens in which soft-and hard-part anatomy are equally present.To explore novel ways of communication and deposition of the acquired datasets as well as 3D models, these were made publicly available through the Internet and by integrating 3D data into PDF-based scientific publications. This approach included also the use of data from a central data repository for protein structures.The axial complex, a highly specialized organ also found in other echinoderm taxa, was then selected for an exemplary comparative study involving dozens of sea urchin species in order to highlight the possibilities offered by non-invasive imaging techniques combined with dissection, histology, and a reappraisal of information from published work. The results suggest an architectural interdependence of the axial complex with various other internal organs present in sea urchins.Finally, an attempt was made to evaluate the potential of echinoid soft tissue structures to extend the current list of morphological characters used for phylogenetic inferences. A set of selected soft tissue characters was therefore assembled and evaluated for every major sea urchin taxon. The results provide significant phylogenetic informa...

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Tissue-specific MR contrast agents

Cited by 238 publications

References 143 publications

The detection limit of a Gd3+-based T1 agent is substantially reduced when targeted to a protein microdomain

The detection limit of a Gd3+-based T1 agent is substantially reduced when targeted to a protein microdomain

Protein MRI contrast agent with unprecedented metal selectivity and sensitivity for liver cancer imaging

Rheinische Friedrich‐Wilhelms‐Universität Bonn

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