pH-sensitive paramagnetic liposomes as MRI contrast agents: in vitro feasibility studies.

A novel type of pH-sensitive paramagnetic contrast agent is introduced; a low molecular weight gadolinium (Gd) chelate (GdDTPA-BMA) encapsulated within pH-sensitive liposomes. The in vitro relaxometric properties of the liposomal Gd chelate were shown to be a function of the pH in the liposomal dispersion and the membrane composition. Only a minor pH-dependency of the T1 relaxivity (r1) was observed for liposomal GdDTPA-BMA composed of the unsaturated lipids dioleoyl phosphatidyl ethanolamine (DOPE) and oleic acid (OA). On the other hand, the r1 of GdDTPA-BMA encapsulated within saturated dipalmitoyl phosphatidyl ethanolamine/palmitic acid (DPPE/PA) liposomes demonstrated a strong pH-dependency. At physiological pH and above, the r1 of this system was significantly lowered compared to that of non-liposomal Gd chelate, which was explained by an exchange limited relaxation process. Lowering the pH below physiological value, however, gave a sharp and 6-7 fold increase in r1, due to liposome destabilisation and subsequent leakage of entrapped GdDTPA-BMA. The pH-sensitivity of the DPPE/PA liposome system was confirmed in an in vitro magnetic resonance imaging (MRI) phantom study.     

Low-molecular weight lanthanide contrast agents: Evaluation of susceptibility and dipolar effects in red blood cell suspensions

Red blood cell (RBC) suspensions, containing low-molecular weight (LMW) dysprosium (Dy) and gadolinium (Gd) chelates, were selected as a two-compartment system for the evaluation of the magnetic dipolar and susceptibility contributions to the transverse (T₂) relaxation of solvent water protons. The influence of RBC geometry and degree of metal chelate compartmentalization on T₂ was investigated by variation of the osmolality and hematocrit (HC), respectively. The T₂-relaxation ability of Dy-chelates was markedly improved in RBC suspensions, in comparison to aqueous solutions, due to the presence of susceptibility effects that more than compensated for the low dipolar relaxation efficacy. Despite a smaller susceptibility effect, the Gd-chelates were still the most efficacious in shortening T₂ due to their comparatively larger dipolar relaxation contribution. The results obtained with the Dy-chelates allowed the evaluation of the relative contributions of susceptibility and dipolar mediated relaxation for the Gd-chelates. The RBC geometry and degree of compartmentalization influenced strongly the T₂ relaxation efficacy of Dy-chelates, as opposed to the Gd-chelates. Hemolysis eliminated the susceptibility effect, essentially removing the T₂ relaxation ability of Dy-chelates. The T₂ relaxation efficacy of Gd-chelates was improved by hemolysis due to enhancement of the dipolar relaxation. As a conclusion, RBC suspensions have clearly been shown to be a suitable ex vivo model with which to distinguish the different contrast mechanisms of LMW Dy- and Gd-based MRI contrast agents.     

Particle size dependence of relaxivity for silica-coated iron oxide nanoparticles

We investigate the particle size dependence of the relaxivity of hydrogen protons in an aqueous solution of iron oxide (Fe₃O₄) nanoparticles coated in silica for biocompatibility. The T₁ and T₂ relaxation times for various concentrations of silica-coated nanoparticles were determined by a magnetic resonance scanner. We find that the relaxivity increased linearly with increasing particle size. The T₂ relaxivity (R₂) is more than 50 times larger than the T₁ relaxivity (R₁) for the nanoparticle contrast agent, which reflects the fact that the T₂ relaxation is mainly influenced by outer sphere processes. The high R₂/R₁ ratio demonstrates that silica-coated iron oxide nanoparticles may serve as a T₂ contrast agents in magnetic resonance imaging with high efficacy.     

Trinuclear Gd(III) Metal Complex with Amide Core Display Remarkable Enhancement in Relaxivity

New trinuclear gadolinium(III) complex having 2-bromoisovaleric acid pendant arm is reported. The longitudinal relaxivity (r _1p) of the complex is 23.17 mM^?1 s^?1 which correspond to a “per Gd” relaxivity of 7.72 mM^?1 s^?1. The transverse relaxivity (r _2p) of the complex is 24.79 mM^?1 s^?1 which correspond to a “per Gd” value of 8.26. The complex exhibit r _1p and r _2p values of 29.19 and 35.20, respectively, in the presence of HSA. The complex also shows pH dependant relaxivity which is an added advantage of the complex for utilization in cancer cell magnetic resonance imaging. The higher relaxivity values in water and HSA indicates a compact solution structure for the complexes and a restricted internal motion about the amide spacer.     

Preparation,physico-chemical characterization,and relaxometry studies of various gadolinium(III)-DTPA-bis(amide) derivatives as potential magnetic resonance contrast agents

Macroscopic protonation constants were measured for a series of DTPA mono- and bis-amide ligands using potentiometric titrations. Proton NMR pH titrations yielded protonation populations of the various nitrogen and oxygen basic sites of the ligands for the different protonation stages. Amide formation decreased the basicity of the backbone nitrogens of the ligands and the thermodynamic stability of the corresponding Gd³⁺ chelates. Nuclear magnetic relaxation dispersion (NMRD) profiles and ESR linewidths were measured for the Gd³⁺ chelates. Some of these exhibited an elevated high field relaxivity relative to Gd(DTPA)²⁻, in response to their high molecular weight. As opposed to Gd(DTPA)²⁻, at 5°C the chemical exchange process of the single inner-sphere water molecule of the bis-amide complexes becomes so slow that it governs the paramagnetic relaxation process, causing the observed NMRD profiles to be close to those expected for the outer-sphere contribution. The chelates containing long alkyl side chains, such as Gd(DTPA-HPA₂), showed increased relaxivity values in the presence of human serum albumin (HSA), indicative of noncovalent interaction with the protein. These chelates could be useful as nonionic hepatobiliary contrast agents.     

Facile Synthesis of Gd(OH)3‐Doped Fe3O4 Nanoparticles for Dual‐Mode T1‐ and T2‐Weighted Magnetic Resonance Imaging Applications

The facile hydrothermal synthesis of polyethyleneimine (PEI)‐coated iron oxide (Fe₃O₄) nanoparticles (NPs) doped with Gd(OH)₃ (Fe₃O₄‐Gd(OH)₃‐PEI NPs) for dual mode T₁‐ and T₂‐weighted magnetic resonance (MR) imaging applications is reported. In this approach, Fe₃O₄‐Gd(OH)₃‐PEI NPs are synthesized via a hydrothermal method in the presence of branched PEI and Gd(III) ions. The PEI coating onto the particle surfaces enables further modification of poly(ethylene glycol) (PEG) in order to render the particles with good water dispersibility and improved biocompatibility. The formed Fe₃O₄‐Gd(OH)₃‐PEI‐PEG NPs have a Gd/Fe molar ratio of 0.25:1 and a mean particle size of 14.4 nm and display a relatively high r₂ (151.37 × 10^?3m ^?1 s^?1) and r₁ (5.63 × 10^?3m ^?1 s^?1) relaxivity, affording their uses as a unique contrast agent for T₁‐ and T₂‐weighted MR imaging of rat livers after mesenteric vein injection of the particles and the mouse liver after intravenous injection of the particles, respectively. The developed Fe₃O₄‐Gd(OH)₃‐PEI‐PEG NPs may hold great promise to be used as a contrast agent for dual mode T₁‐ and T₂‐weighted self‐confirmation MR imaging of different biological systems.     

Paramagnetic Liposomes as Thermosensitive Probes for MRI-Guided Thermal Treatment: In Vitro Feasibility Studies

In this work the potential of thermosensitive paramagnetic liposomes for in vitro temperature monitoring during radiofrequency heating has been assessed. Two thermosensitive liposome formulations with different phase-transition properties were investigated. Temperature-dependent spin–lattice (T ₁) relaxivity measurements were performed at 0.24 T. Magnetic resonance imaging was performed at 2 T in liposome-containing phantom models and T ₁ relaxation rates (R ₁) were quantified as a function of temperature. Independent temperature measurements were performed using both thermocouple and magnetic-resonance-based methods (proton resonance frequency and diffusion-based thermometry). The relaxometric measurements showed that the T ₁ relaxivity increased from low values (about 0.3 s⁻¹mM⁻¹ at 35 °C) to about 4 s⁻¹mM⁻¹ when the temperature approached and exceeded the phase-transition temperature (T _c) of the liposome preparations. These data correlated well to the imaging data where an increased signal intensity was observed on T ₁-weighted images at temperatures above T _c. The derived R ₁ maps reflected the measured liposomal temperature sensitivity and temperature quantification was possible on the basis of the measured linear temperature versus R ₁ correlation in the transition range of the liposomes. The studies have therefore shown that thermosensitive paramagnetic liposomes exhibit the required temperature sensitivity to allow for an accurate mapping of the temperature changes in an in vitro imaging model. Authors' address: Kamil A. Il'yasov, Physics Department, Kazan State University, Kremlevskaya ulitsa 18, Kazan 420008, Russian Federation     

Microwave-assisted synthesis of magnetite nanoparticles for MR blood pool contrast agents

Microwave-assisted polyol process was developed for the synthesis of magnetite nanoparticles with precisely controlled size, high crystallinity and high water solubility. The process is simple, time-saving and low energy-consuming due to the advantages of polyols and microwave irradiation combined. The crystal phases of the nanoparticles were determined by transmission electron microscopy, X-ray powder diffraction and Raman spectrum. The coating materials of the nanoparticles were analyzed by Fourier transformed infrared spectroscopy and thermal gravimetric analysis. Precise size tuning enables an easier way to adjust the relaxation properties of the magnetite nanoparticles. The colloid nanoparticles with high longitudinal relaxivity (r₁) and low ratio of transverse relaxivity (r₂) to r₁ have a potential application in magnetic resonance angiography.     

NMR relaxivity of coated and non-coated size-sorted maghemite nanoparticles

ABSTRACT

The effect of polymer coating on MNR relaxometry of maghemite nanoparticles has been studied. The samples were carefully sorted by size in order to reach narrow size distribution (<0.2) with size ranging from 4.5 to 12.5?nm. Relaxation dispersion profile as well as studies at a fixed Larmor frequency, were recorded for numerous either uncoated or polymer coated samples. The NMR relaxivities r₁ and r₂ increase with nanoparticle diameter. We have analysed the role of polydispersity for nanoparticles with the same mean size on the dispersion curves. We have compared the role of coating on nanoparticles NMR relaxivity between bare and poly(sodium acrylate-co-maleate) coated nanoparticles. We have investigated the influence of nanoparticle size on the T₁ and T₂ activation energy Ea. While Ea decreases with nanoparticle diameter when determined from T₁, it increases from T₂ determination. The influence is more important for small particles (<9?nm) than for big particles (>9?nm). Moreover, the PAAMA coating changes the energy Ea obtained from T₂: Ea becomes independent of the nanoparticle diameter. These results highlight the need of a complete characterisation of the role of the coating on the relaxation of magnetic particles.     

Oxygen effect on spin relaxation of the surface paramagnetic centers in carbon chars

The original technique with the use of longitudinal electron paramagnetic resonance detection was applied to measure longitudinal and transversal electron relaxation times (T ₁ andT ₂) in specially prepared carbon chars containing paramagnetic centers (PCs) on the surface. The results not only confirmed the conclusions of our previous studies but enabled us to determine the exchange integral and clarify the mechanism of interaction between the PCs and adsorbed molecular oxygen O₂. A spin relaxation mechanism was also suggested which takes into account both the exchange and dipolar interactions in the systems combining PC and O₂. The value of the exchange integral between PCs as well as its functional dependence on the oxygen content were estimated.     

Relaxivities of magnetoliposomes: The effect of cholesterol

We present relaxivities measurements for both the longitudinal and transverse relaxations of two types of liposomes loaded with ultra small superparamagnetic iron oxide nanoparticles. The magnetoliposome systems presented are soybean phosphatidylcholine liposomes, with and without cholesterol, in the phospholipid bilayer with different molar ratios lipid:cholesterol. In fact, cholesterol is needed to obtain stable liposomes for intravenous administration. The longitudinal and transverse relaxivities were measured with a NMR spectrometer in a 7 T magnetic field. For the studied concentrations, the liposomes show a negligible effect on the longitudinal relaxation time T₁ of the medium, but they are very efficient on decreasing the transverse relaxation time T₂, the behaviour one expects for a negative CA. We observed a lower transverse relaxivity for the magnetoliposome nanosystem with cholesterol, which strongly decreases with the cholesterol content in the liposome bilayer.     

T1 and T2 relaxivities of succimer-coated MFe2O4 (M=Mn, Fe and Co) inverse spinel ferrites for potential use as phase-contrast agents in medical MRI

Superparamagnetic MFe₂³⁺O₄ (M=Mn²⁺, Fe²⁺ and Co²⁺) inverse spinel ferrite (ISF) nanoparticles with narrow size distribution having average diameters of 6-8 nm were synthesized by a diol reduction of organic metals and the surface was modified to be hydrophilic by coating with succimer. Magnetic resonance imaging (MRI) contrast enhancement by dipolar coupling defined interactions between the synthesized ISFs and protons in the bulk water was investigated with initial susceptibility, magnetization and anisotropy of the succimer-coated ISFs. The relaxivity ratios, r₂/r₁, for MnFe₂O₄, Fe₃O₄ and CoFe₂O₄ were measured to be 12.2, 23.1 and 62.3, respectively, which demonstrate the potential usefulness of these magnetic nanoparticles as T₂ contrast agents for MRI.     

The effects of L‐ to D‐isomerization and C‐terminus deamidation on the secondary structure of antimicrobial peptide Anoplin in aqueous and membrane mimicking environment

UV resonance Raman spectra of the antimicrobial peptide (AMP) Anoplin (L ‐Anoplin‐NH₂) and two of its derivatives (enantiomer D ‐Anoplin‐NH₂ and C‐terminus deamidated L ‐Anoplin‐OH) were measured in aqueous buffer solution and in membrane‐mimetic environments including 2,2,2‐trifluoro ethanol (TFE), zwitterionic lipid dipalmitoylglycerophosphocholine (DPPC) and anionic lipid dipalmitoylglycerophosphoglycerol (DPPG) vesicle solutions. All three peptides were found to adopt random‐coil/β turn‐like conformation in aqueous solution over the temperature range of 1–60 °C. The conformation was found to become more α‐helical in membrane‐mimetic solutions such as TFE and DPPG but not in DPPC for all Anoplin derivatives. The data demonstrate that Anoplin preferentially binds to the anionic over the zwitterionic model cell membranes. Results also showed that deamidation does not change the conformation of L ‐Ano‐NH₂ very significantly, but does alter membrane rupturing and antimicrobial activities thus confirming that it is the physicochemical properties rather than the peptide conformation that define the mechanism of AMP action. Copyright © 2010 John Wiley & Sons, Ltd.     

Dextran‐Coated Antiferromagnetic MnO Nanoparticles for a T1‐MRI Contrast Agent with High Colloidal Stability

A simple approach to synthesize carboxymethyl dextran‐coated MnO nanoparticles (CMDex‐MnONPs) with high colloidal stability in physiological saline solutions is described here for potential applications as a magnetic resonance imaging (MRI) T₁ contrast agent. The thermal decomposition methodology is used to produce uniform MnONPs with an average size of around 20 nm, and its hydrophobic surface is modified with CMDex molecules, conferring hydrophilic properties. After CMDex coating, the nanoparticle presents high colloidal stability in concentrations ranging from 10 to 50 μg mL^?1, average hydrodynamic size (Z‐average) of 130 nm, polydispersity degree of ≈12%, and negative surface charge in both simulated body fluid solutions and pure water with zeta‐potential of –20 and –40 mV, respectively. The CMDex‐MnONPs with 20 nm show antiferromagnetic behavior at room temperature, and the magnetic properties are found to be strongly dependent of the nanoparticle size, increasing the contribution of the ferromagnetic Mn₃O₄ phase with decreasing size for nanoparticles about 3 nm. Cytotoxicity evaluation in cancerous and noncancerous cells in the range of 5.0–50.0 μg mL^?1 shows low toxicity for cancerous cells and lack of the same for healthy cells lines. Related to the magnetic properties, CMDex‐MnONP presents significant r₁ relaxivity and low r₂/r₁ relaxivity ratio. The results suggest that these nanoparticles display characteristics for potential applications as an MRI T₁ contrast agent.     

The glass transition temperature of amorphous poly(ethylene terephthalate) by thermally stimulated currents

The relation between the temperature T_α of the dipolar relaxation, obtained by the technique of thermally stimulated currents (TSC) and the glass transition temperature T_g has been studied in amorphous poly(ethylene terephthalate) samples. The temperature T_α depends fundamentally on the polarization temperature T_p, the polarization time t_p, and the heating rate v. For each heating rate a maximum T_α, T_M, was obtained for an optimum polarization temperature T_po. The value of T_po is 70°C, independent of the heating rate, and very close to the glass transition temperature obtained by differential scanning calorimetry (69°C). The resulting value for T_M coincides with T_po in the limits of null heating rate and null isothermal polarization time, and, consequently, T_M gives the value of the glass transition temperature for each heating rate as a function of the isothermal dipolar contribution on polarizing at the temperature T_po.     

Proton NMR relaxation in albumin solutions doped with Mn(II)

The aim of this study is to obtain further information about the source of proton relaxation in the Mn(II)-human serum albumin complex. For this purpose, proton relaxation rates in albumin solutions 1/T ₁ and 1/T ₂ were measured versus increasing amounts of manganese [Mn_t]. The fractions of manganese bound to albumin [Mn_b] and free manganese [Mn_f] were then determined from proton relaxation rate enhancement data. Paramagnetic contributions of bound manganese to the observed relaxation rates (1/T _1p^*)_b and (1/T _2p^*)_b were also determined. Finally, the (1/T _2p^*)_b/(1/T _1p^*)_b ratio was used in a derived equation to estimate an effective correlation time τ. Mean τ value of the complex was found to be in the order of 3 ns, while the hydration number of bound manganese q was estimated to be about 4. The 1/τ was found to be the sum of the inverse values of rotational correlation time 1/τ _r, mean residence time of water in hydration spheres of the complex 1/τ _m, and longitudinal electronic relaxation time of manganese 1/τ _s in the complex. In conclusion, the relaxation mechanism in albumin solutions containing Mn(II) can be interpreted through dipolar and scalar interactions modulated by τ _r, τ _m and τ _s. This analysis enables one to get reasonable figures for the τ _r and q of Mn(II) in albumin solution.     

An albumin-based gold nanocomposites as potential dual mode CT/MRI contrast agent

In pursuit of the biological detection applications, recent years have witnessed the prosperity of novel multi-modal nanoprobes. In this study, biocompatible bovine serum albumin (BSA)-coated gold nanoparticles (Au NPs) containing Gd (III) as the contrast agent for both X-ray CT and T₁-weighted MR imaging is reported. Firstly, the Au NPs with BSA coating (Au@BSA) was prepared through a moderate one-pot reduction route in the presence of hydrazine hydrate as reducer. Sequentially, the BSA coating enables modification of diethylenetriaminepentaacetic acid (DTPA) as well as targeting reagent hyaluronic acid (HA), and further chelation of Gd (III) ions led to the formation of biomimetic nanoagent HA-targeted Gd-Au NPs (HA-targeted Au@BSA-Gd-DTPA). Several techniques were used to thoroughly characterize the formed HA-targeted Gd-Au NPs. As expected, the as-prepared nanoagent with mean diameter of 13.82 nm exhibits not only good colloid stablility and water dispersibility, but also satisfying low cytotoxicity and hemocompatibility in the tested concentration range. Additionally, for the CT phantoms, the obtained nanocomplex shows an improved contrast in CT scanning than that of Au@BSA as well as small molecule iodine-based CT contrast agents such as iopromide. Meanwhile, for the T₁-weighted MRI images, there is a linear increase of contrast with concentration of Gd for the two cases of HA-targeted Gd-Au NPs and Magnevist. Strikingly, the nanoagent we explored displays a relatively higher r₁ relaxivity than that of commercial MR contrast agents. Therefore, this newly constructed nanoagent could be used as contrast agents for synergistically enhanced X-ray CT and MR phantoms, holding promising potential for future biomedical applications.     

Dynamic dipolar cross-over in EuO

From magnetic relaxation and resonance spectra the kinetic (Onsager) coefficient of the homogeneous magnetization is derived. Its critical behaviour in the dipolar regime and the cross-over to the exchange regime above T_c agrees quantitively with recent mode-coupling calculations. The relevance of these results for line-widths of inelastic neutron scattering is pointed out.     

35Cl N.M.R. relaxation in aqueous sodium perchlorate solutions

The relaxation time, T _1ρ, for ³⁵Cl in perchlorate ion in aqueous solutions is found to be 0·25 s. T _1ρ is insensitive to the presence of most first row transition metals; however, a weak complex with manganous ion is demonstrated, and the perchlorate ion-manganous exchange rate is shown to be between 3 × 10⁴ s^-1 and 3·6 × 10⁷ s^-1. In the absence of manganous ion, the relaxation is dominated by the nuclear electric quadrupole interaction; however, a dipolar contribution is observed with manganous ion present.     

GdGd interaction and frequency dependence of the ESR linewidth in metallic GdxY1−xP,GdxSc1−xP and GdxY1−xAs

We have investigated the frequency dependence of the high temperature ESR linewidth of the metallic rare earth pnictides Gd_xY_1?xP, Gd_xSc_1?xP and Gd_xY_1?xAs (1?x?0.2) from 9 up to 71 GHz. The Gd pnictides represent a group of compounds where the Korringa relaxation rate, which in most metals and metallic compounds determines the ESR linewidth, is unusually small. Thus, the behaviour of the linewidth can be discussed in terms of exchange narrowing of dipolar contributions.