Membranotropic and relaxation properties of water-soluble gadolinium endometallofullerene derivatives (original) (raw)
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Water-soluble gadofullerenes: toward high-relaxivity, pH-responsive MRI contrast agents
2005
The water-soluble endohedral gadofullerene derivatives, Gd@C60(OH)x and Gd@C60[C(COOH)2]10, have been characterized with regard to their MRI contrast agent properties. Water-proton relaxivities have been measured in aqueous solution at variable temperature (278-335 K), and for the first time for gadofullerenes, relaxivities as a function of magnetic field (5 × 10-4 to 9.4 T; NMRD profiles) are also reported. Both compounds show relaxivity maxima at high magnetic fields (30-60 MHz) with a maximum relaxivity of 10.4 mM-1 s-1 for Gd@C60[C(COOH)2]10 and 38.5 mM-1 s-1 for Gd@C60(OH)x at 299 K. Variabletemperature, transverse and longitudinal 17 O relaxation rates, and chemical shifts have been measured at three magnetic fields (B) 1.41, 4.7, and 9.4 T), and the results point exclusively to an outer sphere relaxation mechanism. The NMRD profiles have been analyzed in terms of slow rotational motion with a long rotational correlation time calculated to be τR 298) 2.6 ns. The proton exchange rate obtained for Gd@C60[C(COOH)2]10 is kex 298) 1.4 × 10 7 s-1 which is consistent with the exchange rate previously determined for malonic acid. The proton relaxivities for both gadofullerene derivatives increase strongly with decreasing pH (pH: 3-12). This behavior results from a pH-dependent aggregation of Gd@C60(OH)x and Gd@C60[C(COOH)2]10, which has been characterized by dynamic light scattering measurements. The pH dependency of the proton relaxivities makes these gadofullerene derivatives prime candidates for pH-responsive MRI contrast agent applications.
Bioconjugate Chemistry, 2009
A new magnetic resonance imaging (MRI) contrast agent based on the trimetallic nitride templated (TNT) metallofullerene Gd 3 N@C 80 was synthesized by a facile method in high yield. The observed longitudinal and transverse relaxivities r 1 and r 2 for water hydrogens in the presence of the water-soluble gadofullerene 2 Gd 3 N@C 80 (OH) ∼26 (CH 2 CH 2 COOM) ∼16 (M ) Na or H) are 207 and 282 mM -1 s -1 (per C 80 cage) at 2.4 T, respectively; these values are 50 times larger than those of Gd 3+ poly(aminocarboxylate) complexes, such as commercial Omniscan and Magnevist. This high 1 H relaxivity for this new hydroxylated and carboxylated gadofullerene derivative provides high signal enhancement at significantly lower Gd concentration as demonstrated by in Vitro and in ViVo MRI studies. Dynamic light scattering data reveal a unimodal size distribution with an average hydrodynamic radius of ca. 78 nm in pure water (pH ) 7), which is significantly different from other hydroxylated or carboxylated fullerene and metallofullerene derivatives reported to date. Agarose gel infusion results indicate that the gadofullerene 2 displayed diffusion properties different from those of commercial Omniscan and those of PEG5000 modified Gd 3 N@C 80 . The reactive carboxyl functionality present on this highly efficient contrast agent may also serve as a precursor for biomarker tissue-targeting purposes.
Impact of Endometallofullerene on P84 Copolyimide Transport and Thermomechanical Properties
Polymers
Novel polymer composite materials, including unique nanoparticles, contribute to the progress of modern technologies. In this work, the endohedral fullerene C60 with incapsulated iron atom (endometallofullerene Fe@C60) is used for modification of P84 copolyimide. The impact of 0.1, 0.5, and 1 wt % endometallofullerene on the structure and physicochemical properties of polymer films is studied through scanning electron microscopy, thermogravimetric analysis, and thermomechanical tests. Transport properties are estimated through sorption and pervaporation techniques toward methanol and methyl acetate mixture. The inclusion of endometallofullerene into the copolyimide matrix improves membrane permeability and selectivity in the separation of methanol—methyl acetate mixtures. The maximal effect is achieved with a composite containing 0.5 wt % Fe@C60. The developed composites are effective for energy and resource saving purification of methyl acetate by pervaporation.
Investigative Radiology, 2013
Objective: Macromolecular contrast agents for magnetic resonance imaging (MRI) are useful blood-pool agents because of their long systemic half-life and have found applications in monitoring tumor vasculature and angiogenesis. Macromolecular contrast agents have been able to overcome some of the disadvantages of the conventional small-molecule contrast agent Magnevist (gadolinium-diethylenetriaminepentaacetic acid), such as rapid extravasation and quick renal clearance, which limits the viable MRI time. There is an urgent need for new MRI contrast agents that increase the sensitivity of detection with a higher relaxivity, longer blood half-life, and reduced toxicity from free Gd 3+ ions. Here, we report on the characterization of a novel water-soluble, derivatized, gadolinium-enclosed metallofullerene nanoparticle (Hydrochalarone-1) in development as an MRI contrast agent. Materials and Methods: The physicochemical properties of Hydrochalarone-1 were characterized by dynamic light scattering (hydrodynamic diameter), atomic force microscopy (particle height), X potential analysis (surface charge), and inductively coupled plasma-mass spectrometry (gadolinium concentration). The blood compatibility of Hydrochalarone-1 was also assessed in vitro through analysis of hemolysis, platelet aggregation, and complement activation of human blood. In vitro relaxivities, in vivo pharmacokinetics, and a pilot in vivo acute toxicity study were also performed. Results: An extensive in vitro and in vivo characterization of Hydrochalarone-1 is described here. The hydrodynamic size of Hydrochalarone-1 was 5 to 7 nm depending on the dispersing media, and it was negatively charged at physiological pH. Hydrochalarone-1 showed compatibility with blood cells in vitro, and no significant hemolysis, platelet aggregation, or complement activation was observed in vitro. In addition, Hydrochalarone-1 had significantly higher r 1 and r 2 in vitro relaxivities in human plasma in comparison with Magnevist and was not toxic at the doses administered in an in vivo pilot acute-dose toxicity study in mice.
Paramagnetic water-soluble metallofullerenes having the highest relaxivity for MRI contrast agents
Bioconjugate chemistry
Water-soluble gadolinium (Gd) endohedral metallofullerenes have been synthesized as polyhydroxyl forms (Gd@C(82)(OH)(n)(), Gd-fullerenols) and their paramagnetic properties were evaluated by in vivo as well as in vitro for the novel magnetic resonance imaging (MRI) contrast agents for next generation. The in vitro water proton relaxivity, R(1) (the effect on 1/T(1)), of Gd-fullerenols is significantly higher (20-folds) than that of the commercial MRI contrast agent, Magnevist (gadolinium-diethylenetriaminepentaacetic acid, Gd-DTPA) at 1.0 T close to the common field of clinical MRI. This unusually high proton relaxivity of Gd-fullerenols leads to the highest signal enhancement at extremely lower Gd concentration in MRI studies. The strong signal was confirmed in vivo MRI at lung, liver, spleen, and kidney of CDF1 mice after i.v. administration of Gd-fullerenols at a dose of 5 micromol Gd/kg, which was 1/20 of the typical clinical dose (100 micromol Gd/kg) of Gd-DTPA.
Primer on gadolinium chemistry
Journal of Magnetic Resonance Imaging, 2009
Gadolinium is widely known by all practitioners of MRI but few appreciate the basic solution chemistry of this trivalent lanthanide ion. Given the recent linkage between gadolinium contrast agents and nephrogenic systemic fibrosis, some basic chemistry of this ion must be more widely understood. This short primer on gadolinium chemistry is intended to provide the reader the background principles necessary to understand the basics of chelation chemistry, water hydration numbers, and the differences between thermodynamic stability and kinetic stability or inertness. We illustrate the fundamental importance of kinetic dissociation rates in determining gadolinium toxicity in vivo by presenting new data for a novel europium DOTA-tetraamide complex that is relatively unstable thermodynamically yet extraordinarily inert kinetically and also quite nontoxic. This, plus other literature evidence forms the basis of the fundamental axiom that it is the kinetic stability of a gadolinium complex, not its thermodynamic stability, that determines its in vivo toxicity.
Structural insights on nanoparticles containing gadolinium complexes as potential theranostic
Colloid and Polymer Science, 2014
Nanostructures are gaining interest in drug release applications. Amphiphilic molecules can give, in water solution, a variety of nanostructures as well as thermodynamically stable mesophases three-dimensional inverse cubic structures. These mesophases are attractive candidates for biomedical applications containing extensive water channel networks and could act as very efficient delivery systems of drugs or contrast agents. In order to discover, optimize, and develop these systems, we have performed a deep physicochemical characterization by dynamic light scattering and small-angle neutron scattering of nanoparticles of monoolein (MO) and Pluronic PF127, containing different amounts (1, 5, 10, and 20 %) of the synthetic amphiphilic gadolinium complex (C18) 2 DTPA(Gd). Nanoparticle size is found in the 70-400 nm range for all investigated systems; the morphology of the aggregates is driven by the main constituents MO/PF127 and is a mixture of multilayer vesicles and bicontinuous aggregates. Nanostructures are also able to encapsulate doxorubicin (drug-loading content between 70 and 90 % for the different systems) acting as a potential theranostic for simultaneous cancer therapy and MRI visualization.
Organic Biomolecular Chemistry, 2011
A family of novel amphiphilic gadolinium chelates was successfully obtained by coupling the hydrophilic DOTA ligand [1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecane] to squalenoyl moieties. Thanks to the self-assembling properties of their squalenoyl lipophilic moieties, all these derivatives were able to form, without any adjuvant, micellar or liposome-like supramolecular nanoassemblies, endowed with high relaxivities (r 1 = 15-22 mM -1 s -1 at 20 MHz and 37 • C). The remarkably high payloads of Gd 3+ ions reached 10 to 17 wt %. Moreover, one of these derivatives interacted with human serum albumin (HSA) forming mixed micelles, which induced a remarkable increase in relaxivity. Liposome-like structures were obtained when the Gd 3+ complex of DOTA was coupled to two squalene units. These liposomal structures were characterized by a high loading of Gd 3+ (about 74 000 gadolinium ions per particle of 100 nm). The supramolecular architecture of these nano-objects has been investigated by electron microscopy and small-angle X-ray scattering. Squalenoylation of gadolinium derivatives offers a platform to conceive contrast agents (CAs) in mild conditions (no toxic solvents, no surfactants, no energy input). These new amphiphilic gadolinium chelates could also find potential applications in theranostics, by forming mixed systems with other squalenoylated drugs, or to delineate blood vessels owing to the interaction with HSA.
Relaxivity and Water Exchange Studies of a Cationic Macrocyclic Gadolinium(III) Complex
Chemistry, 2001
We conducted relaxometric and water exchange studies of the cationic [Gd((S,S,S,S)-THP)(H 2 O)] 3 complex (THP 1,4,7,10-tetrakis(2-hydroxypropyl)-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 17 O NMR investigations revealed a relatively high water exchange rate (k 298 ex 1.89 Â 10 7 s À1 ). These results dif-fer 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-(H 2 O)] 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 a-position with respect to the Gd III -bound O atoms of THP.
Diamagnetic Clusters of Paramagnetic Endometallofullerenes: A Solid-State MAS NMR Study
The Journal of Physical Chemistry B, 2004
Solid powder samples of complexes of the endometallofullerenes (EMF) La@C 82 and Y@C 82 with hexamethylphosphoramide (HMPA) were studied by magic-angle spinning (MAS) NMR. We have obtained well-resolved 31 P NMR spectra and 13 C NMR spectra for both La-EMF/HMPA and Y-EMF/HMPA and 139 La spectra for the La-EMF/HMPA. The 31 P measurements on La-EMF/HMPA and Y-EMF/HMPA have revealed considerable chemical shifts of 31 P signals relative to pure HMPA. Two-dimensional exchange 31 P experiments revealed that HMPA molecules at different sites in the EMF/HMPA complex do not change positions at a time scale of up to 1 s. Both EMF samples demonstrate a vast chemical shift range for 31 P of the bound HMPA molecules. In addition, the La-EMF/HMPA exhibits the enormous spreading of the chemical shifts for 139 La. The experimental results suggest that paramagnetic La@C 82 and Y@C 82 in the solid state form clusters (nanoparticles) in which the exchange coupling of the EMF takes place with quenching of the most electron spins.