Gd@C82(OH)16的合成及其核磁共振成像

采用电弧放电法合成和HPLC 2步分离法,得到了纯度为95％以上的Gd@C82。以四丁基氢氧化铵(TBAH)为催化剂,用NaOH溶液对Gd@C82进行羟基衍生化,并利用同步辐射XPS分析其C(12)确定Gd@C82羟基化产物的羟基数,得到水溶性的Gd@C82(OH)16。对Gd@C82(OH)16进行了体外弛豫率及体内的核磁共振成像研究。结果表明,与(NMG)2-Gd-DTPA相比,在相同Gd浓度下,Gd@C82(OH)16的质子弛豫率R1提高约3倍,R2提高约7倍。体内核磁成像结果也显示,Gd@C82(OH)16提高了核磁成像对比的效果,其信号在2 h内维持稳定。说明Gd@C82(OH)16在作为磁共振增强剂方面具有较大的潜力。     

Rapid analysis technique for strontium,thorium, and uranium in urine samples

The electronic properties of the metal atoms encaged in a fullerence cage were investigated using synchrotron X-ray photoelectron spectroscopy. Systematic variations in photoemission of valence band of Gd@C₈₂, Gd@C₈₂(OH)₁₂, and Gd@C₈₂(OH)₂₂ were observed in Gd 5p levels. The results suggest that the electronic properties of the inner metal atom can be efficiently modulated by surface chemistry of the fullerene cage.     

Quantitative analysis of Gd@C<Subscript>82</Subscript>(OH)<Subscript>22</Subscript> and cisplatin uptake in single cells by inductively coupled plasma mass spectrometry

Cisplatin is a commonly used chemotherapeutic drug in cancer treatment, whereas Gd@C₈₂(OH)₂₂ is a new nanomaterial anti-tumor agent. In this study, we determined intracellular Gd@C₈₂(OH)₂₂ and cisplatin after treatment of Hela and 16HBE cells by single cell inductively coupled plasma-mass spectrometry (SC-ICP-MS), which could provide quantitative information at a single-cell level. The cell digestion method validated the accuracy of the SC-ICP-MS. The concentrations of Gd@C₈₂(OH)₂₂ and cisplatin in cells at different exposure times and doses were studied. The SC-ICP-MS is a promising complement to available methods for single cell analysis and is anticipated to be applied further to biomedical research.

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Graphical Abstract The quantitative results of Gd@C₈₂(OH)₂₂ in single cells determined by SC-ICP-MS and acid digestion method, respectively

     

Metallofullerenol Inhibits Cellular Iron Uptake by Inducing Transferrin Tetramerization

Herein, A549 tumor cell proliferation was confirmed to be positively dependent on the concentration of Fe³⁺ or transferrin (Tf). Gd@C₈₂(OH)₂₂ or C₆₀(OH)₂₂ effectively inhibited the iron uptake and the subsequent proliferation of A549 cells. The conformational changes of Tf mixed with FeCl₃, GdCl₃, C₆₀(OH)₂₂ or Gd@C₈₂(OH)₂₂ were obtained by SAXS. The results demonstrate that Tf homodimers can be decomposed into monomers in the presence of FeCl₃, GdCl₃ or C₆₀(OH)₂₂, but associated into tetramers in the presence of Gd@C₈₂(OH)₂₂. The larger change of SAXS shapes between Tf+C₆₀(OH)₂₂ and Tf+FeCl₃ implies that C₆₀(OH)₂₂ is bound to Tf, blocking the iron‐binding site. The larger deviation of the SAXS shape from a possible crystal structure of Tf tetramer implies that Gd@C₈₂(OH)₂₂ is bound to the Tf tetramer, thus disturbing iron transport. This study well explains the inhibition mechanism of Gd@C₈₂(OH)₂₂ and C₆₀(OH)₂₂ on the iron uptake and the proliferation of A549 tumor cells and highlights the specific interactions of a nanomedicine with the target biomolecules in cancer therapy.     

Voltammetric Behavior of Water‐Soluble Endohedral Metallofullerene Derivatives

Voltammetric behavior of water‐soluble endohedral metallofullerene derivatives Gd@C₈₂(OH)₅(NHCH₂COOH)₉ (GN) and Gd@C₈₂(OH)₆(NHCH₂CH₂SO₃H)₈ (GS) was characterized in 0.1 M KCl solution by CV and DPV. They showed similar redox behavior, that is, a reversible electroreduction process on HMDE was found; in the mean time, an irreversible oxidation process and an irreversible reduction process on GC electrodes were also observed. The results reveal that these two water‐soluble endohedral metallofullerene derivatives have good electron donating ability and poor electron accepting ability due to hydroxy groups, aminoacetic acid and aminoethyl sulfonic acid connected to the C₈₂ cage in comparison with Gd@C₈₂.     

Theoretical and Quantitative Structural Relationship Studies of Electrochemical Properties of the Nanostructures of Cis-Unsaturated Thiocrown Ethers and Their Supramolecular Complexes [X-UT-Y][M@C82] (M˭Ce,Gd)

The endohedral lanthanidofullerenes, an important type of organolanthanides, are stabilized by the delocalization of the negative charges on the cages of fullerenes. Since the discovery of these classes of carbon compounds and their unusual structures and properties of these molecules, many potential applications have been suggested. Unsaturated thiocrown ethers with cis-geometry are a group of crown ethers that, in light of the size of their cavities and their conformational restriction compared to a corresponding saturated system (1–9), demonstrate interesting properties for physicochemical studies. Endohedral lanthanidofullerenes M@C_x (x = 82 and M = Ce, Gd) were introduced as a new class of the spherical fullerene group with unique properties. Formation of endohedral metallofullerenes is thought to involve the transfer of electrons from the encapsulated metal atom(s) to the surrounding fullerene cage. Two of these molecules are the Ce@C₈₂ (10) and Gd@C₈₂ (11). The supramolecular complexes of 1–9 with Ce@C₈₂ (10) and Gd@C₈₂ (11) have been shown to possess a host–guest interaction for electron transfer processes, and these behaviors have previously been reported. Topological indices have been successfully used to construct effective and useful mathematical methods for finding good relationships between structural data and the various chemical and physical properties. To establish a good structural relationship between the structures of 1–9 and M@C_x that were introduced here, an index that is represented as μ_cs was utilized. This index is the ratio of summation of the number of carbon atoms (n_c ) and the number of sulfur atoms (n_s ) to the product of these two numbers for 1–9. In this study, the relationship between this index and oxidation potential ( ^oxE₁ ) of 1–9, as well as the free energy of electron transfer (ΔG_et , by the Rehm-Weller equation) between 1–9 and 10 and 11 as [X-UT-Y][Ce@C₈₂] (12) and [X-UT-Y][Gd@C₈₂] (13) complexes, is presented.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

Size‐Selective Complexation and Extraction of Endohedral Metallofullerenes with Cycloparaphenylene

A new strategy for the non‐chromatographic extraction of metallofullerenes from solutions of arc‐processed raw soot is based on the size‐selective complexation with cycloparaphenylene (CPP). [11]CPP has a high affinity for M_x@C₈₂ (x=1, 2); for example, Gd@C₈₂ can be selectively extracted from a fullerene mixture by the addition of [11]CPP. This approach should open new opportunities in metallofullerene chemistry, including for the bulk extraction of metallofullerenes.     

Diblock‐Copolymer‐Mediated Self‐Assembly of Protein‐Stabilized Iron Oxide Nanoparticle Clusters for Magnetic Resonance Imaging

Superparamagnetic iron oxide nanoparticles (SPIONs) can be used as efficient transverse relaxivity (T₂) contrast agents in magnetic resonance imaging (MRI). Organizing small (D<10 nm) SPIONs into large assemblies can considerably enhance their relaxivity. However, this assembly process is difficult to control and can easily result in unwanted aggregation and precipitation, which might further lead to lower contrast agent performance. Herein, we present highly stable protein–polymer double‐stabilized SPIONs for improving contrast in MRI. We used a cationic–neutral double hydrophilic poly(N‐methyl‐2‐vinyl pyridinium iodide‐block‐poly(ethylene oxide) diblock copolymer (P2QVP‐b‐PEO) to mediate the self‐assembly of protein‐cage‐encapsulated iron oxide (γ‐Fe₂O₃) nanoparticles (magnetoferritin) into stable PEO‐coated clusters. This approach relies on electrostatic interactions between the cationic N‐methyl‐2‐vinylpyridinium iodide block and magnetoferritin protein cage surface (pI≈4.5) to form a dense core, whereas the neutral ethylene oxide block provides a stabilizing biocompatible shell. Formation of the complexes was studied in aqueous solvent medium with dynamic light scattering (DLS) and cryogenic transmission electron microcopy (cryo‐TEM). DLS results indicated that the hydrodynamic diameter (D_h) of the clusters is approximately 200 nm, and cryo‐TEM showed that the clusters have an anisotropic stringlike morphology. MRI studies showed that in the clusters the longitudinal relaxivity (r₁) is decreased and the transverse relaxivity (r₂) is increased relative to free magnetoferritin (MF), thus indicating that clusters can provide considerable contrast enhancement.     

Visible and near-IR spectroscopy of endohedral Gd@C82(C 2v ) and Ho@C82(C 2v ) metallofullerenes and their monoanions

Solutions of endohedral Gd@C₈₂(C _2v ) and Ho@C₈₂(C _2v ) metallofullerenes are studied by means of visible and near-IR spectroscopy upon their conversion from neutral to the anionic form via a redox reaction with the electron donor potassium perchlorotriphenylmethide K(18-crown-6)[C(C₆Cl₅)₃]. The concentrations of the studied solutions of endohedral Gd@C₈₂(C _2v ) and Ho@C₈₂(C _2v ) metallofullerenes in o-dichlorobenzene were determined from the spectroscopic data, and their molar extinction coefficients are calculated.

     

Electrochemical properties of Gd@C82 and its anions

Cyclic voltammogram (CV) and differential pulse voltammogram (DPV) of Gd@C₈₂ were measured by using mixed solvent system and low temperature. The sixth and seventh electron transfers for Gd@C₈₂ were observed under this condition. Analysis of its electrochemical data and the changes of its UV–VIS–NIR spectrum indicated that Gd@C₈₂(n−) (n=1,3) anions had been generated by chemical method.     

Platinum(II)–Gadolinium(III) Complexes as Potential Single‐Molecular Theranostic Agents for Cancer Treatment

Theranostic agents are emerging multifunctional molecules capable of simultaneous therapy and diagnosis of diseases. We found that platinum(II)–gadolinium(III) complexes with the formula [{Pt(NH₃)₂Cl}₂GdL](NO₃)₂ possess such properties. The Gd center is stable in solution and the cytoplasm, whereas the Pt centers undergo ligand substitution in cancer cells. The Pt units interact with DNA and significantly promote the cellular uptake of Gd complexes. The cytotoxicity of the Pt–Gd complexes is comparable to that of cisplatin at high concentrations (≥0.1 mM ), and their proton relaxivity is higher than that of the commercial magnetic resonance imaging (MRI) contrast agent Gd–DTPA. T₁‐weighted MRI on B6 mice demonstrated that these complexes can reveal the accumulation of platinum drugs in vivo. Their cytotoxicity and imaging capabilities make the Pt–Gd complexes promising theranostic agents for cancer treatment.     

Acid-catalyzed proton exchange as a novel approach for relaxivity enhancement in Gd-HPDO3A-like complexes

A current challenge in medical diagnostics is how to obtain high MRI relaxation enhancement using Gd^III-based contrast agents (CAs) containing the minimum concentration of Gd^III ions. We report that in GdHPDO3A-like complexes a primary amide group located in close proximity to the coordinated hydroxyl group can provide a strong relaxivity enhancement at slightly acidic pH. A maximum relaxivity of r₁ = 9.8 mM⁻¹ s⁻¹ (20 MHz, 298 K) at acidic pH was achieved, which is more than double that of clinically approved MRI contrast agents under identical conditions. This effect was found to strongly depend on the number of amide protons, i.e. it decreases with a secondary amide group and almost completely vanishes with a tertiary amide. This relaxivity enhancement is attributed to an acid-catalyzed proton exchange process between the metal-coordinated OH group, the amide protons and second sphere water molecules. The mechanism and kinetics of the corresponding H⁺ assisted exchange process are discussed in detail and a novel simultaneous double-site proton exchange mechanism is proposed. Furthermore, ¹H and ¹⁷O NMR relaxometry, Chemical Exchange Saturation Transfer (CEST) on the corresponding Eu^III complexes, and thermodynamic and kinetic studies are reported. These highlight the optimal physico-chemical properties required to achieve high relaxivity with this series of Gd^III-complexes. Thus, proton exchange provides an important opportunity to enhance the relaxivity of contrast agents, providing that labile protons close to the paramagnetic center can contribute.

A novel GdHPDO3A-like complex featuring primary amide side chain induces extraordinary high relaxivity by virtue of a simultaneous double-site proton exchange mechanism under slight acidic conditions.     

Synthesis,Water Adsorption,and Proton Conductivity of Solid‐Solution‐Type Metal–Organic Frameworks Al(OH)(bdc‐OH)x(bdc‐NH2)1−x

Mixed‐ligand metal–organic frameworks Al(bdc‐OH)_x(bdc‐NH₂)_1?x (H₂bdc‐NH₂=aminoterepthalic acid, H₂bdc‐OH=hydroxyterephthalic acid) were synthesized and their water adsorption behavior and proton conductivity were investigated. All obtained compounds were isostructural to MIL‐53 (MIL=Materials of Institut Lavoisier) according to XRD measurements under ambient humidity conditions, and were also found to be single phase across the whole mixing ratio from the XRD measurements under humidified conditions. This result clearly shows that all compounds are a solid‐solution‐type mixture of ligands. MIL‐53‐NH₂ adsorbs one water molecule per formula with humidification whereas MIL‐53‐OH adsorbs five water molecules. The mixing ratio of the ligands in Al(OH)(bdc‐OH)_x(bdc‐NH₂)_1?x affected the gate‐opening pressure for water adsorption and total water uptake. Proton conductivity of these compounds largely depends on the adsorbed amount of water, which indicates that the proton conductivity of these compounds depends strongly on the hydrogen‐bond network of the conducting media.     

Novel radical‐responsive MRI contrast agent based on paramagnetic liposomes

A novel, radical responsive MRI contrast agent based on a gadolinium chelate conjugated to a liposome through a disulfide linker was synthesized, with the aim of pursuing the in vivo mapping of radicals. The liposome was prepared by incorporating a thiol‐activated phospholipid, which was subsequently reacted with a gadolinium chelate containing a free thiol group. The long reorientational motion of the supramolecular adduct endows the paramagnetic agent with a relaxivity significantly higher than that of the free complex. The disulfide bond represents a radical‐sensitive moiety and a large decrease in contrast efficacy (T₁ relaxivity) is shown upon its cleavage. A preliminary assessment of the system was made by means of in vitro gamma‐irradiation and thiol–disulfide bond exchange with dithiothreitol. Both methods showed a clear dose‐dependent decrease in T₁‐relaxivity. Copyright © 2003 John Wiley & Sons, Ltd.     

The strong MRI relaxivity of paramagnetic nanoparticles

We developed a method to synthesize paramagnetic nanoparticles of Gd@C82(OH)22+/-2. Such nanoparticles are with ordered microstructures and have strong MRI proton relaxation in vitro/vivo. Compared with commercial Gd-DTPA, a 12x MRI relaxivity of Gd@C82(OH)22+/-2 nanoparticles with ordered microstructures was achieved in vitro. The small Gd@C82(OH)22+/-2 nanoparticles, approximately 65nm, could easily escape the RES uptake in vivo; this opens the door for their clinical applications.     

Synthesis and Characterization of a Hypoxia‐Sensitive MRI Probe

Tissue hypoxia occurs in pathologic conditions, such as cancer, ischemic heart disease and stroke when oxygen demand is greater than oxygen supply. An imaging method that can differentiate hypoxic versus normoxic tissue could have an immediate impact on therapy choices. In this work, the gadolinium(III) complex of 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) with a 2‐nitroimidazole attached to one carboxyl group via an amide linkage was prepared, characterized and tested as a hypoxia‐sensitive MRI agent. A control complex, Gd(DO3A‐monobutylamide), was also prepared in order to test whether the nitroimidazole side‐chain alters either the water proton T₁ relaxivity or the thermodynamic stability of the complex. The stabilities of these complexes were lower than that of Gd(DOTA)^? as expected for mono‐amide derivatives. The water proton T₁ relaxivity (r₁), bound water residence lifetime (τ_M) and rotational correlation time (τ_R) of both complexes was determined by relaxivity measurements, variable temperature ¹⁷O NMR spectroscopy and proton nuclear magnetic relaxation dispersion (NMRD) studies. The resulting parameters (r₁=6.38 mM ^?1 s^?1 at 20 MHz , τ_M=0.71 μs, τ_R=141 ps) determined for the nitroimidazole derivative closely parallel to those of other Gd(DO3A‐monoamide) complexes of similar molecular size. In vitro MR imaging experiments with 9L rat glioma cells maintained under nitrogen (hypoxic) versus oxygen (normoxic) gas showed that both agents enter cells but only the nitroimidazole derivative was trapped in cells maintained under N₂ as evidenced by an approximately twofold decrease in T₁ measured for hypoxic cells versus normoxic cells exposed to this agent. These results suggest that the nitroimidazole derivative might serve as a molecular reporter for discriminating hypoxic versus normoxic tissues by MRI.     

A conjugated polymer-Gd (III) complex as pH sensitive contrast agent in magnetic resonance imaging

A novel pH-responsive contrast agent (PFP-aa/Gd) for magnetic resonance imaging (MRI) was prepared by binding Gd(III) to a water-soluble conjugated polyfluorene with pendant carboxylate and amine moieties. The PFP-aa is a good chelator for Gd³⁺ and the PFP-aa/Gd complex has good stability. As the pH changes from 10.0 to 4.0, both the carboxylate and amine are protonated, thus PFP-aa exhibits positive charges and forms tight aggregation, which reduces molecular tumbling and accelerates the exchange of bound water leading to the increase of relaxivity R ₁. More importantly, the R ₁ increases by about eight fold as the pH changes from 8.0 to 6.0, which makes PFP-aa/Gd suitable as a potential marker of the pH below physiological level. In comparison to other contrast agents, the unique sensitivity of the water relaxivity of PFP-aa/Gd indicates that this complex could be used in MRI experiments to monitor physiological pH change.     

Structure of the Au23−xAgx(S‐Adm)15 Nanocluster and Its Application for Photocatalytic Degradation of Organic Pollutants

Ligands play an important role in determining the atomic arrangement within the metal nanoclusters. Here, we report a new nanocluster [Au_23?xAg_x(S‐Adm)₁₅] protected by bulky adamantanethiol ligands which was obtained through a one‐pot synthesis. The total structure of [Au_23?xAg_x(S‐Adm)₁₅] comprises an Au_13?xAg_x icosahedral core, three Au₃(SR)₄ units, and one AgS₃ staple motif in contrast to the 15‐atom bipyramidal core previously seen in [Au_23?xAg_x(SR)₁₆]. UV/Vis spectroscopy indicates that the HOMO–LUMO gap of [Au_23?xAg_x(S‐Adm)₁₅] is 1.5 eV. DFT calculations reveal that [Au₁₉Ag₄(S‐Adm)₁₅] is the most stable structure among all structural possibilities. Benefitting from Ag doping, [Au_23?xAg_x(S‐Adm)₁₅] exhibits drastically improved photocatalytic activity for the degradation of rhodamine B (RhB) and phenol under visible‐light irradiation compared to Au₂₃ nanoclusters.     

Supramolecular adducts between macrocyclic Gd(iii) complexes and polyaromatic systems: a route to enhance the relaxivity through the formation of hydrophobic interactions

The set-up of reversible binding interactions between the hydrophobic region of macrocyclic GBCAs (Gadolinium Based Contrast Agents) and SO₃⁻/OH containing pyrene derivatives provides new insights for pursuing relaxivity enhancements of this class of MRI contrast agents. The strong binding affinity allows attaining relaxation enhancements up to 50% at pyrene/GBCA ratios of 3 : 1. High resolution NMR spectra of the Yb-HPDO3A/pyrene system fully support the formation of a supramolecular adduct based on the set-up of hydrophobic interactions. The relaxation enhancement may be accounted for in terms of the increase of the molecular reorientation time (τ_R) and the number of second sphere water molecules. This effect is maintained in blood serum and in vivo, as shown by the enhancement of contrast in T_1w-MR images obtained by simultaneous injection of GBCA and pyrene derivatives in mice.

The set-up of reversible binding interactions between the hydrophobic region of macrocyclic gadolinium based contrast agents and SO₃⁻/OH containing pyrene derivatives provides new insights for pursuing relaxivity enhancement of MRI contrast agents.     

Multifunctional Nanoprobe for MRI/Optical Dual‐Modality Imaging and Radical Scavenging

The development of novel nanomaterials for the diagnosis and/or treatment of human diseases has become an important issue. In this work, a multifunctional theranostic agent was designed by covalently binding hydroxyl‐ and amino‐bearing C₆₀ derivatives (C₆₀O_～10(OH)_～16(NH₂)_～6(NO₂)_～6 ? 24 H₂O) with gadolinium diethylenetriaminepentaacetic acid (Gd‐DTPA) to yield C₆₀O_～10(OH)_～16(NH₂)_～6(NO₂)_～6 ? 24 H₂O/(Gd‐DTPA)₃ ( DF₁Gd₃ ). The obtained DF₁Gd₃ shows more than fourfold contrast improvement over commercial Gd‐DTPA along with multiwavelength fluorescent emission for dual‐modality diagnosis. An inner‐ear magnetic resonance imaging (MRI) study was designed as a model of biological barriers, including the blood/brain barrier (BBB) for DF₁Gd₃ to investigate its in vivo behavior. This revealed that the fabricated contrast agent dramatically increases the local contrast but can not cross the middle ear/inner ear barrier and endolymph/perilymph barrier in the inner ear, and thus it is also BBB‐prohibited in normal individuals. In vivo biodistribution studies suggested that 1) DF₁Gd₃ could circulate in vessels for a relatively long time and is mainly eliminated through liver and kidney, 2) DF₁Gd₃ may potentially function as a liver‐specific MRI contrast agent. Interestingly, DF₁Gd₃ also shows an excellent quenching effect on hydroxyl radicals, as revealed by the DMPO spin trap/ESR method. The combination of enhanced MRI/FL imaging and local treatment of lesions is unique to DF₁Gd₃ and potentiates the medical paradigm of “detect and treat/prevent” in combating human diseases related to reactive oxygen.