Lanthanide(<scp>III</scp>) Chelates of DTPA Bis(amide) Glycoconjugates: Potential Imaging Agents Targeted at the Asyaloglycoprotein Receptor

Baía, Paula; André, João P.; Geraldes, Carlos F. G. C.; Martins, José A.; Merbach, André E.; Tóth, Éva

doi:10.1002/ejic.200400766

Cited by 20 publications

(19 citation statements)

References 49 publications

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“…Although these are often highly convenient and flexible, they also have disadvantages, such as the toxicity (22) of CdS-based fluorescent quantum dots and the ligand-lability of gold clusters (23,24), which is exacerbated in biological media (25). The use of glycosylated contrast agents, until now, has been limited to T 1 -type reagents that rely on water exchange in their inner coordination sphere (26)(27)(28)(29)(30). They bring with them disadvantages of low sensitivity and low avidity for carbohydrate-binding protein targets since they display low carbohydrate copy numbers (31).…”

mentioning

confidence: 99%

Glyconanoparticles allow pre-symptomatic in vivo imaging of brain disease

Kasteren

Campbell

Serres

et al. 2009

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

257

193

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Initial recruitment of leukocytes in inflammation associated with diseases such as multiple sclerosis (MS), ischemic stroke, and HIV-related dementia, takes place across intact, but activated brain endothelium. It is therefore undetectable to symptom-based diagnoses and cannot be observed by conventional imaging techniques, which rely on increased permeability of the blood–brain barrier (BBB) in later stages of disease. Specific visualization of the early-activated cerebral endothelium would provide a powerful tool for the presymptomatic diagnosis of brain disease and evaluation of new therapies. Here, we present the design, construction and in vivo application of carbohydrate-functionalized nanoparticles that allow direct detection of endothelial markers E-/P-selectin (CD62E/CD62P) in acute inflammation. These first examples of MRI-visible glyconanoparticles display multiple copies of the natural complex glycan ligand of selectins. Their resulting sensitivity and binding selectivity has allowed acute detection of disease in mammals with beneficial implications for treatment of an expanding patient population suffering from neurological disease.

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mentioning

confidence: 99%

Glyconanoparticles allow pre-symptomatic in vivo imaging of brain disease

Kasteren

Campbell

Serres

et al. 2009

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

257

193

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“…The 1 H nuclear magnetic relaxation dispersion (NMRD) profiles showed that the relaxivity increase of these compounds relative to the respective parent compounds without the sugar derivatives (Gd-DOTA; 2 and Gd-DTPA-BMA; 3) is much lower that that expected for their molecular weight increase [32,33]. As an example, at 20 MHz and 298 K, r 1 of Gd-DTPALac 2 is only 13% higher than that of Gd-DTPA-BMA, although its molecular weight is approximately three-times higher [33]. An evaluation of the parameters governing their relaxivity showed that r 1 of these Gd(III) complexes of glycoconjugate ligands is limited by:…”

Section: Mri Contrast Agentsmentioning

confidence: 96%

“…Chemically well-defined, mono disperse and characterized multivalent agents can be assembled by an alternative molecular design: the conjugation of dendrimeric-clustered carbohydrate bifunctional reagents through spacers to an MRI reporter group. Various Gd(III) complexes of the DTPA-and DOTA-type ligands, peripherally substituted with one or more targeting group(s) consisting of a clustered carbohydrate of variable valence, with different topologies (FiguRe 3), containing an increasing number of terminal galactosyl (Gal), lactosyl (Lac) or glycosyl (Glc) groups, have been synthesized and studied [31][32][33][34][35][36]. The ligands included various DOTA monoamide derivatives (FiguRe 4), with one (DOTAGal, DOTAGlc and DOTALac; 9), two (DOTAGal 2 , DOTAGlc 2 and DOTALac 2 ;10) or four (DOTAGal 4 ; 12) terminal sugar groups, one DOTA cis-bisamide derivative with two terminal sugar groups (DO2A(cis)Gal 2 ; 11) and DTPA bisamides with two (DTPAGal 2 and DTPALac 2 ; 13) or four (DTPAGal 4 ; 14) terminal sugar groups.…”

Section: Mri Contrast Agentsmentioning

confidence: 99%

“…The ligands included various DOTA monoamide derivatives (FiguRe 4), with one (DOTAGal, DOTAGlc and DOTALac; 9), two (DOTAGal 2 , DOTAGlc 2 and DOTALac 2 ;10) or four (DOTAGal 4 ; 12) terminal sugar groups, one DOTA cis-bisamide derivative with two terminal sugar groups (DO2A(cis)Gal 2 ; 11) and DTPA bisamides with two (DTPAGal 2 and DTPALac 2 ; 13) or four (DTPAGal 4 ; 14) terminal sugar groups. All dendrimeric sugar units were bound thioglycosidically, in order to prevent them from being cleaved off by enzymes [32][33][34][35]. The 1 H nuclear magnetic relaxation dispersion (NMRD) profiles showed that the relaxivity increase of these compounds relative to the respective parent compounds without the sugar derivatives (Gd-DOTA; 2 and Gd-DTPA-BMA; 3) is much lower that that expected for their molecular weight increase [32,33].…”

Section: Mri Contrast Agentsmentioning

confidence: 99%

“…All dendrimeric sugar units were bound thioglycosidically, in order to prevent them from being cleaved off by enzymes [32][33][34][35]. The 1 H nuclear magnetic relaxation dispersion (NMRD) profiles showed that the relaxivity increase of these compounds relative to the respective parent compounds without the sugar derivatives (Gd-DOTA; 2 and Gd-DTPA-BMA; 3) is much lower that that expected for their molecular weight increase [32,33]. As an example, at 20 MHz and 298 K, r 1 of Gd-DTPALac 2 is only 13% higher than that of Gd-DTPA-BMA, although its molecular weight is approximately three-times higher [33].…”

Section: Mri Contrast Agentsmentioning

confidence: 99%

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Glycoconjugate Probes and Targets for Molecular Imaging Using Magnetic Resonance

2010

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Review Molecular recognition of sugar residues applied in molecular imagingMolecular imaging aims at probing the molecular abnormalities that are the basis of diseases rather than to image their effects [1]. An important prerequisite of this approach is the selection of appropriate markers of disease and of targeting vectors to recognize them. The latter can include low-molecular weight substrates for enzymes or high-molecular weight affinity ligands, such as monoclonal antibodies, hormone analogs and recombinant proteins. Of the three major classes of biomolecules (proteins, nucleic acids and carbohydrates), the latter class is the least exploited in molecular imaging. However, a dense layer of glyco conjugates covers all cells and carbohydrate mediated cellular recognition plays an important role in nature, both in normal and malignant processes, such as cell-cell communication, infection, inflammation, metastasis and reproduction. As carriers of information, the carbohydrates have far greater potential than proteins and nucleic acids; three different nucleotides or amino acids can generate only six distinguishable structures, while over 1000 structures can be built up from three different monosaccharides [2]. This level of complexity is probably the reason for the fact that the exploration of these compounds in molecular imaging is lagging behind [3]. Recently, significant progress has been made in glycochemistry and glycobiology; for example, automated solid-phase synthesis of oligo saccharides has become possible [4], carbohydrate-based vaccines have been developed [5] and high-throughput methods have been designed for the screening of molecular interactions [6]. The exciting new developments in glycoscience are opening way for new challenges in exploring the full potential of carbohydrates in molecular imaging. Therefore, here we give an overview of the recent literature on the use of glycoconjugates either as probes or targets in molecular imaging using MRI.MRI contrast agents (CAs) are broadly described as positive or negative, depending on whether they give rise to a brightening or a darkening effect on the MR image, respectively. The positive or brightening effect predominantly relates to the longitudinal proton relaxation time (T 1 ) and the negative or darkening effect predominantly relates to the transverse proton relaxation time (T 2 ). To date, the majority of commercially available and clinically applied positive CAs are Gd 3+ complexes of the polyaminocarboxylates diethylene triamine pentacetic acid (DTPA) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (see FiguRe 1 for some typical examples) and negative CAs are various iron oxide particles. These agents are not actively targeting. The targeted CAs for application in molecular imaging that are currently under development and described below are generally based on compounds 1 (Gd-DTPA) and 2 (Gd-DOTA), as well as iron oxide nanoparticles.Glycoconjugate probes and targets for molecular imaging using magnetic resonanceRecently...

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Supramolecular Assembly of an Amphiphilic Gd^IIIChelate: Tuning the Reorientational Correlation Time and the Water Exchange Rate

Torres¹,

Martins²,

André³

et al. 2006

Chemistry A European J

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We report the synthesis and characterization of the novel ligand H5EPTPA‐C16 ((hydroxymethylhexadecanoyl ester)ethylenepropylenetriaminepentaacetic acid). This ligand was designed to chelate the GdIII ion in a kinetically and thermodynamically stable way while ensuring an increased water exchange rate (kex) on the GdIII complex owing to steric compression around the water‐binding site. The attachment of a palmitic ester unit to the pendant hydroxymethyl group on the ethylenediamine bridge yields an amphiphilic conjugate that forms micelles with a long tumbling time (τR) in aqueous solution. The critical micelle concentration (cmc = 0.34 mM) of the amphiphilic [Gd(eptpa‐C16)(H2O)]2− chelate was determined by variable‐concentration proton relaxivity measurements. A global analysis of the data obtained in variable‐temperature and multiple‐field 17O NMR and 1H NMRD measurements allowed for the determination of parameters governing relaxivity for [Gd(eptpa‐C16)(H2O)]2−; this is the first time that paramagnetic micelles with optimized water exchange have been investigated. The water exchange rate was found to be ${k{{\,298\hfill \atop {\rm ex}\hfill}}}$ = 1.7×108 s−1, very similar to that previously reported for the nitrobenzyl derivative [Gd(eptpa‐bz‐NO2)(H2O)]2− (${k{{\,298\hfill \atop {\rm ex}\hfill}}}$ = 1.5×108 s−1). The rotational dynamics of the micelles were analysed by using the Lipari–Szabo approach. The micelles formed in aqueous solution show considerable flexibility, with a local rotational correlation time of ${\tau {{\,298\hfill \atop {\rm l0}\hfill}}}$ = 330 ps for the GdIII segments, which is much shorter than the global rotational correlation time of the supramolecular aggregates, ${\tau {{298\hfill \atop {\rm g0}\hfill}}}$ = 2100 ps. This internal flexibility of the micelles is responsible for the limited increase of the proton relaxivity observed on micelle formation (r1 = 22.59 mM−1 s−1 for the micelles versus 9.11 mM−1 s−1 for the monomer chelate (20 MHz; 25 °C)).

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Lanthanide(III) Chelates of DTPA Bis(amide) Glycoconjugates: Potential Imaging Agents Targeted at the Asyaloglycoprotein Receptor

Abstract: The synthesis and characterisation of a new class of DTPA bis (amide)

Cited by 20 publications

References 49 publications

Glyconanoparticles allow pre-symptomatic in vivo imaging of brain disease

Glyconanoparticles allow pre-symptomatic in vivo imaging of brain disease

Glycoconjugate Probes and Targets for Molecular Imaging Using Magnetic Resonance

Supramolecular Assembly of an Amphiphilic Gd^IIIChelate: Tuning the Reorientational Correlation Time and the Water Exchange Rate

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Lanthanide(III) Chelates of DTPA Bis(amide) Glycoconjugates: Potential Imaging Agents Targeted at the Asyaloglycoprotein Receptor

Abstract: The synthesis and characterisation of a new class of DTPA bis (amide)

Cited by 20 publications

References 49 publications

Glyconanoparticles allow pre-symptomatic in vivo imaging of brain disease

Glyconanoparticles allow pre-symptomatic in vivo imaging of brain disease

Glycoconjugate Probes and Targets for Molecular Imaging Using Magnetic Resonance

Supramolecular Assembly of an Amphiphilic GdIIIChelate: Tuning the Reorientational Correlation Time and the Water Exchange Rate

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Product

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Supramolecular Assembly of an Amphiphilic Gd^IIIChelate: Tuning the Reorientational Correlation Time and the Water Exchange Rate