Christos Apostolidis

Magnetic Memory Effect in a Transuranic Mononuclear Complex

Molecular nanomagnets that display magnetic bistability are the subject of intensive investigation due to their unique potential in ultrahigh-density memory components and spintronic devices. So far, the best practical realization of such single-molecule magnets (SMMs) are polymetallic transition-metal complexes with strong intramolecular exchange coupling, giving rise to a high-spin ground state and negligible intercluster interactions. However, 3d metals are restricted by their comparatively low anisotropy, and SMMs with better performance could be produced by exploiting the higher single-ion anisotropy typical of felectron ions. This possibility has been practically demonstrated by Ishikawa et al., who discovered that mononuclear rare earth metal bis-phthalocyanine compounds (Pc2RE) display magnetic hysteresis under favorable conditions. On these grounds, the use of actinides in molecular magnetism appears timely, and indeed slow relaxation effects have recently been reported in a mononuclear uranium-based molecule. Future SMMs displaying magnetic hysteresis could benefit from the fact that, whilst the 5f electron shell can remain relatively well localized, its larger radial extension with respect to the 4f shell can result both in an increased ligand-field potential (and therefore a higher anisotropy energy barrier) and in the possibility to trigger a sizeable exchange coupling in polynuclear complexes, usually precluded to trivalent rare earth metal ions. Moreover, discrete molecules based on 5f ions should allow much greater understanding of the peculiar behavior observed in actinide materials, including multipolar superexchange coupling. Recently, we obtained evidence that a neptunium trimetallic compound displays slow magnetic relaxation and superexchange interaction; nevertheless, we were unable to find any signs of hysteresis in the measured magnetization curves. Here we report the first observation of such low-temperature magnetic memory effects in another transuranic molecular complex, namely, bis(cyclooctatetraenyl)neptunium(IV), commonly known as neptunocene [Np(COT)2] (COT= C8H8 2 ), which was first described in 1970 and belongs to the whole actinocene row. The molecule has a single Np ion between two planar COT rings in a sandwich structure (Figure 1) with D8h symmetry. [9] The degeneracy of the lowest

Preparation and characterization of the first triscyclopentadienyl lanthanoid complexes containing two aliphatic nitrile ligands: Crystal and molecular structures of the isomorphous compounds Trans-bis(acetonitrile)tris(η5cyclopentadienyl)lanthanoid(III) (Ln = La, Ce, Pr). A successful confirmation of the solid ‘solid angle sum rule’

Abstract Systematic studies to arrive at some first examples of the sterically congested complex type Cp3Ln(NCR)2 (Cp = η5-C5H5, Ln = lanthanoid element) resulted in the preparation and detailed spectroscopic characterization of analytically pure representatives of this type with Ln = La, Ce and Pr, but not with Nd (R = CH3, and C2H5 for Ln = La only). The crystal and molecular structures of representatives of the isomorphous series Cp3Ln(NCCH3)2, (Ln = La, Ce, Pr) were determined from three-dimensional X-ray diffraction data. The compounds crystallize in the orthorhombic space group Pnca (standard group Pbcn) with: a = 14.940(3), b = 14.074(3), c = 8.596(2)A, Z = 4, R = 0.070, Rw = 0.079 for 1633 intensity data (La derivative, I); a = 14.906(3), b = 13.974(3), c = 8.502(2)A, R = 0.041, Rw = 0.047 for 1378 intensity data (Ce derivative, VII); a = 14.936(3), b = 13.986(3), c = 8.498(2)A, R = 0.031 for 1372 intensity data (Pr derivative, IX). According to the X-ray crystallographic results, the novel complexes are trigonal bipyramidally coordinated with three η5-bonded Cp rings in the equatorial plane (Ln—ring centre distances 2.62, 2.64 for La, 2.58, 2.59Afor Ce and 2.57, 2.57Afor Pr and two acetonitrile groups in the axial positions (Ln N 2.785 for La, 2.749 for Ce, 2.752 for Pr). The range of the distances in the three derivatives is in agreement with the trend in the crystal radii along the lanthanoid series. Pure 1:2 adducts involving any alkyl group larger than R = C2H5 could not be isolated. The relative stabilities of the novel Cp3Ln(NCR)2 systems, with respect to the decreasing ionic radius (i.e. from La to Nd) and to the variable space demanded by the group R, are in excellent accord with independent expectations based on the recently developed cone packing model (‘SAS-rule’) for f-element organometallics.

Targeted Killing of Virally Infected Cells by Radiolabeled Antibodies to Viral Proteins

Background The HIV epidemic is a major threat to health in the developing and western worlds. A modality that targets and kills HIV-1-infected cells could have a major impact on the treatment of acute exposure and the elimination of persistent reservoirs of infected cells. The aim of this proof-of-principle study was to demonstrate the efficacy of a therapeutic strategy of targeting and eliminating HIV-1-infected cells with radiolabeled antibodies specific to viral proteins in vitro and in vivo. Methods and Findings Antibodies to HIV-1 envelope glycoproteins gp120 and gp41 labeled with radioisotopes bismuth 213 (213Bi) and rhenium 188 (188Re) selectively killed chronically HIV-1-infected human T cells and acutely HIV-1-infected human peripheral blood mononuclear cells (hPBMCs) in vitro. Treatment of severe combined immunodeficiency (SCID) mice harboring HIV-1-infected hPBMCs in their spleens with a 213Bi- or 188Re-labeled monoclonal antibody (mAb) to gp41 resulted in a 57% injected dose per gram uptake of radiolabeled mAb in the infected spleens and in a greater than 99% elimination of HIV-1-infected cells in a dose-dependent manner. The number of HIV-1-infected thymocytes decreased 2.5-fold in the human thymic implant grafts of SCID mice treated with the 188Re-labeled antibody to gp41 compared with those treated with the 188Re-control mAb. The treatment did not cause acute hematologic toxicity in the treated mice. Conclusions The current study demonstrates the effectiveness of HIV-targeted radioimmunotherapy and may provide a novel treatment option in combination with highly active antiretroviral therapy for the eradication of HIV.

Interim analysis of toxicity and response in phase 1 trial of systemic targeted alpha therapy for metastatic melanoma

Purpose. The aim is to assess toxicity and response of systemic alpha therapy for metastatic melanoma. Experimental design. This is an open-labelled Phase 1 dose escalation study to establish the effective dose of the alpha-immunoconjugate 213Bi-cDTPA-9.2.27 mAb (AIC). Tools used to investigate the effects were physical examination; imaging of tumours; pathology; GFR; CT and changes in tumour marker. Responses were assessed using RECIST criteria. Results and Discussion. 22 patients with stage IV melanoma/ in-transit metastasis were treated with activities of 55-947 MBq. Using RECIST criteria 50% showed stable disease and 14% showed partial response. One patient (6%) showed near complete response and was retreated because of an excellent response to the initial treatment. Another patient showed response in his tumour on mandible and reduction in lung lesions. Overall 30% showed progressive disease. The tumour marker melanoma inhibitory activity protein (MIA) showed reductions over 8 weeks in most of the patients. The disparity of dose with responders is discussed. No toxicity was observed over the range of administered activities. Conclusion. Observation of responses without any toxicity indicates that targeted alpha therapy has the potential to be a safe and effective therapeutic approach for metastatic melanoma.

An Improved Method for the Production of Ac‐225/Bi‐213 from Th‐229 for Targeted Alpha Therapy

Abstract This work describes an improved method for radium/actinium separation as part of a process for the production of Ac‐225 from a Th‐229 source for targeted alpha therapy of cancer. The separation method is based on the use of a newly developed extraction chromatographic resin containing the diglycolamide (DGA) class of molecules. The weight distribution ratios of Ac(III) on the extraction chromatographic resins N,N,N′N′ tetraoctyldiglycolamide (TODGA) and N,N,N′N′ tetrakis‐2‐ethylhexyldiglycolamide (TEHDGA) (both Eichrom Inc.) were determined at varying nitric and hydrochloric acid concentrations by batch experiments to optimize conditions for the separation of Ac(III) from Ra(II). Consequently, a robust and rapid procedure based on the use of TEHDGA resin was developed yielding a carrier‐free, clinical‐grade Ac‐225 with an overall yield exceeding 98%.

Spectroscopic study of the interaction of U(VI) with transferrin and albumin for speciation of U(VI) under blood serum conditions

The quantitative description of the interactions of uranium with blood serum components is of high relevance for a rational design of molecules suitable for in vivo chelation of uranium. We have determined the stability constants for the complexation of U(VI) with human serum transferrin and albumin by time-resolved laser-induced fluorescence spectroscopy and difference ultraviolet spectroscopy. Both proteins interact strongly with U(VI), forming ternary complexes with carbonate acting as a synergistic anion. Together with literature data describing the interaction of U(VI) with low molecular weight inorganic and organic serum components, the speciation of U(VI) in blood serum was calculated. In agreement with published experimental data, the model calculation shows that complexation with proteins and carbonate ion governs U(VI) speciation; 35% of U(VI) is bound to proteins and 65% to carbonate. Among the protein pool, albumin is the main protein interacting with U(VI). In addition, the results show that Ca(II) must be considered in the model as a competitive metal ion with respect to U(VI) for binding to albumin surface sites. Based on these findings several promising molecules for in vivo chelation of (230)U could be identified.

Analysis of patient survival in a Phase I trial of systemic targeted α-therapy for metastatic melanoma.

Targeted α-therapy is an experimental approach to the management of cancer. Short range α-particle radiation from a radioisotope attached to a targeting monoclonal antibody kills targeted cancer cells. Survival results are analyzed from a previously reported Phase I study of systemic targeted α-therapy for patients with stage IV metastatic melanoma or in-transit metastases. Following intravenous administration of 46-925 MBq of the α-immunoconjugate, (213)Bi-cDTPA-9.2.27, 38 patients were followed to observe response and toxicity. Responses were measured by physical examination, computed tomography at 8 weeks and blood sampling. Toxicity was monitored by blood pathology, urine analysis, glomerular filtration rate and human antimouse antibody response. The maximum tolerance dose was not achieved as there were no adverse events of any type or level. However, an objective partial response rate of 10% was observed, with 40% stable disease at 8 weeks and a median survival of 8.9 months. These results were unexpected because of the short half-life of the (213)Bi and short range of the α-radiation. Survival analysis demonstrated melanoma-inhibitory activity, disease stage, lactate dehydrogenase and treatment effects to be significant prognostic indicators for survival.

Metallorganische Chemie des Technetiums: VIII. Technetium(I)-carbonyl-Komplexe mit Polypyrazol-1-yl-borato-Liganden im Vergleich mit seinen Mn- und Re-Homologen

Abstract The compounds HB(C3H3N2)3Tc(CO)3 and HB(3,5-Me2C3HN2)3Tc(CO)3 have been synthesized for the first time, and their molecular and crystal structure as well as the structures of the known analogous compounds of manganese and rhenium determined by single-crystal X-ray diffraction. The IR-, 1H-NMR-, 13C-NMR-, UV- and EI-MS-spectroscopic data are discussed in correlation to the electric dipole moment and the charge distribution within the molecule.

Synthesis of bimetallic uranium and neptunium complexes of a binucleating macrocycle and determination of the solid-state structure by magnetic analysis.

Syntheses of the bimetallic uranium(III) and neptunium(III) complexes [(UI)(2)(L)], [(NpI)(2)(L)], and [{U(BH(4))}(2)(L)] of the Schiff-base pyrrole macrocycles L are described. In the absence of single-crystal structural data, fitting of the variable-temperature solid-state magnetic data allows the prediction of polymeric structures for these compounds in the solid state.

Non‐aqueous Synthesis of Isotropic and Anisotropic Actinide Oxide Nanocrystals

The huge interest of the scientific community in the controlled synthesis, structural characterization and assembly into 2and 3-dimensional architectures of nano-objects as well as investigations of their corresponding chemical and physical properties cannot be denied anymore. Within the past two decades, it has been shown that size reduction means more than simply making things smaller. Indeed, size decreasing (as well as shape controlling) is a powerful way to tune materials properties (magnetic, electronic, optical, catalytic, etc.). Whereas nanoscience is a very active field when one considers stable elements, it is still in its infancy when dealing with radioactive actinides. Actinide compounds are important in the nuclear industry and actinide-based nano-objects could be used as new building blocks for the preparation of innovative nuclear fuels or as model systems to study the migration of radionuclides in the environment (e.g., in nuclear waste disposal). The actinide series is also characterized by the emergence of 5f electrons in the valence shell. The behaviour of the 5f electrons determines the solid-sate properties of the actinides and their compounds. Compared to the stable elements, questions related to size and shape effects on the physical and chemical properties of actinide compounds are still open and should find their way into the nanoscience. Accordingly, our main goal is dedicated to the controlled synthesis, the structural characterization and the investigation of the properties of actinide-based nano-objects. Here, we report on the controlled synthesis of uranium oxide and thorium oxide nanocrystals (NCs) by a non-aqueous approach. The obtained NCs have been characterized by powder X-ray diffraction (PXRD), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR). The results of this study therefore present an important step for moving to the preparation of transuranium oxide NCs (e.g., NpO2, PuO2). Uranium and thorium oxide NCs were synthesized by the so-called “heating-up” method by using standard air-free techniques. Uranyl acetylacetonate (UO2ACHTUNGTRENNUNG(acac)2) or thorium acetylacetonate (ThACHTUNGTRENNUNG(acac)4) are introduced in a degassed mixture of dibenzyl ether (BnOBn) with different concentrations of stabilizing agents, like oleic acid (OA), oleylACHTUNGTRENNUNGamine (OAm), trioctylamine (N ACHTUNGTRENNUNG(Oct)3) and trioctylphosphine oxide (OP ACHTUNGTRENNUNG(Oct)3). The resulting mixtures are then heated up to 280 8C. After being cooled to room temperature, the NCs are precipitated with ethanol followed by centrifugation and re-dispersion in toluene. Surprisingly, the experimental conditions well-suited for the formation of uranium oxide NCs cannot be applied when considering the formation of thorium oxide NCs. The modification of the reactivity (for a given organic system) as a function of the nature of the actinide precursor and/or the actinide centre seems to be essential when taking into account the synthesis of actinide oxide NCs. Because of these differences in the reactivity of uranium and thorium precursors, different solvent compositions were tested in order to find the best reaction conditions to obtain well defined NCs. A black precipitate can be isolated from the reaction of UO2ACHTUNGTRENNUNG(acac)2 in a mixture of BnOBn/OA/OAm. The PXRD data of the as-prepared compound along with the corresponding Rietveld refinement are presented in Figure 1 a. The PXRD pattern exhibits Bragg reflections characteristic of the fluorite structure (space group Fm-3m). The experimental PXRD pattern was calculated by using the bulk structure of uranium dioxide (UO2). The detailed results of the Rietveld refinement are given in the Supporting Information. The peak broadening is the result of the small size of the coherent domains (the crystallites), which has been estimated with the fundamental approach to be 4.5 nm. Under the same experimental conditions (i.e., BnOBn/ OA/OAm), the reaction of ThACHTUNGTRENNUNG(acac)4 did not give rise to the formation of thorium-based NCs. Indeed, in the presence of [a] Dr. D. Hudry, Dr. C. Apostolidis, Dr. O. Walter, Dr. T. Gouder European Commission: Joint Research Center Institute for Transuranium Elements, P. O. Box 2340 76125 Karlsruhe (Germany) Fax: (+49) 7247-951-599 E-mail : damien.hudry@ec.europa.eu damien.hudry@gmail.com [b] Dr. E. Courtois, Dr. C. K bel Karlsruhe Institute of Technology, Institute of Nanotechnology Hermann-von-Helmholtz-Platz 1 76344 Eggenstein–Leopoldshafen (Germany) [c] Dr. C. K bel Karlsruhe Nano Micro Facility, Hermann-von-Helmholtz-Platz 1 76344 Eggenstein–Leopoldshafen (Germany) [d] Dr. D. Meyer Institut de Chimie S parative de Marcoule, UMR 5257 BP 17171, 30207 Bagnols sur C ze Cedex (France) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201200513.