Ternary Gd(III)L-HSA adducts: evidence for the replacement of inner-sphere water molecules by coordinating groups of the protein. Implications for the design of contrast agents for MRI

Aime, Silvio; Gianolio, Eliana; Terreno, Enzo; Giovenzana, Giovanni B.; Pagliarin, Roberto; Sisti, Massimo; Palmisano, Giovanni; Botta, Maurizio; Lowe, Mark P.; Parker, David

doi:10.1007/pl00021449

Cited by 149 publications

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“…The systems with q ϭ 2, whose higher hydration obviously is a positive feature in the search for high relaxivities, may suffer a "quenching" effect upon interacting with proteins, as donor atoms from aspartate (Asp) or glutamate (Glu) residues may replace the coordinated water molecules (14). One may anticipate the occurrence of such an interaction by exploring the formation of ternary complexes between a given complex and substrates, such as lactate, malonate, or simply carbonate (15).…”

Section: Rational Design Of Gd(iii)-based Systems Endowed With High Rmentioning

confidence: 99%

Insights into the use of paramagnetic Gd(III) complexes in MR‐molecular imaging investigations

Aime

Cabella

Colombatto³

et al. 2002

Magnetic Resonance Imaging

328

275

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Can gadolinium III [Gd(III)] complexes be considered good candidates for magnetic resonance (MR)-molecular imaging studies? In this review article, we examine the principal issues that are the basis of successful use of Gd-based protocols in molecular imaging applications. High relaxivity is the primary requisite. Therefore, the design of such paramagnetic probes has to be pursued keeping in mind the relationships between structure, dynamics, and the relevant parameters involved in paramagnetic relaxation processes. Moreover, the limited number of target molecules on cellular membranes makes it necessary to define strategies aimed at delivering many Gd-containing moieties to the sites of interest. Examples are reported for the attainment of very high relaxivities for the design of new routes for pursuing the accumulation of small sized Gd(III) complexes at the targeting sites. An efficient cellular uptake of Gd-containing probes is the key step for attaining the visualization of targeted cells by MR imaging, and selected examples are reported. In this context, the problem of the assessment of the minimum amount of Gd(III) complexes necessary for the MR imaging-visualization of cells has been addressed by reporting the authors' observations on the cell-internalization of Gd(III) complexes. A particularly efficient delivery system is represented by Gd-loaded apoferritin, which allows the MR visualization of hepatocytes when the number of Gd-complexes per cell is 4 Ϯ 1 ϫ 10 7 . Finally, the potential of responsive systems is considered by outlining the exploitation of the amplification effect brought about by the action of a specific enzymatic activity on the relaxivity of a suitably functionalized Gd(III) complex. IT IS NOW WELL ESTABLISHED that magnetic resonance imaging (MRI) is the pre-eminent methodology among the various diagnostic modalities currently available, as it offers a powerful way to map structure and function in soft tissues by sampling the amount, flow, and environment of water protons in vivo. The intrinsic contrast can be augmented by the use of contrast agents (CA) in both clinical and experimental settings. Thus, the use of CA adds highly relevant physiological information to the superb anatomical resolution obtained in MR images. Most of the work with CAs has dealt with the use of gadolinium (III) [Gd(III)] complexes, because this metal ion couples a large magnetic moment with a long electron spin relaxation time.The new scenery of molecular imaging applications requires the development of a novel class of CAs characterized by a higher contrasting ability and improved targeting capabilities (1). In this survey, we intend to tackle some basic issues that are of fundamental importance for the use of Gd(III)-based systems in molecular imaging applications, namely: 1) actual understanding of the determinants of T 1 -relaxivity of Gd(III) complexes, and how to proceed to attain very high relaxivities; 2) how one may envisage efficient routes for the delivery of a high number of Gd(III) complexes a...

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Section: Rational Design Of Gd(iii)-based Systems Endowed With High Rmentioning

confidence: 99%

Insights into the use of paramagnetic Gd(III) complexes in MR‐molecular imaging investigations

Aime

Cabella

Colombatto³

et al. 2002

Magnetic Resonance Imaging

328

275

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“…One way of overcoming this problem could be the substitution of some groups, in either the chelate or the c-CD, by others that promote a more effective inclusion and stronger interactions between the two molecules. While the first approach has been pursued with some success for adducts of b-CD [5][6][7], preliminary results from on-going modelling studies on substituted c-CDs show that this can be indeed the case. In fact, and as an example, we have found out that both the ammonium and the trimethylammonium ions acting as substituents for selected groups of the CDs, have good association energies.…”

Section: Discussionmentioning

confidence: 99%

“…For each inclusion complex, the initial structure (figure 2) was achieved by placing the chelate at a distance d of 0.27 nm from the plane defined by the anomeric oxygen atoms of the glucose units of the CD host, as suggested in [7]. This distance, taken from the lanthanide atom of the chelate, was then increased in steps of 0.03 nm up to 0.51 nm and then, with larger increments, to 0.70 nm, 0.90 nm, 0.120 nm, 0.170 nm, and finally 0.210 nm, at which point intermolecular interaction energies become negligible.…”

Section: Conformational Analysismentioning

confidence: 99%

“…Following this line of thought, lanthanide polyazamacrocyclic chelates might form inclusion complexes with cyclodextrins (CDs), thus possibly providing an alternative mechanism whereby the solvent proton relaxation rates and the bio-distribution of these agents could be altered in vivo. This line of investigation has been explored by inclusion of hydrophobic side chains attached to Ln (III) chelates in b-CD or its oligomers [5][6][7], and with Ln (III) macrocyclic chelates with b-CD and c-CD [8,9], but the results of this latter approach have been very disappointing in what concerns the degree of host-guest association [8,9]. Given the fact that the design of new contrast agents would undoubtfully benefit from the formation of such c-CD based adducts, we thought it worthwhile to find out the actual reasons for their unexpected limited success, and whether they could be improved.…”

Section: Introductionmentioning

confidence: 99%

“…

AbstractThe complexes between c-cyclodextrin and lanthanide (III) chelates of the polyazamacrocycles DOTA (DOTA 1,4,7,4,7, and DOTP (DOTP 1,4,7,4,7, have been thought out to enhance the potential of such chelates as contrast agents for MRI. Given the actual demand for the design of new contrast agents, we thought it worthwhile to confirm previous results for the equilibrium constant K obtained by one of us by NMR on the DOTP complex, as well as to determine K for a new one with DOTA.

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confidence: 99%

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Studies of inclusion complexes between cyclodextrins and polyazamacrocyclic chelates of lanthanide (III) ions

Henriques¹,

Bastos²,

Geraldes³

et al. 2003

The Journal of Chemical Thermodynamics

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The complexes between c-cyclodextrin and lanthanide (III) chelates of the polyazamacrocycles DOTA (DOTA 1,4,7,4,7, and DOTP (DOTP 1,4,7,4,7, have been thought out to enhance the potential of such chelates as contrast agents for MRI. Given the actual demand for the design of new contrast agents, we thought it worthwhile to confirm previous results for the equilibrium constant K obtained by one of us by NMR on the DOTP complex, as well as to determine K for a new one with DOTA. Further, we wanted to study and quantify the interactions present in these complexes, with a view to improve them in newly designed complexes.The interactions between c-cyclodextrin and the lanthanide (III)-polyazamacrocyclic chelates, [Tm(DOTP)] 5À , and [Gd(DOTA)] À were then studied by isothermal calorimetry (ITC) and molecular dynamics. The calorimetric experiments can be interpreted by considering that in both cases there is a weak association, characterized by low values for the equilibrium constant as well as for the molar enthalpy change for complex formation, at T ¼ 298:15 K. The K value for the complex with DOTP obtained now by ITC is of the same order of magnitude of the one determined previously by NMR. Further, the complex formation seems We have also carried out molecular dynamics simulations on these very same inclusion complexes, which provided quantitative data on the interactions present, as well as a plausible explanation for the data obtained, leading to the proposal of possible solutions to improve the modelling of new contrast agents on a host-guest basis.

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A Calix[4]arene GdIII Complex Endowed with High Stability, Relaxivity, and Binding Affinity to Serum Albumin

et al. 2001

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An interesting class of macrocyclic ligands uses calixarenes as a molecular platform. These ionophores [1] are characterized by high lipophilicity and have been mainly used as selective extractants or carriers of alkali, [2] alkaline earth, [3] lanthanide, and actinide metal ions. [4] The complexation of lanthanide ions by calix[4]arene ligands has also been studied with the purpose of developing new luminescent probes. [5] Very little is known on the use of calixarene lanthanide complexes as contrast agents for magnetic resonance imaging (MRI), [6] although this possibility has been envisaged [7] and a recent example has been reported. [8] To develop efficient systems for MRI the problem of water solubility and stability of the complexes has to be solved. Several years ago we reported the luminescent properties of lanthanide complexes of a calix[4]arene tetraamide derivative in water. [9] However, the complexes were not very stable and after a short time the free ligand precipitated out of the solution. One efficient way to complex hard divalent and trivalent metal ions in water is to use aminopolycarboxylic acid derivatives. [10] Herein we report the synthesis of a new calix[4]arene-based ligand which presents two acetamide and two ethylenaminodicarboxy groups at the lower rim of the macrocycle, able to form complexes with Gd III in water, these complexes are characterized by high values of relaxivity. [6] The diamide tetraacid derivative 1 was synthesized in 45 % overall yield, by alkylation of the diamide of calix[4]arene 2 [11] with Na 2 CO 3 and 2-[N,N-bis(tert-butyloxycarbonylmethyl)amino]-1-bromo-ethane (3) [12] in acetonitrile, followed by hydrolysis of tert-butyl esters using trifluoroacetic acid (TFA) and triethyl silane (Scheme 1). The 1 H NMR spectrum of 1 in CD 3 OD, clearly show that the calixarene ligand is in the cone 0.110; H atoms treated by a riding model; max. and min. residual electron densities were 0.550 and À 0.453, respectively. Crystallographic data (excluding structure factors) for the structure reported in this paper has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-55327. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: ( 44) 1223-336-033; e-mail: deposit@ ccdc.cam.ac.uk). Susceptibilities from a Pd-standard-calibrated Quantum Design MPMS5S SQUID, at a field of 0.1 T. The diamagnetic correction applied for 1 was À 5.32 Â 10 À4 cm 3 mol À1 .[**] This work was supported by CNR (Programma M.U.R.S.T. -Chimica Legge 95/95) ™Agenti di contrasto, di shift e sonde luminescenti∫. We thank C.I.M. (Centro Interdipartimentale Misure) dell×Universita ¡ di Parma for the NMR and mass spectroscopy facilities.

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Ternary Gd(III)L-HSA adducts: evidence for the replacement of inner-sphere water molecules by coordinating groups of the protein. Implications for the design of contrast agents for MRI

Cited by 149 publications

References 0 publications

Insights into the use of paramagnetic Gd(III) complexes in MR‐molecular imaging investigations

Insights into the use of paramagnetic Gd(III) complexes in MR‐molecular imaging investigations

Studies of inclusion complexes between cyclodextrins and polyazamacrocyclic chelates of lanthanide (III) ions

A Calix[4]arene GdIII Complex Endowed with High Stability, Relaxivity, and Binding Affinity to Serum Albumin

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