A beta-cyclodextrin "click cluster" decorated with seven paramagnetic chelates containing two water exchange sites

The development of novel macromolecular contrast agents that offer enhanced relaxivity profiles at high magnetic fields have the potential to greatly improve the diagnosis, understanding, and treatment of disease. To this end, we have designed a monodiperse paramagnetic beta-cyclodextrin click cluster decorated with seven paramagnetic arms. A novel alkyne-functionalized diethylenetriaminetetraacetic acid (DTTA) chelate (6) has been created and coupled to a per-azido-beta-cyclodextrin core (7) to yield the precursor macromolecule (8). After removal of the protecting groups and titrating with Gd (3+), the final paramagnetic click cluster, Gd10, was obtained. Luminescence measurements were carried out in H 2O and D 2O on an analogous structure, Eu10, and indicated that at each lanthanide has an average of 1.8 water exchange sites, which is important for enhancing relaxivity and MRI resolution. This discrete paramagnetic click cluster yields a high relaxivity profile (43.4 mM (-1) s (-1) per molecule and 6.2 mM (-1) s (-1) per Gd (3+) at 9.4 T) and enhanced contrast on a human MRI scanner as compared to a commercial agent, Magnevist (3.2 mM (-1) s (-1) at 9.4 T). Moreover, the useful inclusion properties exhibited by beta-cyclodextrin also make this an excellent host scaffold to functionalize via noncovalent assembly with receptor specific targeting moieties for biomolecular imaging.     

From monomers to micelles: investigation of the parameters influencing proton relaxivity

17O NMR and (1)H NMRD studies have been performed on a series of Gd(III) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) derivatives as potential liver-specific magnetic resonance imaging (MRI) contrast agents. They bear aliphatic side chains which make them capable of micellar self-organization. The compounds differ in the length (C10-C18) and in the chemical nature (alkyl or monoamide-alkyl) of their lipophilic chain. We have established a convenient method to determine the critical micellar concentration (cmc) of paramagnetic surfactants by (1)H relaxivity measurements. This technique can be easily used over a large temperature range; thus, it can find wide application outside the field of MRI contrast agents. The knowledge of the cmc allowed us to determine the parameters governing the water proton relaxivity of the Gd(III) chelates in both nonaggregated and aggregated micellar forms. The relaxation data of the micellar complexes have been interpreted with the Lipari-Szabo approach. This model allows a local motion to be separated from the global tumbling of the whole micelle (modulated by a local, tau(l), and a global, tau(g), rotational correlation time, respectively). The aggregation substantially affects the rotational dynamics and thus increases the proton relaxivity of the Gd(III) chelates. The global rotational correlation times increase with increasing length of the side chain (500-2800 ps for C10-C18). Local motions are also influenced by the length and by the hydrophobicity of the side chain. The analysis of the relaxation data reveals considerable flexibility for these micellar aggregates. The rate of water exchange obtained for these chelates is identical to that for [Gd(DOTA)(H(2)O)](-) (k(ex)(298)= 4.8 x 10(6)s(-1))and is not sensitive either to micellization or to differences in the aliphatic chain. A relaxivity gain in such systems could be attained by simultaneously optimizing the water exchange by modifications of the chelate and increasing the micelle rigidity by using water-soluble surfactants with more hydrophobic side chains.     

Molecular amplifiers: synthesis and functionalization of a poly(aminopropyl)dextran bearing a uniquely reactive terminus for univalent attachment to biomolecules.

The synthesis and characterization of the versatile dextran-based molecular amplifier 6 is described. Dextran (Mr = 40,200) was selectively monofunctionalized in high yield at its reducing terminus via reductive amination with 2-(4-nitrophenyl)ethylamine to give 1. The nitro group in 1 serves as a masked amino group which is eventually converted into a reactive isothiocyanato group used for monovalent attachment of the completed assembly to a target molecule. Cyanoethylation of 1 gave the terminally nitrophenylated poly(cyanoethyl)dextran 5 which was selectively reduced to the corresponding poly(aminopropyl) derivative 6 with BH3.THF, a reagent which preserved the end nitro group. Conjugation of amplifier 6 with the isothiocyanate-derivatized Gd(III) chelate 7 gave conjugate 9 containing about 22 mol of chelate/mol of amplifier. The T1 relaxivity per Gd(III) ion of 9 in H2O was 15.0 mM-1 s-1, about 3-fold higher than that of free Gd(III)DTPA in H2O. The nitro group of 9 was then selectively reduced to the corresponding amine 10, which was converted into isothiocyanate 11. The reactivity of the single isothiocyanate group in 11 was demonstrated by coupling to 5-aminoeosin, giving conjugate 12. Amplifier 6 was also conjugated with the acid-labile N-cis-aconityl derivative 8 of the potent anticancer agent daunomycin. The nitro group of the resulting conjugate 13 was then reduced and the resulting amine 14 was converted into mono isothiocyanate 15. Compound 15 reacted with a water-insoluble amine-containing solid support to give 16. Free daunomycin was released from 16 by exposure to citrate-phosphate buffer at pH 4.0.     

Lipari-Szabo approach as a tool for the analysis of macromolecular gadolinium(III)-based MRI contrast agents illustrated by the [Gd(EGTA-BA-(CH2)12)] n n + polymer

The parameters governing the water proton relaxivity of the [Gd(EGTA-BA-(CH2)12)]nn+ polymeric complex were determined through global analysis of 17O NMR, EPR and nuclear magnetic relaxation dispersion (NMRD) data [EGTA-BA2- = 3,12-bis(carbamoylmethyl)- 6,9-dioxa-3,12-diazatetradecanedioate(2-)]. The Lipari-Szabo approach that distinguishes the global motion of the polymer (tau g) from the local motion of the Gd(III)-water vector (tau l) was necessary to describe the 1H and 17O longitudinal relaxation rates; therefore for the first time it was included in the global simultaneous analysis of the EPR, 17O NMR and NMRD data. The polymer consists on average of only five monomeric units, which limits the intramolecular hydrophobic interactions operating between the (CH2)12 groups. Hence the global rotational correlation time is not very high (tau g298 = 3880 +/- 750 ps) compared to the corresponding DTPA-BA-based polymer (about 15 monomeric units), where tau g298 = 6500 ps. As a consequence, the relaxivity is limited by the rotation, which precludes the advantage obtained from the fast exchanging chelating unit (kex298 = 2.2 +/- 0.1 x 10(6) s-1).     

Herbicides interacting with lanthanide(III) and calcium(II) ions: structural and biological similarities of Gd and Ca polymers

In this paper we report the synthesis and characterization of Ca(II), Gd(III) and Ce(III) complexes with chlorophenoxyalkanoic acids, which are commonly used as herbicides. The Gd(III) and Ca(II) complexes were characterized by the typical formulas [Gd(III)(L)(3)(H(2)O)(2).2dmf](n) and [Ca(L)(2)(MeOH)(2)](n) [L=[2,4-D=2,4-dichlorophenoxyacetic acid, 2,4,5-T=2,4,5-trichlorophenoxyacetic acid, MCPA=2-methyl-4-chlorophenoxy acetic acid and 2,4-DP=2-(2,4-dichlorophenoxy)propanoic acid]]. The crystal structure of the Gd(III) complex with 2,4-D shows that the compound is a one-dimensional polymer with a [Gd(III)(2)(2,4-D)(6)(H(2)O)(4)] dimeric repeat unit and the gadolinium atoms are in a nine-coordination environment, while the crystal structure of the Ca analog shows that it also has a polymeric structure with a [Ca(2)(2,4-D)(4)(CH(3)OH)(4)] dimeric repeat unit and the calcium atoms are in an eight-coordination environment. The gadolinium compound displays three different coordination modes for the carboxylato moiety, bidentate chelate, bidentate double bound and bidentate triple bound, while the calcium compound displays only one, bidentate triple bound. Coordination spheres are completed with oxygens of H(2)O or MeOH molecules, respectively. The complexes were tested against a few common bacteria by minimum inhibitory concentration (MIC) experiments and did not exhibit any antimicrobial action at concentrations up to 1600 microg/ml.     

Synthesis and Evaluation of a Peptide Targeted Small Molecular Gd-DOTA Monoamide Conjugate for MR Molecular Imaging of Prostate Cancer

Tumor extracellular matrix has an abundance of cancer related proteins that can be used as biomarkers for cancer molecular imaging. Innovative design and development of safe and effective targeted contrast agents to these biomarkers would allow effective MR cancer molecular imaging with high spatial resolution. In this study, we synthesized a low molecular weight CLT1 peptide targeted Gd(III) chelate CLT1-dL-(Gd-DOTA)(4) specific to clotted plasma proteins in tumor stroma for cancer MR molecular imaging. CLT1-dL-(Gd-DOTA)(4) was synthesized by conjugating four Gd-DOTA monoamide chelates to a CLT1 peptide via generation 1 lysine dendrimer. The T(1) relaxivity of CLT1-dL-(Gd-DOTA)(4) was 40.4 mM(-1) s(-1) per molecule (10.1 mM(-1) s(-1) per Gd) at 37 °C and 1.5 T. Fluorescence imaging showed high binding specificity of CLT1 to orthotopic PC3 prostate tumor in mice. The contrast agent resulted in improved tumor contrast enhancement in male athymic nude mice bearing orthotopic PC3 prostate tumor xenograft at a dose of 0.03 mmol Gd/kg. The peptide targeted MRI contrast agent is promising for high-resolution MR molecular imaging of prostate tumor.     

Synthesis and evaluation of nanoglobular macrocyclic Mn(II) chelate conjugates as non-gadolinium(III) MRI contrast agents

Because of the recent observation of the toxic side effects of Gd(III) based MRI contrast agents in patients with impaired renal function, there is strong interest on developing alternative contrast agents for MRI. In this study, macrocyclic Mn(II) chelates were conjugated to nanoglobular carriers, lysine dendrimers with a silsesquioxane core, to synthesize non-Gd(III) based MRI contrast agents. A generation 3 nanoglobular conjugate of Mn(II)-1,4,7-triaazacyclononane-1,4,7-triacetate-GA amide (G3-NOTA-Mn) was also synthesized and evaluated. The per ion T(1) and T(2) relaxivities of G2, G3, G4 nanoglobular Mn(II)-DOTA monoamide conjugates decreased with increasing generation of the carriers. The T(1) relaxivities of G2, G3, and G4 nanoglobular Mn(II)-DOTA conjugates were 3.3, 2.8, and 2.4 mM(-1) s(-1) per Mn(II) chelate at 3 T, respectively. The T(1) relaxivity of G3-NOTA-Mn was 3.80 mM(-1) s(-1) per Mn(II) chelate at 3 T. The nanoglobular macrocyclic Mn(II) chelate conjugates showed good in vivo stability and were readily excreted via renal filtration. The conjugates resulted in much less nonspecific liver enhancement than MnCl(2) and were effective for contrast-enhanced tumor imaging in nude mice bearing MDA-MB-231 breast tumor xenografts at a dose of 0.03 mmol Mn/kg. The nanoglobular macrocyclic Mn(II) chelate conjugates are promising nongadolinium based MRI contrast agents.     

New complexes of La(III), Ce(III), Pr(III), Nd(III), Sm(III), Eu(III) and Gd(III) ions with morin

New solid complex compounds of La(III), Ce(III), Pr(III), Nd(III), Sm(III), Eu(III) and Gd(III) ions with morin were synthesized. The molecular formula of the complexes is Ln(C₁₅H₉O₇)₃ · nH₂O, where Ln is the cation of lanthanide and n = 6 for La(III), Sm(III), Gd(III) or n = 8 for Ce(III), Pr(III), Nd(III) and Eu(III). Thermogravimetric studies and the values of dehydration enthalpy indicate that water occurring in the compounds is not present in the inner coordination sphere of the complex. The structure of the complexes was determined on the basis of UV-visible, IR, MS, ¹H NMR and ¹³C NMR analyses. It was found that in binding the lanthanide ions the following groups of morin take part: 3OH and 4CO in the case of complexes of La, Pr, Nd, Sm and Eu, or 5OH and 4CO in the case of complexes of Ce and Gd. The complexes are five- and six-membered chelate compounds.     

Relaxometric evaluation of novel manganese(II) complexes for application as contrast agents in magnetic resonance imaging

Three novel Mn(II) complexes bearing benzyloxymethyl functionalities are reported and their ability to enhance water (1H and 17O) relaxation times is investigated in detail. Two of them contain one coordinated water molecule and display relaxivity values only slightly smaller than those shown by the most clinically used contrast agents (e.g. [Gd(DTPA)(H2O)]2-). Moreover, in these Mn(II) chelates the exchange rate of the coordinated water is ca. one order of magnitude higher if compared to the exchange rates previously reported for Gd(III) complexes with octadentate ligands. The occurrence of such fast exchange rates of the coordinated water is exploited in the formation of macromolecular adducts with human serum albumin to attain systems displaying relaxivity values in the upper range of those so far reported for analogous Gd(III) systems. These results strongly support the view that Mn(II) complexes, in spite of the lower effective magnetic moment, can be considered as viable alternatives to the currently used Gd(III) complexes as contrast agents for MRI applications.     

Synthesis and physicochemical characterization of a novel precursor for covalently bound macromolecular MRI contrast agents

 The ligand DOTASA was designed and synthesized in the aim of obtaining a kinetically and thermodynamically stable Gd(III) chelate which, through its uncoordinated carboxylate function, will provide an efficient pathway to couple the complex to bio- or macromolecules without affecting the coordination pattern of DOTA. Furthermore, it allows us to study the influence of an extra carboxylate arm on the parameters determining proton relaxivity in comparison to the commercial agent [Gd(DOTA)(H₂O)]^–. A combined variable-temperature ¹⁷O NMR, EPR and nuclear magnetic relaxation dispersion study on the Gd(III) chelate resulted in k ²⁹⁸ _ex=(6.3±0.2)×10⁶ s^–1 for the water exchange rate and τ²⁹⁸ _R=125±2 ps for the rotational correlation time. The slight increase in both k ²⁹⁸ _ex and τ²⁹⁸ _R, as compared to those for [Gd(DOTA)(H₂O)]^–, is attributed to the presence of the extra negative charge. The longer rotational correlation time results in a proton relaxivity of 5.03 mM^–1 s^–1 for [Gd(DOTASA)(H₂O)]^2–, which is approximately 30% higher than that for [Gd(DOTA)(H₂O)]^–. The increased water exchange rate of [Gd(DOTASA)(H₂O)]^2– has no consequence for proton relaxivity since this latter is exclusively limited by fast rotation for both complexes. However, for slowly rotating macromolecular agents, which contain a covalently coupled DOTASA unit instead of a coupled DOTA, this increased exchange rate will have a significant positive effect. Received: 31 December 1998 / Accepted: 4 March 1999     

A dinuclear europium(III) complex with thenoyltrifluoroacetonato and 1-(2-pyridylzao)-2-naphtholato ligands and its optical properties

Dinuclear lanthanide complexes of the general for Ln₂(TTA)₄(PAN)₂ (Ln = Eu, Gd, Tb, Yb; TTA and monodeprotonated thenoyltrifluoroacetone and PAN 1-(2-pyridylazo)-2-naphthol, respectively) were prepared and structurally characterized. These novel complexes, representing the first examples of crystallographically characterized lanthanide-PAN complexes, each feature a dinuclear core with the metal atoms bridged by the phenolato O atoms of the chelating-bridging PAN ligands. Electronic spectroscopic and photoluminescence studies were carried out for the Eu(III) complex, and the results are consistent with ligand-mediated energy transfer and ligand-sensitized luminescence characteristic of Eu(III). The Eu(III) complex doped into a polymeric film was shown to effectively limit a nanosecond 523-nm laser pulse, and the limiting effect is rationalized in terms of reverse saturable absorption due to the strong absorption of the metal’s excited triplet states that are populated by intersystem crossing.     

Cathodic electrochemiluminescence of acetonitrile, acetonitrile-1,10-phenanthroline and acetonitrile-ternary Eu(III) complexes at a gold electrode.

Cathodic electrochemiluminescence (ECL) behaviours of the acetonitrile, acetonitrile-1,10-phenanthroline (phen) and acetonitrile-ternary Eu(III) complex systems at a gold electrode were studied. One very weak cathodic ECL-2 at -3.5 V was observed in 0.1 mol/L tetrabutylammonium tetrafluoroborate (TBABF(4)) acetonitrile solution. When 10 mmol/L tetrabutylammonium peroxydisulphate [(TBA)(2)S(2)O(8)] was added to 0.1 mol/L TBABF(4) acetonitrile solution, another cathodic ECL-1 at -2.7 V appeared and the potential for ECL-2 was shifted from -3.5 to -3.1 V. Furthermore, ECL-2 intensity was enhanced about 20-fold. When 1 x 10(-4) mol/L phen was added to 0.1 mol/L TBABF(4) + 10 mmol/L (TBA)(2)S(2)O(8) acetonitrile solution, the ECL intensities of ECL-1 and ECL-2 were enhanced about 20-fold compared with those of 0.1 mol/L TBABF(4) + 10 mmol/L (TBA)(2)S(2)O(8) acetonitrile solution. The maximum emission peaks of ECL-1 and ECL-2 in the three systems mentioned above appeared at about 530 nm. The products obtained by electrolysing 0.1 mol/L TBABF(4) acetonitrile solution at -3.5 V for 20 min were analysed by Fourier Transform Infrared (FTIR) spectra and gas chromatography-mass spectrometry (GC-MS) and the emitter of ECL-1 and ECL-2 was identified as excited state polyacetonitrile. When ternary Eu(III) complexes were presented in 0.1 mol/L TBABF(4) + 10 mmol/L (TBA)(2)S(2)O(8) acetonitrile solution, another maximum emission peak with a narrow band centred at about 610 nm appeared in ECL-1 in addition to the maximum emission peaks at about 530 nm for ECL-1 and ECL-2. The emitter of ECL emission at 610 nm was identified as the excited states Eu(III)*. The mechanisms for cathodic ECL behaviours of the acetonitrile, acetonitrile-phen and acetonitrile-ternary Eu(III) complex systems at a gold electrode have been proposed. The extremely sharp emission bands for ternary Eu(III) complexes may have analytical potential.     

A dual lanthanide probe suitable for optical (Tb3+ luminescence) and magnetic resonance imaging (Gd3+ relaxometry)

A new polyaminocarboxylate ligand derived from N,C-pyrazolylpyridine was synthesized. The luminescence and relaxometry properties of its Tb(3+) and Gd(3+) chelates were investigated in aqueous solutions. The Tb(3+) chelate is strongly luminescent having remarkable lifetime and quantum yield (tau=1.82ms and Phi=0.42). The 1/T(1) proton relaxivity at 20MHz and 25 degrees C (5.3s(-1)mM(-1)) of the Gd(3+) chelate was found to be comparable to that of the clinically used Gd-DTPA.     

A gadolinium(III) complex of a carboxylic-phosphorus acid derivative of diethylenetriamine covalently bound to inulin, a potential macromolecular MRI contrast agent

A novel conjugate of a polysaccharide and a Gd(III) chelate with potential as contrast agent for magnetic resonance imaging (MRI) was synthesized. The structure of the chelate was derived from H5DTPA by replacing the central pendant arm by a phosphinic acid functional group, which was covalently bound to the polysaccharide inulin. On the average, each monosaccharide unit of the inulin was attached to approximately one (0.9) chelate moiety. The average molecular weight is 23110 and the average number of Gd3+ ions per molecule is 24. The ligand binds the Gd3+ ion in an octadentate fashion via three nitrogen atoms, four carboxylate oxygen atoms, and one P-O oxygen atom, and its first coordination sphere is completed by a water molecule. This compound shows promising properties for application as a contrast agent for MRI thanks to a favorable residence lifetime of this water molecule (170 ns at 298 K), a relatively long rotational correlation time (866 ps at 298 K), and the presence of two water molecules in the second coordination sphere of the Gd3+ ion. Furthermore, its stability toward transmetalation with Zn(II) is as high as that of the clinically used [Gd(DTPA)(H2O)]2-.     

Synthesis and characterization of a new bioactivated paramagnetic gadolinium(III) complex [Gd(DOTA-FPG)(H2O)] for tracing gene expression

A smart contrast agent for magnetic resonance imaging (MRI) can be used to exploit an enzymatic activity specific to the tissue or disease state signified by converting an MRI-inactivated agent to an activated MRI agent. In this study, a beta-galactopyranose-containing gadolinium(III) complex [Gd(DOTA-FPG)(H 2O)] was designed, synthesized, and characterized as being potentially suitable for a bioactivated MRI contrast agent. The (17)O NMR experiments were conducted to estimate the water exchange rate k e x 298 and rotational correlation time tau R 298 . The k ex 298 value of [Gd(DOTA-FPG)(H 2O)] is similar to that of [Gd(DO3A-bz-NO 2)(H 2O)]. The rotational correlation time value of [Gd(DOTA-FPG)(H 2O)] is dramatically longer than that of [Gd(DOTA)(H 2O)] (-) Relaxometric studies show that the percentage change in the T 1 value of [Gd(DOTA-FPG)(H 2O)] decreases dramatically in the presence of beta-galactosidase and human serum albumin. The T(1) change percentage of [Gd(DOTA-FPG)(H 2O)] (60%) is significantly higher than those of Egad and gadolinium(III)-1-(4-(2-(1-(4,7,10-triscarboxymethyl-(1,4,7,10-tetraazacyclododecyl)))-ethylcarbamoyloxymethyl)-2-nitrophenyl)-beta- d-glucopyronuronate. The signal intensity of the MR image for [Gd(DOTA-FPG)(H 2O)] in the presence of human serum albumin and beta-galactosidase (2670 +/- 210) is significantly higher than that of [Gd(DOTA-FPG)(H 2O)] in the sodium phosphate buffer solution (1490 +/- 160). In addition, the MR images show a higher-intensity enhancement in CT26/beta-gal tumor with beta-galactosidase gene expression but not for the CT26 tumor without beta-galactosidase gene expression. We conclude that [Gd(DOTA-FPG)(H 2O)] is a suitable candidate for a bioactivated MRI contrast agent in tracing gene expression.     

Novel paramagnetic macromolecular complexes derived from the linkage of a macrocyclic Gd(III) complex to polyamino acids through a squaric acid moiety

Macromolecular Gd(III) complexes may find useful application as contrast agents for magnetic resonance angiography (MRA). Herein two novel systems are reported, namely Gd(DO3ASQ)3-lys16 and Gd(DO3ASQ)30-orn114. Their syntheses are based on the ability of the squaric acid moiety to act as a linker between the DO3A (1,4,7, 10-tetraazacyclododecane-1,4,7-triacetic acid) chelate moiety and the polyamino acidic chain. Moreover, the squaric acid participates in the coordination cage of the Gd(III) ion. The investigation of 1H and 17O NMR relaxation processes of solvent water nuclei allowed a detailed characterization of the systems under study. Gd(DO3ASQ)30-orn114 displays a remarkable ability to enhance the water proton relaxation rate of its solutions, and it may be considered as potential contrast agent for MRA applications.     

Synthesis, characterization, and DNA-binding properties of the Ln(III) complexes with 6-hydroxy chromone-3-carbaldehyde-(2'-hydroxy) benzoyl hydrazone

A new ligand, 6-hydroxy chromone-3-carbaldehyde-(2'-hydroxy) benzoyl hydrazone (L), was prepared by condensation of 6-hydroxy-3-carbaldehyde chromone (CDC) with 2-hydroxy benzoyl hydrazine. Its four rare earth complexes have been synthesized and characterized on the basis of elemental analyses, molar conductivities, mass spectra, 1H NMR, thermogravimetry/differential thermal analysis (TG-DTA), UV-vis spectra, fluorescence spectra, and IR spectra. The general formula of the complexes is [LnL2.(NO3)2].NO3 [Ln=La(1), Sm(2), Dy(3), Eu(4)]. Spectrometric titration, ethidium bromide displacement experiments, and viscosity measurements indicate that Eu(III) complex and ligand, especially the Eu(III) complex, strongly bind with calf-thymus DNA, presumably via an intercalation mechanism. The intrinsic binding constants of Eu(III) complex and ligand with DNA were 3.55 x 10(6) and 1.33 x 10(6)M(-1) through fluorescence titration data, respectively. In addition, the suppression ratio for O2-* and OH* of the ligand and its complexes was studied by spectrophotometric methods. The experimental results show that La (1), Sm (2), and Eu (4) complexes are better effective inhibitor for OH* than that of mannitol. It indicates that the complexes have the activity to suppress O2-* and OH* and exhibit more effective antioxidants than ligand alone.     

Synthesis and Relaxometric Characterization of New Poly[N,N‐bis(3‐aminopropyl)glycine] (PAPGly) Dendrons Gd‐Based Contrast Agents and Their in Vivo Study by Using the Dynamic Contrast‐Enhanced MRI Technique at Low Field (1 T)

The synthesis of poly[N,N‐bis(3‐aminopropyl)glycine] (PAPGly) dendrons Gd‐based contrast agents (GdCAs) via an orthogonal protection of the different functional groups and an activation/coupling strategy wherein a specific number of synthetic steps add a generation to the existing dendron has been described. The aim of this protocol is to build up two different generations of dendrons ( G‐0 or dendron's core, and G‐1 ) with peripheral NH₂ groups to conjugate a 1,4,7,10‐tetraazacyclododecane‐1,4,7‐triacetic acid (DO3A) derivative and afterwards to chelate with Gd³⁺ paramagnetic ions. These complexes, which have a well‐defined molecular weight, are of relevance to MRI as an attempt to gain higher ¹H relaxivity by slowing down the rotation of molecule compared to monomeric Gd(III) complexes used as contrast agents and to increase the number of paramagnetic centers present in one molecular structure. From the study of their water ¹H longitudinal relaxation rate at different magnetic fields (NMRD, Nuclear Magnetic Relaxation Dispersion) and by evaluating the variable temperature ¹⁷O‐NMR data we determined the parameters characterizing the water exchange rate and the rotational correlation time of each complex, both affecting ¹H relaxivity. Furthermore, these two novel PAPGly GdCAs were objects of i) an in vivo study to determine their biodistributions in healthy C57 mice at several time points, and ii) the Dynamic Contrast‐Enhanced MRI (DCE‐MRI) approach to assess their contrast efficiency measured in the tumor region of C57BL/6 mice transplanted subcutaneously with B16‐F10 melanoma cells. The aim of the comparison of these two dendrons GdCAs, having different molecular weights (MW), is to understand how MW and relaxivity may influence the contrast enhancement capabilities in vivo at low magnetic field (1 T). Significant contrast enhancement was observed in several organs (vessel, spleen and liver), already at 5 min post‐injection, for the investigated CAs. Moreover, these CAs induced a marked contrast enhancement in the tumor region, thanks to the enhanced permeability retention effect of those macromolecular structures.     

Antioxidation and DNA-Binding Properties of Binuclear Lanthanide(III) Complexes with a Schiff Base Ligand Derived from 8-Hydroxyquinoline-7-carboxaldehyde and Benzoylhydrazine

8-Hydroxyquinoline-7-carboxaldehyde (8-HQ-7-CA), Schiff-base ligand 8-hydroxyquinoline-7-carboxaldehyde benzoylhydrazone, and binuclear complexes [LnL(NO(3) )(H(2) O)(2) ](2) were prepared from the ligand and equivalent molar amounts of Ln(NO(3) )?6 H(2) O (Ln=La(3+) , Nd(3+) , Sm(3+) , Eu(3+) , Gd(3+) , Dy(3+) , Ho(3+) , Er(3+) , Yb(3+) , resp.). Ligand acts as dibasic tetradentates, binding to Ln(III) through the phenolate O-atom, N-atom of quinolinato unit, and C?N and ?O?C?N? groups of the benzoylhydrazine side chain. Dimerization of this monomeric unit occurs through the phenolate O-atoms leading to a central four-membered (LnO)(2) ring. Ligand and all of the Ln(III) complexes can strongly bind to CT-DNA through intercalation with the binding constants at 10(5) -10(6) M(-1) . Moreover, ligand and all of the Ln(III) complexes have strong abilities of scavenging effects for hydroxyl (HO(.) ) radicals. Both the antioxidation and DNA-binding properties of Ln(III) complexes are much better than that of ligand.     

P(M) and P(R) forms of cytochrome c oxidase have different spectral properties

This work presents the study of the interaction between zidovudine (AZT) and rare earth (RE) ions with thenoyltrifluoroacetonate (TTA). The complexes [RE(TTA)(3) x (AZT)(2)] (where RE(III)=Eu and Gd) were prepared by reaction between the [RE(TTA)(3) x (H(2)O)(2)] precursors and AZT dissolved in acetone in the molar ratio 1:2. The obtained luminescent materials were characterized by microanalyses (C, H, N), complexometric titration, IR spectroscopy, X-ray powder diffraction and thermal analysis (DSC and TG/DTG). The luminescence data indicate that the substitution of the two water molecules by AZT in the europium complex causes an intensification of luminescence corresponding to the (5)D(0) -->(7)F(J) (J=0-4) transitions associated with one of the site symmetries. Based on the luminescence spectrum of the Eu(III)-compound the Omega(lambda) experimental intensity parameters (lambda=2 and 4) were calculated for the electronic transitions (5)D(0)-->(7)F(2, 4). The Omega(2) intensity parameter for this new compound is higher than for the precursor compound, suggesting an effective interaction between the AZT and the chemical environment of the Eu(III) ion. Luminescence data confirm that the AZT complex and precursor compound have a comparable emission quantum efficiency.