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Biomedical subjects

Silvio Aime

Publications and source records attributed to Silvio Aime.

At least 37 records · Page 2Linked to original sources
PubMed2006

Water exchange across the erythrocyte plasma membrane studied by HR-MAS NMR spectroscopy.

Water exchange across the plasma membrane of erythrocytes (red blood cells (RBCs)) was studied by means of high-resolution magic angle spinning (HR-MAS) NMR spectroscopy. Under HR-MAS conditions, the centrifugal force causes the splitting of RBC suspensions into a two-phase system composed of a central core of cell free water and an outer layer of tightly packed cells. Water belonging to each of these phases gives rise to two separated resonances. Chemical exchange between them is not detectable on the chemical shift or saturation transfer (ST) NMR time scale because of the physical separation between the phases. When the RBCs are dispersed and immobilized within a matrix made of cross-linked albumin, the splitting into a two-phase system is prevented and a single exchange-averaged peak for water is detected in (1)H HR-MAS NMR spectra. The lineshape of this peak is dependent on transmembrane exchange kinetics, since MAS averages out all the anisotropic magnetic interactions that are responsible for additional line-broadening under conventional liquid conditions. Line-shape analysis according to a two-site exchange model yielded a residence lifetime on the order of about 10 ms (at 37 degrees C) for a water molecule within the intracellular compartment, which is not too far from the generally accepted value of 9.6-14.8 ms.

Body Water↗
PubMed2005

Polarization transfer from para-hydrogen to heteronuclei: effect of H/D substitution. The case of AA'X and A2A2'X spin systems.

Upon hydrogenation from para-hydrogen (p-H(2)), hyperpolarization transfer toward a heteronucleus may be possible even if the two protons are chemically equivalent in the final product (but not magnetically equivalent), provided that J couplings with the heteronucleus exist. It is however shown (theoretically and experimentally) that this transfer effectively occurs if the spin system in the hydrogenated molecule is of the type AA'X (A and A' denoting the two protons originating from p-H(2) and X the heteronucleus) but does not occur for a spin system of the A(2)A(2)(')X type. A theory has been worked out for assessing the details of the X spectrum (multiplet patterns) in the case of ALTADENA and PASADENA experiments. Experimental verifications are provided.

Journal Article↗
PubMed2005

para-Hydrogenation of unsaturated moieties on poly(lysine) derived substrates for the development of novel hyperpolarized MRI contrast agents.

Four alkyne-functionalized poly(lysine) derivatives have been synthesized and characterized by 1H and 13C NMR spectroscopy. In the first poly(lysine) derivative, phenylpropiolate moieties are directly bound to the aminic arms, whereas in the other derivatives, propargylamine moieties are bound to the aminic poly(lysine) arms through glucaric acid and diethylene glycol (DG) chains, respectively. para-Hydrogenation of the alkyne-functionalized poly(lysine) compounds has been investigated and the results have been discussed in terms of spin lattice relaxation properties of the hydrogenated products. It is shown that the longer the mobile chain separating the unsaturation from the poly(lysine) backbone, the more intense the polarized signals when para-hydrogenation is carried out. This is due to (a) the maintenance of short reorientational times on the unsaturated ends, and therefore a sufficiently long T(1) of the protons added during hydrogenation, and (b) the minor effect of steric hindrance by the poly(lysine) backbone that decreases interaction of the unsaturation with the catalyst, allowing higher hydrogenation rates.

Alkynes↗
PubMed2005

A multinuclear NMR relaxometry study of ternary adducts formed between heptadentate Gd(III) chelates and L-lactate.

Dramatic relaxation enhancements of L-lactate resonances have been observed upon formation of ternary adducts with Gd(III) complexes of heptadentate DO3A and DO3A-like ligands (DO3A = 1,4,7,10-tetraazaciclododecane-1,4,7-triacetic acid). Detailed 1H and 17O NMR relaxometry investigations allow us to obtain structural, dynamic and thermodynamic information on the ternary complexes in which L-lactate acts as a bidentate ligand replacing two water molecules in the inner coordination sphere of the Gd(III) ion. It has been found that the exchange rate of the coordinated L-lactate is modulated by the structural and electronic properties of the parent Gd-heptacoordinated macrocyclic chelate. In addition to the characterisation of the relaxation behaviour of the 1H methyl resonance of L-lactate, this study has been extended to its 13C isomer (fully enriched at the three positions) and to the trifluoro-L-lactate. The obtained results may be relevant to the development of relaxation agents able to promote the relaxation enhancement of specific substrates detectable by in vivo magnetic resonance spectroscopy.

Chelating Agents↗
PubMed2005

Iopamidol: Exploring the potential use of a well-established x-ray contrast agent for MRI.

Iopamidol is one of the most common contrast media used for diagnostic CT-based clinical protocols. Chemically, this molecule contains two pools of mobile protons (amide and alcoholic) that are in exchange with water. At 7.05 T, pH 7.4, and 312 K, the exchange rate of the alcoholic protons is too fast to affect the NMR properties of water protons, whereas the slowly exchanging amide protons induce a T(2)-shortening effect on the "bulk" water signal that is detectable when the concentration is about 12 mM. Moreover, a more pronounced contrast is observed when the amide resonances are saturated by the application of an appropriate RF irradiation field, making iopamidol a potential chemical exchange saturation transfer (CEST) agent whose effect can be detected at a concentration as low as 7 mM (at 7.05 T). The exploitation of the MRI properties of iopamidol could facilitate novel and interesting diagnostic applications for combined MRI and CT studies.

Contrast Media↗
PubMed2005

HR-MAS of cells: A "cellular water shift" due to water-protein interactions?

Under HR-MAS conditions, cells are subjected to high centrifugal forces that may cause irreversible cell damage. First, conditions have been defined to monitor and keep to a minimum unwanted effects in HR-MAS spectra arising from the loss of cell integrity. Then, the HR-MAS spectra of reasonably intact cells have been analyzed. Cell suspensions subjected to MAS rates as low as 1 kHz split into a two-compartment system that is composed of a cell-rich phase (H(2)O(i)) and a cell-free phase (H(2)O(o)). Each of these phases is characterized by its own water (1)H-NMR signal. Transport of water molecules between the cell-rich and cell-free compartments is limited by the very low contact area between the two compartments, and water exchange dynamics consequently fall into the slow exchange limit on the NMR timescale. Since the exchange between the two water populations is "frozen," the separation between the H(2)O(o) and H(2)O(i) water signals (Deltanu(water)) detected in an HR-MAS experiment is not affected by chemical exchange but reflects only chemical differences in the two environments. Different cell lines show a different Deltanu(water), leading to the concept of "cellular water shift." This shift roughly correlates with the cellular protein content, supporting the view that the most important determinant of the cellular water shift is the interaction between water and proteins in the intracellular compartment.

Animals↗
PubMed2005

Blast from the past: the aluminum's ghost on the lanthanum salts.

Hyperphosphatemia is a common serious complication of chronic renal diseases, which needs appropriate continuous treatment in order to avoid ominous side effects. Therefore, oral chelating agents able to avoid phosphate absorption by the gut are mandatory. In the past, Aluminium salts, and more recently Calcium and Magnesium salts, and a synthetic resin polyallylamine hydrochloride have been employed, but Aluminium was later abandoned, because it has been a silent killer of many uremic patients, due to subtle absorption eventually leading to toxicity on Central Nervous System and bone, with allucinations, seizures, dementia, and osteomalacia, bone pain, fracturing osteodystrophy, and death. Recently, a new chelating agent able to bind dietary phosphate, namely Lanthanum carbonate has been introduced, with a proven efficacy profile for short-term treatment. However, after careful examination of the very few scientific papers available to date, we strongly advise caution before adopting, at present, lanthanum carbonate as a phosphate binder in uremic patients. In fact, notwithstanding minimized, some data are worrying: first, Lanthanum ions are absorbed, though at a minimal extent, by human gut; 2) pharmacokinetic evaluations show a greater exposure to Lanthanum in uremic patients;3) Lanthanum concentration is increased tenfold in blood and fivefold in bone after short-term supplementation in uremic patients; 4) there is no proofs that Lanthanum cannot cross the blood brain barrier in uremic patients; 5)Lanthanum has many biological effects and is potentially highly toxic. The Aluminum story should serve as cautionary tale when considering the use of new metal ions.

Area Under Curve↗
PubMed2004

Hetero-tripodal hydroxypyridonate gadolinium complexes: syntheses, relaxometric properties, water exchange dynamics, and human serum albumin binding.

The synthesis and relaxometric properties of hetero-tripodal hydroxypyridonate-terephthalamide gadolinium (Gd(3+)) chelates with differing structural features for probing human serum albumin (HSA) interactions are reported. The Gd(3+) complexes are divided into two series. The first series (3-5) features a benzyl derivative connected to the hydroxypyridonate (HOPO) moiety. The second series of complexes (6-10) has the common feature of a poly(ethylene glycol) (PEG) attached to the terephthalamide (TAM) moiety and is nonbenzylated. The water exchange of the complexes is in the fast exchange regime with rates (k(ex)) in the range 0.45-1.11 x 10(8) s(-1). The complexes have a moderate interaction with HSA with association constants (K(A)'s) in the range 0.7-8.6 x 10(3) M(-1). Protein binding results in an enhancement in proton relaxivity from 7.7-10.4 mM(-1) s(-1) (r(1p)) to 15-29 mM(-1) s(-1) (r(1p)(b)). It is concluded that the interaction of the complexes with HSA (i) is enhanced by the presence of benzyl groups, (ii) is entropically driven, and (iii) results in a lower hydration number (q).

Contrast Media↗
PubMed2004

Magnetic resonance imaging visualization of targeted cells by the internalization of supramolecular adducts formed between avidin and biotinylated Gd3+ chelates.

The high binding affinity between avidin and biotin has been exploited to develop a procedure for magnetic resonance imaging (MRI) visualization of target cells. SHIN3 and PANC1 tumor cell lines have been used as target cells because they possess on their membranes galactosyl receptors able to bind avidin molecules. Avidin-Gd chelate adducts have been built by using two Gd complexes containing one (Gd-I) and two (Gd-II) biotin residues, respectively. The relaxivities of such supramolecular adducts are significantly higher than those shown by free Gd-I and Gd-II. There is evidence of the occurrence of multilayered adducts in which the bis-biotinylated Gd(3+) complex acts as a bridge between adjacent avidin molecules. MRI differentiation of labeled versus unlabeled cells has been attained when approximately 6 x 10(8) Gd units were internalized in each cell. Furthermore, there is a marked decrease in the measured intracellular T(1) relaxivity as the number of internalized Gd complexes increases, probably owing to too short relaxation times of endosomic water protons with respect to their diffusion lifetime.

Avidin↗
PubMed2004

[Gd-AAZTA]-: a new structural entry for an improved generation of MRI contrast agents.

An innovative MRI contrast agent based on the unprecedented and easily obtained ligand AAZTA is described. The simple and straightforward synthesis of the ligand, together with the potentiometric and relaxometric behavior of the corresponding Gd(III) chelate, is reported. The complex [Gd(AAZTA)]- shows outstanding magnetic properties connected with high thermodynamic stability in aqueous solution and a nearly complete inertness toward the influence of bidentate endogenous anions, placing this compound as one of the most promising candidates for the development of high performance MRI contrast agents.

Contrast Media↗
PubMed2004

Synthesis of a bifunctional monophosphinic acid DOTA analogue ligand and its lanthanide(III) complexes. A gadolinium(III) complex endowed with an optimal water exchange rate for MRI applications.

A new bifunctional octa-coordinating ligand containing an aminobenzyl moiety, DO3APABn (H4DO3APABn = 1,4,7,10-tetraazacyclododecane-4,7,10-triacetic-1-{methyl[(4-aminophenyl)methyl]phosphinic acid}), has been synthesized. Its lanthanide(III) complexes contain one water molecule in the first coordination sphere. The high-resolution 1H and 31P spectra of [Eu(H2O) (DO3APABn)]- show that the twisted square-antiprismatic form of the complexes is more abundant in respect to the corresponding Eu(III)-DOTA complex. The 1H NMRD and variable-temperature 17O relaxation measurements of [Gd(H2O)(DO3APABn)]- show that the water residence time is short (298tauM = 16 ns) and falls into the optimal range predicted by theory for the attainment of high relaxivities once this complex would be endowed by a slow tumbling rate. The relaxivity (298r1 = 6.7 mM(-1) s(-1) at 10 MHz) is higher than expected as a consequence of a significant contribution from the second hydration sphere. These results prompt the use of [Gd(H2O)(DO3APABn)]- as a building block for the set-up of highly efficient macromolecular MRI contrast agents.

Gadolinium↗
PubMed2004

Detection and quantification of lanthanide complexes in cell lysates by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Gadolinium (III) complexes are under intense scrutiny as contrast agents for magnetic resonance imaging. Although currently used mainly as extracellular agents, there is a growing interest to exploit their contrast enhancing ability in the intracellular environment. To ascertain the preservation of their chemical integrity upon the intracellular entrapment, it is necessary to have a method for their dosage in the cell lysates. Herein, a mass spectrometric method for detection and quantification of gadolinium complexes in cell lysates is reported. The detection by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) was carried out by using a non-acidic matrix (2,4,6-trihydroxyacetophenone), which does not allow any leakage of gadolinium from the complex. Quantification has been possible by using as an internal standard an ytterbium complex with the same ligand of the analyte. Ytterbium was chosen because, among the lanthanides, it is the one with the isotopic distribution pattern the most similar to that of gadolinium. Sensitivity was enough to detect low micromolar quantities of a cationic complex and high micromolar quantities of a neutral complex in cell lysates of rat hepatoma cells. In the case of anionic complexes, sensitivity was too low for quantitative analysis. To the best of our knowledge, this is the first report concerning the quantification of metal complexes by MALDI-TOF-MS.

Animals↗
PubMed2004

Towards targeted MRI: new MRI contrast agents for sialic acid detection.

The detection of sialic acid in living systems is of importance for the diagnosis of several types of malignancy. We have designed and synthesized two new lanthanide ion ligands (L1 and L2) that are capable of molecular recognition of sialic acid residues. The basic structure of these ligands consists of a DTPA-bisamide (DTPA, diethylenetriamine pentaacetic acid) whose amide moieties each bear both a boronic function for interaction with the diol groups in the side chain of sialic acid, and a functional group that is positively charged at physiologic pH values and is designed to interact with the carboxylate anion of sialic acid. The relaxometric properties of the Gd3+ complexes of these two ligands were evaluated. The relaxivity of the GdL1 complex has a significant second-sphere contribution at pH values above the pKa of its phenylboronic acid moiety. The interaction of the Gd3+ complexes of L1 and L2 with each of several saccharides was investigated by means of a competitive fluorescent assay. The results show that both complexes recognize sialic acid with good selectivity in the presence of other sugars. The adduct formed by GdL2 with sialic acid has the higher conditional formation constant (50.43+/-4.61 M(-1) at pH 7.4). The ability of such complexes to recognize sialic acid was confirmed by the results of a study on the interaction of corresponding radiolabeled complexes (153SmL1 and 153SmL2) with C6 glioma rat cells. 153SmL2 in particular is retained on the cell surface in significant amounts.

Boronic Acids↗