Biomedical subjects

R N Muller

Publications and source records attributed to R N Muller.

At least 19 recordsLinked to original sources

PubMed2004

Optimising the design of paramagnetic MRI contrast agents: influence of backbone substitution on the water exchange rate of Gd-DTPA derivatives.

Among other factors influencing the residence time of the coordinated water (tauM) of paramagnetic contrast agents, the steric hindrance around the gadolinium ion seems to play a beneficial role. Such a crowding can be achieved by substituting the Gd-DTPA backbone on the C4 position. Several Gd-DTPA complexes carrying diverse groups at this position have thus been synthesised and characterised: GdS-C4-Me-DTPA, GdS-C4-n-Bu-DTPA, GdS-C4-iBu-DTPA, GdS-C4-iPr-DTPA, and Gd-C4-diMe-DTPA. TauM has been measured through the evolution of the water oxygen-17 transverse relaxation rate as a function of the temperature. The data show a reduction of tauM of GdS-C4-Me-DTPA, GdS-C4-n-Bu-DTPA, GdS-C4-iBu-DTPA, GdS-C4-iPr-DTPA, and Gd-C4-diMe-DTPA (tauM310 = 91,82, 108,98, and 57 ns respectively, as compared to Gd-DTPA (tauM310 = 143 ns)). At 310 K, the nuclear magnetic dispersion relaxation profiles of water protons are very similar for the five complexes which present longitudinal relaxivities slightly higher than those of Gd-DTPA. Regarding zinc transmetallation, C4-monosubstituted derivatives are more stable than Gd-DTPA. These results confirm that a judicious substitution of the DTPA skeleton allows for an acceleration of the coordinated water exchange rate. This observation can be useful for the design of vectorised contrast agents for molecular imaging.

Contrast Media↗

PubMed2002

Dy-complexes as high field T2 contrast agents: influence of water exchange rates.

Dy complexes can act as suitable negative (T2) contrast agents for Magnetic Resonance Imaging (MRI). As clinical MRI moves toward higher fields, tuning of the exchange rate of coordinated water molecules will become necessary to optimize the r2 relaxivity. For Dy complexes, this will require lengthening of the water residence time, a strategy opposite that required to optimize the r1 relaxivity of Gd complexes. However, very slow water exchange can be deleterious. This is illustrated here by a Dy complex that is characterized by a very slow water exchange. This complex, Dy-DOTA-4AmCE, is compared with several Dy-DTPA derivatives known for their efficacy as T2 contrast agents at high magnetic fields.

Body Water↗

PubMed2001

Relaxivity and water exchange studies of a cationic macrocyclic gadolinium(III) complex.

We conducted relaxometric and water exchange studies of the cationic [Gd((S,S,S,S)-THP)(H2O)]3+ complex (THP 1,4,7,10-tetrakis(2-hydroxy-propyl)-1,4,7,10-tetraazacyclododecane). While the NMRD profiles obtained are typical for DOTA-like complexes (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate), variable-temperature 7O NMR investigations revealed a relatively high water exchange rate (k(298)(ex) = 1.89 x 10(7) s(-1)). These results differ from those reported for other cationic tetraamide macrocyclic Gd(III) complexes, which exhibit characteristically low exchange rates. Since the low exchange rates are attributed partially to the geometry of the M isomer (square antiprismatic) in the tetraamide derivatives, the atypical water exchange rate observed in [Gd((S,S,S,S)-THP-(H2O)]3+ may result from a twisted square antiprismatic structure in this complex and from the relatively high steric strain at the water coordination site as a result of the presence of methyl groups at the alpha-position with respect to the Gd(III)-bound O atoms of THP.

Journal Article↗

PubMed2001

Inulin as a carrier for contrast agents in magnetic resonance imaging.

Magnetic resonance angiography (MRA) has put forth an impetus for the development of macromolecular GdIII complexes that have a prolonged lifetime in the vascular system. Herein, we report the synthesis and GdIII complexation of a new sugar conjugate based on inulin and the DO3A ligand (DO3A = 1,4,7,10-tetraazacyclododecan-1,4,7-triacetic acid). Two API-DO3ASQ conjugates (API = O-(aminopropyl)inulin, SQ = squaric acid = 3,4-dihydroxy-3-cyclobutene-1,2-dione) with different degrees of substitution (ds = 0.7 and ds = 1.5) were prepared from API by using the diethyl ester of squaric acid as a linking agent for the DO3A chelate. The efficacies of the resulting GdIII compounds were evaluated by investigation of their water 1H longitudinal-relaxation-rate enhancements at variable field (NMRD). A dramatic increase in relaxivity was observed in the more highly substituted conjugate (ds = 1.5); this prompted us to do a variable-temperature (17)O study in order to further characterize the relaxation parameters involved in this system. [Gd(API-DO3ASQ)] shows promising properties for application as a contrast agent for MRI.

Chelating Agents↗

PubMed2001

Slow clearance gadolinium-based extracellular and intravascular contrast media for three-dimensional MR angiography.

The objective of this study was to assess two new slow-clearance contrast media with extracellular and intravascular distribution for magnetic resonance angiography (MRA). Extracellular Gd-DTPA-BC(2)glucA and intravascular Gd(DO3A)(3)-lys(16) were developed within the European Biomed2 MACE Program and compared with two reference compounds, intravascular CMD-A2-Gd-DOTA and extracellular GdDOTA, in 12 rats. Pre- and post-contrast three-dimensional MR (TR/TE = 5 msec/2.2 msec; isotropic voxel size 0.86 mm(3)) was acquired for 2 hours. Signal-to-noise enhancement (DeltaSNR) was calculated. Two minutes after injection, all contrast media provided strong vascular signal enhancement. The DeltaSNR for Gd-DTPA-BC(2)glucA, Gd(DO3A)(3)-lys(16), CMD-A2-Gd-DOTA, and GdDOTA were 13.0 +/- 1.8, 25.0 +/- 3.2, 25.0 +/- 4.0, and 18.0 +/- 3.4, respectively. Gd-DTPA-BC(2)glucA, Gd(DO3A)(3)-lys(16), and CMD-A2-Gd-DOTA cleared slowly from the circulation, whereas GdDOTA cleared rapidly. Vascular DeltaSNR at 2 hours were 2.9 +/- 0.6, 25.0 +/- 3.2, 25.0 +/- 4.0, and 0.4 +/- 1.0. Gd(DO3A)(3)-lys(16) provided strong vascular and minor background enhancement, and thus may be useful for MRA or perfusion imaging. Gd-DTPA-BC(2)glucA produces persistent enhancement of extracellular water, and thus may allow quantification of extracellular distribution volume and assessment of myocardial viability.

Animals↗

PubMed2001

Ultrasmall particulate iron oxides as contrast agents for magnetic resonance spectroscopy: a dose-effect study.

Long-distance effects of a superparamagnetic contrast agent (AMI227) were investigated by phosphorus-31 NMR spectroscopy at 7.05 Tesla. In an initial methodological approach, the effects observed on phantoms were compared to the results of theoretical calculations. In a second step, the particles were administered to excised and perfused rat livers (N = 5) and hearts (N = 5) through the perfusion medium for 12 minutes at various concentrations (0.9, 1.8, and 3.6 mM Fe). Organs were subsequently rinsed with the perfusion medium for 42 minutes. During particle perfusion, the spectral lines were shifted and exhibited a strong broadening, although the peak area remained constant, testifying to the inocuity of the material. For hearts only, these disturbances disappeared upon organ rinsing. These through-space susceptibility effects of the particles located in the vessels on phosphorus nuclei, which are strictly confined to the intracellular space, show that high-susceptibility intravascular agents could be useful to evaluate tissue perfusion by contrast-enhanced spectroscopy.

Analysis of Variance↗

PubMed2001

Water relaxation by SPM particles: neglecting the magnetic anisotropy? A caveat.

Magnetometric and relaxometric data from SPM particles are revisited, leading to a double conclusion rather different from the original one: accounting for the anisotropy energy not only allows a considerable improvement of the fit of the data to theory, but it also invalidates the conclusion obtained from the high field data (without accounting for anisotropy) concerning an important reduction of the diffusion coefficient by the coating of the particles.

Anisotropy↗

PubMed2001

Cesium-133: a potential reporter of the hepatic uptake of contrast agents.

NMR spectroscopy of intracellularly located (133)Cs has been used to monitor the uptake of Gd-EOB-DTPA by the isolated rat liver. As shown by (31)P spectroscopy, accumulation of (133)Cs ions in hepatocytes does not produce detectable effects on the metabolism. The hepatic internalization of Gd-EOB-DTPA was followed by the paramagnetic relaxation enhancement of the intracellular (133)Cs ions, and confirmed by parallel quantitations of Gd and Cs run by inductively coupled plasma (ICP) analysis of liver samples and aliquots of perfusate. The relaxation data significantly underestimate the Gd content, suggesting a potential compartmentation of Cs(+) and/or the contrast agent. Magn Reson Med 45:711-715, 2001.

Animals↗

PubMed2001

Nuclear magnetic relaxation dispersion of ferritin and ferritin-like magnetic particle solutions: a pH-effect study.

The relaxation mechanism of water protons in the presence of ferritin is still being debated. In this work, the pH dependence of the relaxation induced by ferritin and Fercayl, a ferritin-like akaganeite particle, is studied through T1 and T2 nuclear magnetic relaxation dispersion (NMRD) profiles. To differing extents, the relaxation brought about by both systems is significantly affected by pH. A proton exchange time of 33 ns (at pH 6 and 37 degrees C) is deduced from the fittings of Fercayl T1 NMRD profiles. The linearity of the relationship between 1/T2 and the magnetic field B0 for ferritin and Fercayl solutions is not altered by changes in pH. The parameters of this linearity strongly depend on pH for the latter, while remaining unchanged for the former. These results are interpreted in terms of an exchange between protons belonging to hydroxyl groups at the surface of the particle and bulk water protons.

Animals↗

PubMed2001

Deuterium NMR study of the MP-2269: albumin interaction--a step forward to the dynamics of non-covalent binding.

MP-2269, the Gd(III) complex of 4-pentylbicyclo[2.2.2]octane-1-carboxyl-di-L-aspartyl-lysine-derived-DTPA, is a small Gd-agent that binds non-covalently to serum albumin in vivo to assume the enhanced relaxivities associated with macromolecular agents, (due in part to increased rotational correlation time, tau(R)). To further explore the fundamental parameters that govern the dynamics of water proton relaxation enhancement by this prototypical albumin-binding agent, the rotational correlation time (tau(R)) for the deuterated La(III) analog of MP-2269 has been independently measured in the presence and absence of 4% albumin using 2H-NMR approaches. The diamagnetic La(III) analog of MP-2269 was deuterated at the alpha-position of the carbonyl groups. 2H-NMR studies were conducted at 7.05T (46 MHz) and 310 degrees K on a Bruker NMR spectrometer. Spectral deconvolution permitted calculation of transverse relaxation rates, 1/T(2), from the NMR linewidths and subsequently, tau(R). The results yielded a tau(R) of the albumin bound complex of approximately 8 ns. This value is intermediate between those earlier estimated by 17O-NMR ( approximately 1 ns) and 1H-NMRD ( approximately 20-50 ns) and significantly shorter than that of albumin. The 2H-NMR study results also indicate that the exchange between free and albumin-bound forms of the La(III) analog is slow (exchange lifetimes >1 ms). This slow exchange does not affect the water residence lifetimes (tau(M) 140-280 ns).

Contrast Media↗

PubMed2001

Albumin-bound MRI contrast agents: the dilemma of the rotational correlation time.

Human serum albumin (HSA) binds numerous molecules, among which are suitably designed MRI contrast agents. The rotational tumbling of the protein is thus one of the parameters likely to affect the in vivo relaxivity of these agents. Literature unveils discrepancies about the value of the rotational correlation time (tau(R)) of HSA. In the present work, the tau(R) of this protein has been determined by studying the deuterium relaxation rate of small molecules known for their strong binding to HSA (warfarin and 4-hydroxycoumarin). Values of approx. 20-22 ns are obtained at 310 K in a 4% HSA solution and are in good agreement with the theoretical predictions.

4-Hydroxycoumarins↗

PubMed2001

Stereospecific binding of MRI contrast agents to human serum albumin: the case of Gd-(S)-EOB-DTPA (Eovist) and its (R) isomer.

The water proton relaxation rate enhancement of the hepatospecific Gd-(S)-EOB-DTPA (Eovist) and of its (R) isomer in aqueous solutions free of protein, in serum and in 4% human serum albumin solution, are compared. In the absence of proteins, both compounds exhibit, as expected, the same proton relaxivity, as measured by the nuclear magnetic relaxation dispersion (NMRD) profiles. In serum and albumin solution, non-covalent binding of the paramagnetic complexes to macromolecules is observed. Both isomers are likely to bind to the same site of human serum albumin, but the affinity of the (S) isomer is larger than for the (R) isomer.

Contrast Media↗

PubMed2001

Stability of MRI paramagnetic contrast media: a proton relaxometric protocol for transmetallation assessment.

RATIONALE AND OBJECTIVES: The suitability of paramagnetic complexes as magnetic resonance contrast agents depends on various factors such as their relaxivity, stability, selectivity, and the inertness toward transmetallation by endogenous ions. The transmetallation of a series of 18 gadolinium complexes by the Zn2+ ion was studied in vitro by proton relaxometry. METHODS: Transmetallation was analyzed through the evolution of the paramagnetic longitudinal relaxation rate of water protons at 37 degrees C in pH = 7 phosphate buffer solutions containing 2.5 mmol/L of the gadolinium complexes and 2.5 mmol/L zinc chloride. The measurements were performed at 0.47 T over a period of at least 3 days. RESULTS: The results confirm the high stability of macrocyclic systems and a high sensitivity of Gd-diethylenetriamine-pentaacetic acid (DTPA) derivatives to transmetallation by Zn2+ ions. The decreasing order of stability with respect to metal exchange is as follows: Gd-macrocyclics > Gd-C-functionalized DTPA > Gd-DTPA > primary and secondary Gd-DTPA bisamides. The ternary bisamide analyzed in this study [Gd-DTPA-1,11-bisbismethylamino-1,11-dioxo-3,6,9-triaza-3,6,9-tris(carboxymethyl)undecane] is more stable than the parent compound Gd-DTPA. CONCLUSIONS: A simple relaxometric protocol has been successfully developed to study the in vitro transmetallation process of gadolinium complexes. The importance of the functionalization and substitution of the DTPA-like complexes is clearly shown.

Chromatography, High Pressure Liquid↗

PubMed2001

Hepatocyte-mediated transport to the bile of AMI-HS, a particulate contrast agent.

RATIONALE AND OBJECTIVES: The elimination of hepatocyte-directed particulate contrast agents has not been studied in the same detail as particles eliminated mainly by the mononuclear phagocyte system. The aim of the present study was to elucidate the fate of these particles by a multidisciplinary approach. METHODS: After intravenous injection of AMI-HS particles directed to the hepatocytes, rats were killed and cytological studies, by both electron microscopy and histochemistry, and spectroscopic studies of the bile were performed. The data were compared with a dynamic magnetic resonance study of the heart and liver. RESULTS: The particles were rapidly cleared from the blood by Kupffer cells and hepatocytes and then found first in the vascular and later in the biliary pole of the hepatocytes. After 24 hours, a relaxometric characterization of the bile showed the presence of unchanged particles in the bile. CONCLUSIONS: These results show the capacity of the liver to excrete unchanged AMI-HS particles directly into the bile.

Animals↗

PubMed2000

Relaxation induced by ferritin and ferritin-like magnetic particles: the role of proton exchange.

Proton T1 and T2 in solutions of ferritin and fercayl (a ferritin-like iron-dextran particle) solutions were measured, over a wide range of various parameters (Bo, temperature, interecho-time and pH). The window of the previously referred linear dependence of 1/T2 on the static field was increased, up to 500 MHz, and the independence of T2 on the echo time was confirmed. Correlation times were extracted from T1 nuclear magnetic relaxation dispersion profiles. In the pH range studied, no strong variation of the relaxivities of ferritin solutions was noticed. Fercayl, which, unlike ferritin, remains stable under large pH variations, is characterized by strongly pH-dependent relaxation rates. This feature is interpreted as due to the effect of proton exchange in the water relaxation process. Outer sphere theory, which ignores proton binding, is shown to be unable to describe the relaxation of ferritin and ferritin-like particles solutions, first because it predicts a quadratic rate dependence on Bo, but also because it severely underestimates the relaxation rate. Explaining relaxation induced by ferritin and ferritin-like particle solutions will likely require a model that accounts for proton binding.

Animals↗

PubMed1999

Use of T(2)-weighted susceptibility contrast MRI for mapping the blood volume in the glioma-bearing rat brain.

The aim of this work was to evaluate the potential of T(2)-weighted, steady-state susceptibility-enhanced contrast magnetic resonance imaging (MRI), to characterize brain tumor heterogeneity and tumor vascularization. In vivo T(2)-weighted MRI experiments were carried out on normal rats (n = 11) and rats bearing C6 glioma (n = 17), before and after the injection of a remanent superparamagnetic contrast agent. The DeltaR(2) variations of the transverse relaxation rate due to the injection of the contrast agent were used to generate relative cerebral blood volume (CBV) maps. Contrast enhancement of the tumor was shown to reflect tissue vascularization rather than leakage of the blood-brain barrier. The quantitative results clearly show the heterogeneity of tumor vascularization and reveal a high vessel density in the peripheral area (CBV(per) approximately 17.2 +/- 2.3 sec(-1)) and a low vessel density in the central area of the tumor (CBV(cen) approximately 2.5 +/- 0.5 sec(-1)). Magn Reson Med 42:754-761, 1999.

Animals↗

PubMed1999

Field strength and dose dependence of contrast enhancement by gadolinium-based MR contrast agents.

The relaxivities r1 and r2 of magnetic resonance contrast agents and the T1 relaxation time values of tissues are strongly field dependent. We present quantitative data and simulations of different gadolinium-based extracellular fluid contrast agents and the modulation of their contrast enhancement by the magnetic field to be able to answer the following questions: How are the dose and field dependences of their contrast enhancement? Is there an interrelationship between dose and field dependence? Should one increase or decrease doses at specific fields? Nuclear magnetic relaxation dispersion data were acquired for the following contrast agents: gadopentetate dimeglumine, gadoterate meglumine, gadodiamide injection, and gadoteridol injection, as well as for several normal and pathological human tissue samples. The magnetic field range stretched from 0.0002 to 4.7 T, including the entire clinical imaging range. The data acquired were then fitted with the appropriate theoretical models. The combination of the diamagnetic relaxation rates (R1 = 1/T1 and R2 = 1/T2) of tissues with the respective paramagnetic contributions of the contrast agents allowed the prediction of image contrast at any magnetic field. The results revealed a nearly identical field and dose-dependent increase of contrast enhancement induced by these contrast agents within a certain dose range. The target tissue concentration (TTC) was an important though nonlinear factor for enhancement. The currently recommended dose of 0.1 mmol/kg body weight seems to be a compromise close to the lower limits of diagnostically sufficient contrast enhancement for clinical imaging at all field strengths. At low field contrast enhancement might be insufficient. Adjustment of dose or concentration, or a new class of contrast agents with optimized relaxivity, would be a valuable contribution to a better diagnostic yield of contrast enhancement at all fields.

Brain↗

PubMed1999

Paramagnetic liposomes as MRI contrast agents: influence of liposomal physicochemical properties on the in vitro relaxivity.

The in vitro contrast efficacy of liposome encapsulated gadolinium-[10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1, 4,7-triacetic acid] (GdHPDO3A) has been assessed by relaxometry. The internal concentrations were 150 and 250 mM Gd. Two types of liposome compositions were investigated: a phospholipid blend consisting of both hydrogenated phosphatidylcholine (HPC) and phosphatidylserine (HPS) with a gel-to-liquid crystalline phase transition temperature (Tm) of 50 degrees C, and a mixture of dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG) with a Tm of 41 degrees C. The investigated liposome size range was 70-400 nm. The T1 and T2 relaxivities (r1 and r2) of liposome encapsulated GdHPDO3A were significantly reduced at 37 degrees C and 0.47 T, compared to those of non-liposomal metal chelate, due to an exchange limitation of the dipolar relaxation process. The highest relaxivity values were obtained for the DPPC/DPPG liposomes, and were attributed to a higher liposome water permeability and to a more efficient water exchange across the membrane. A reduction in liposome size increased the r1, confirming the exchange limited dipolar relaxation. The increased r1 with increasing temperature demonstrated the prerequisite of rapid water exchange between the interior and exterior of the liposome for efficient dipolar relaxation enhancement. Susceptibility effects were present in the liposome systems as the r2/r1 ratio increased with increasing liposome size and internal Gd concentration. In summary, the current work has shown the influence of key physicochemical properties, such as liposome size, membrane composition and permeability, on the in vitro relaxivity of liposome encapsulated GdHPDO3A.

1,2-Dipalmitoylphosphatidylcholine↗