Iron-carbohydrate complexes treating iron anaemia: Understanding the nano-structure and interactions with proteins through orthogonal characterisation.

Intravenous (IV) iron-carbohydrate complexes are widely used nanoparticles (NPs) to treat iron deficiency anaemia, often associated with medical conditions such as chronic kidney disease, heart failure and various inflammatory conditions. Even though a plethora of physicochemical characterisation data and clinical studies are available for these products, evidence-based correlation between physicochemical properties of iron-carbohydrate complexes and clinical outcome has not fully been elucidated yet. Studies on other metal oxide NPs suggest that early interactions between NPs and blood upon IV injection are key to understanding how differences in physicochemical characteristics of iron-carbohydrate complexes cause variance in clinical outcomes. We therefore investigated the core-ligand structure of two clinically relevant iron-carbohydrate complexes, iron sucrose (IS) and ferric carboxymaltose (FCM), and their interactions with two structurally different human plasma proteins, human serum albumin (HSA) and fibrinogen, using a combination of cryo-scanning transmission electron microscopy (cryo-STEM), x-ray diffraction (XRD), small-angle x-ray scattering (SAXS) and small-angle neutron scattering (SANS). Using this orthogonal approach, we defined the nano-structure, individual building blocks and surface morphology for IS and FCM. Importantly, we revealed significant differences in the surface morphology of the iron-carbohydrate complexes. FCM shows a localised carbohydrate shell around its core, in contrast to IS, which is characterised by a diffuse and dynamic layer of carbohydrate ligand surrounding its core. We hypothesised that such differences in carbohydrate morphology determine the interaction between iron-carbohydrate complexes and proteins and therefore investigated the NPs in the presence of HSA and fibrinogen. Intriguingly, IS showed significant interaction with HSA and fibrinogen, forming NP-protein clusters, while FCM only showed significant interaction with fibrinogen. We postulate that these differences could influence bio-response of the two formulations and their clinical outcome. In conclusion, our study provides orthogonal characterisation of two clinically relevant iron-carbohydrate complexes and first hints at their interaction behaviour with proteins in the human bloodstream, setting a prerequisite towards complete understanding of the correlation between physicochemical properties and clinical outcome.

3D Virtual Histopathology by Phase-Contrast X-Ray Micro-CT for Follicular Thyroid Neoplasms.

Histological analysis is the core of follicular thyroid carcinoma (FTC) classification. The histopathological criteria of capsular and vascular invasion define malignancy and aggressiveness of FTC. Analysis of multiple sections is cumbersome and as only a minute tissue fraction is analyzed during histopathology, under-sampling remains a problem. Application of an efficient tool for complete tissue imaging in 3D would speed-up diagnosis and increase accuracy. We show that X-ray propagation-based imaging (XPBI) of paraffin-embedded tissue blocks is a valuable complementary method for follicular thyroid carcinoma diagnosis and assessment. It enables a fast, non-destructive and accurate 3D virtual histology of the FTC resection specimen. We demonstrate that XPBI virtual slices can reliably evaluate capsular invasions. Then we discuss the accessible morphological information from XPBI and their significance for vascular invasion diagnosis. We show 3D morphological information that allow to discern vascular invasions. The results are validated by comparing XPBI images with clinically accepted histology slides revised by and under supervision of two experienced endocrine pathologists.

Critical nanomaterial attributes of iron-carbohydrate nanoparticles: Leveraging orthogonal methods to resolve the 3-dimensional structure.

Intravenous iron-carbohydrate nanomedicines are widely used to treat iron deficiency and iron deficiency anemia across a wide breadth of patient populations. These colloidal solutions of nanoparticles are complex drugs which inherently makes physicochemical characterization more challenging than small molecule drugs. There have been advancements in physicochemical characterization techniques such as dynamic light scattering and zeta potential measurement, that have provided a better understanding of the physical structure of these drug products in vitro. However, establishment and validation of complementary and orthogonal approaches are necessary to better understand the 3-dimensional physical structure of the iron-carbohydrate complexes, particularly with regard to their physical state in the context of the nanoparticle interaction with biological components such as whole blood (i.e. the nano-bio interface).

Lanthanide-Doped Hafnia Nanoparticles for Multimodal Theranostics: Tailoring the Physicochemical Properties and Interactions with Biological Entities.

High-Z metal oxide nanoparticles hold promise as imaging probes and radio-enhancers. Hafnium dioxide nanoparticles have recently entered clinical evaluation. Despite promising early clinical findings, the potential of HfO2 as a matrix for multimodal theranostics is yet to be developed. Here, we investigate the physicochemical properties and the potential of HfO2-based nanoparticles for multimodal theranostic imaging. Undoped and lanthanide (Eu3+, Tb3+, and Gd3+)-doped HfO2 nanoparticles were synthesized and functionalized with various moieties including poly(vinylpyrrolidone) (PVP), (3-aminopropyl)triethoxysilane (APTES), and folic acid (FA). We show that different synthesis routes, including direct precipitation, microwave-assisted synthesis, and sol-gel chemistry, allow preparation of hafnium dioxide particles with distinct physicochemical properties. Sol-gel based synthesis allows preparation of uniform nanoparticles with dopant incorporation efficiencies superior to the other two methods. Both luminescence and contrast properties can be tweaked by lanthanide doping. We show that MRI contrast can be unified with radio-enhancement by incorporating lanthanide dopants in the HfO2 matrix. Importantly, ion leaching from the HfO2 host matrix in lysosomal-like conditions was minimal. For Gd:HfO2 nanoparticles, leaching was reduced >10× compared to Gd2O3, and no relevant cytotoxic effects have been observed in monocyte-derived macrophages for nanoparticle concentrations up to 250 µg/mL. Chemical surface modification allows further tailoring of the cyto- and hemocompatibility and enables functionalization with molecular targeting entities, which lead to enhanced cellular uptake. Taken together, the present study illustrates the manifold properties of HfO2-based nanomaterials with prospective clinical utility beyond radio-enhancement.

Crystal structures of trans-di-chlorido-tetra-kis-[1-(2,6-diiso-propyl-phen-yl)-1H-imidazole-κN (3)]iron(II), trans-di-bromido-tetra-kis-[1-(2,6-diiso-propyl-phen-yl)-1H-imidazole-κN (3)]iron(II) and trans-di-bromido-tetra-kis-[1-(2,6-diiso-propyl-phen-yl)-1H-imidazole-κN (3)]iron(II) diethyl ether disolvate.

The title compounds, [FeCl2(C15H20N2)4], (I), [FeBr2(C15H20N2)4], (II), and [FeBr2(C15H20N2)4]·2C4H10O, (IIb), respectively, all have triclinic symmetry, with (I) and (II) being isotypic. The Fe(II) atoms in each of the structures are located on an inversion center. They have octa-hedral FeX 2N4 (X = Cl and Br, respectively) coordination spheres with the Fe(II) atom coordinated by two halide ions in a trans arrangement and by the tertiary N atom of four aryl-imidazole ligands [1-(2,6-diiso-propyl-phen-yl)-1H-imidazole] in the equatorial plane. In the two independent ligands, the benzene and imidazole rings are almost normal to one another, with dihedral angles of 88.19 (15) and 79.26 (14)° in (I), 87.0 (3) and 79.2 (3)° in (II), and 84.71 (11) and 80.58 (13)° in (IIb). The imidazole rings of the two independent ligand mol-ecules are inclined to one another by 70.04 (15), 69.3 (3) and 61.55 (12)° in (I), (II) and (IIb), respectively, while the benzene rings are inclined to one another by 82.83 (13), 83.0 (2) and 88.16 (12)°, respectively. The various dihedral angles involving (IIb) differ slightly from those in (I) and (II), probably due to the close proximity of the diethyl ether solvent mol-ecule. There are a number of C-H⋯halide hydrogen bonds in each mol-ecule involving the CH groups of the imidazole units. In the structures of compounds (I) and (II), mol-ecules are linked via pairs of C-H⋯halogen hydrogen bonds, forming chains along the a axis that enclose R 2 (2)(12) ring motifs. The chains are linked by C-H⋯π inter-actions, forming sheets parallel to (001). In the structure of compound (IIb), mol-ecules are linked via pairs of C-H⋯halogen hydrogen bonds, forming chains along the b axis, and the diethyl ether solvent mol-ecules are attached to the chains via C-H⋯O hydrogen bonds. The chains are linked by C-H⋯π inter-actions, forming sheets parallel to (001). In (I) and (II), the methyl groups of an isopropyl group are disordered over two positions [occupancy ratio = 0.727 (13):0.273 (13) and 0.5:0.5, respectively]. In (IIb), one of the ethyl groups of the diethyl ether solvent mol-ecule is disordered over two positions (occupancy ratio = 0.5:0.5).

1,4-Bis(hex-yloxy)-2,5-diiodo-benzene.

The centrosymmetric title compound, C(18)H(28)I(2)O(2), crystallized in the monoclinic space group P2(1)/c with the alkyl chains having extended all-trans conformations, similar to those in the centrosymmetric bromo analogue [Li et al. (2008 ▶). Acta Cryst. E64, o1930] that crystallized in the triclinic space group P. The difference between the two structures lies in the orientation of the two alkyl chains with respect to the C(aromatic)-O bond. In the title compound, the O-C(alk-yl)-C(alk-yl)-C(alk-yl) torsion angle is 55.8 (5)°, while in the bromo analogue this angle is -179.1 (2)°. In the title compound, the C-atoms of the alkyl chain are almost coplanar [maximum deviation of 0.052 (5) Å] and this mean plane is inclined to the benzene ring by 50.3 (3)°. In the bromo-analogue, these two mean planes are almost coplanar, making a dihedral angle of 4.1 (2)°. Another difference between the crystal structures of the two compounds is that in the title compound there are no halide⋯halide inter-actions. Instead, symmetry-related mol-ecules are linked via C-H⋯π contacts, forming a two-dimensional network.

Main-chain organometallic polymers comprising redox-active iron(II) centers connected by ditopic N-heterocyclic carbenes.

Main-chain organometallic polymers were synthesized from bimetallic iron(ii) complexes containing a ditopic N-heterocyclic carbene (NHC) ligand [(cp)(CO)LFe(NHC approximately NHC)Fe(cp)(CO)L]X(2) (where NHC approximately NHC represents a bridging dicarbene ligand, L = I(-) or CO). Addition of a diimine ligand such as pyrazine or 4,4'-bipyridine, interconnected these bimetallic complexes and gave the corresponding co-polymers containing iron centers that are alternately linked by a dicarbene and a diimine ligand. Diimine coordination depended on the wingtip groups at the carbene ligands and was accomplished either by photolytic activation of a carbonyl ligand from the cationic [Fe(cp)(NHC)(CO)(2)](+) precursor (alkyl wingtips) or by AgBF(4)-mediated halide abstraction from the neutral complex [FeI(cp)(NHC)(CO)] (mesityl wingtips). Remarkably, the polymeric materials were substantially more stable than the related bimetallic model complexes. Electrochemical analyses indicated metal-metal interactions in the pyrazine-containing polymers, whereas in 4,4'-bipyridine-linked systems the metal centers were electronically decoupled.

One-dimensional manganese coordination polymers composed of polynuclear cluster blocks and polypyridyl linkers: structures and properties.

The synthesis, crystal structures and magnetic properties of five new manganese compounds are reported. These include a linear trinuclear cluster [Mn(II)(3)(O(2)CCHMe(2))(6)(dpa)(2)].2MeCN (1) (dpa = 2,2'-dipyridylamine), a tetranuclear cluster [Mn(II)(2)Mn(III)(2)O(2)(O(2)CCMe(3))(6)(bpy)(2)] (3) (bpy = 2,2'-bipyridine), and chain coordination polymers composed of cluster blocks such as Mn(3), Mn(3)O, and Mn(4)O(2) bridged by 2,2'-bipyrimidine (bpm) or hexamethylentetramine (hmta) ligands to give ([Mn(II)(3)(O(2)CCHMe(2))(6)(bpm)].2EtOH)(n) (2), [Mn(II)(2)Mn(III)(2)O(2)(O(2)CCHMe(2))(6)(bpm)(EtOH)(4)](n) (4), and (([Mn(II)Mn(III)(2)O(O(2)CCHMe(2))(6)(hmta)(2)].EtOH)(n) (5). The magnetic analysis of the compounds was achieved using a combination of vector coupling and full-matrix diagonalization methods. Susceptibility data for compound 1 was fitted using a vector coupling model to give g = 2.02(1) and 2J/k(B) = -5.38(2) K. To model the trimer chain, we used vector coupling for initial values of J(1) and then diagonalization techniques to estimate J(2) to give g = 1.98(1), 2J(1)/k(B) = -3.3(1) K and 2J(2)/k(B) = -1.0(1) K by approximating the system to a dimer of trimers. The analysis of 3 was made difficult by the mixture of polymorphs and the difficulties of a three-J model, while for 4 an analysis was not possible because of the size of the computation and the relative magnitudes of the three couplings. Compound 5 was modeled using the same techniques as 2 to give g = 1.99(1), 2J(1)/k(B) = +32.5(2) K, 2J(2)/k(B) = -16.8(1) K, and 2J(3)/k(B) = +0.4(1) K. The combination of techniques has worked well for compounds 2 and 5 and thus opens up a method of modeling complex chains.

One-dimensional mu-chloromanganese(II)-tetrathiafulvalene (TTF) coordination compound.

A new tetrathiafulvalene derivative 1 bearing a single pyridine group and its coordination complex 2, with stoichiometry [Mn(mu-Cl)Cl(1)2(CH3OH)]n, have been synthesized and fully characterized. The complex 2 shows an extended chain structure, which is potentially favorable for electrical conductivity. Notably, this is the first monohalogen-bridged Mn(II) polymer exhibiting a moderate antiferromagnetic coupling between the Mn(II) centers.

Diastereoselective synthesis of coordination compounds: a chiral tripodal ligand based on bipyridine units and its ruthenium(II) and iron(II) complexes.

The enantiomerically pure chiral tris-chelating ligand (+)-(7S,10R)-L(L) comprising three 4,5-pinenobipyridine subunits connected through a mesityl spacer has been synthesized. Complexes of L with RuII and FeII have been prepared and characterised. NMR spectroscopy indicates that only one diastereoisomer is formed, and the CD spectra show that the complexes have the [capital Lambda] configuration on the metal centre. The X-ray crystal structure of the iron complex shows that in the octahedral complex, the ligand L coils around the metal and confirms the absolute configuration. The RuII and FeII compounds were also characterised by mass spectrometry, electronic absorption, and, in the case of Ru(II), fluorescence spectroscopy. The photostability of the ruthenium compound was checked by photochemical experiments.

Iron-promoted nucleophilic additions to diimine-type ligands: a synthetic and structural study.

We report here three examples of the reactivity of protic nucleophiles with diimine-type ligands in the presence of Fe(II) salts. In the first case, the iron-promoted alcoholysis reaction of one nitrile group of the ligand 2,3-dicyano-5,6-bis(2-pyridyl)-pyrazine (L1) permitted the isolation of an stable E-imido-ester, [Fe(L1')(2)](CF(3)SO(3))(2) (1), which has been characterized by spectroscopic studies (IR, ES-MS, Mössbauer), elemental analysis, and crystallographically. Compound 1 consists of mononuclear octahedrally coordinated Fe(II) complexes where the Fe(II) ion is in its low-spin state. The iron-mediated nucleophilic attack of water to the asymmetric ligand 2,3-bis(2-pyridyl)pyrido[3,4-b]pyrazine (L2) has also been studied. In this context, the crystal structures of two hydration-oxidation Fe(III) products, [Fe(L2')(2)](ClO(4))(3).3CH(3)CN (2) and trans-[FeL2"Cl(2)] (3), are described. Compounds 2 and 3 are both mononuclear Fe(III) complexes where the metals occupy octahedral positions. In principle, L2 is expected to coordinate to metal ions through its bipyridine-type units to form a five-membered ring; however, this is not the case in compounds 2 and 3. In 2, the ligand coordinates through its pyridines and through the hydroxyl group attached to the pyrazine imino carbon after hydration, that is, in an N,O,N tridentate manner. In compound 3, the ligand has suffered further transformations leading to a very stable diamido complex. In this case, the metal ion achieves its octahedral geometry by means of two pyridines, two amido N atoms, and two axial chlorine atoms. Magnetic susceptibility measurements confirmed the spin state of these two Fe(III) species: compounds 2 and 3 are low-spin and high-spin, respectively.

Trinuclear Zinc(II) Complexes and Polymeric Cadmium(II) Complexes with the Ligand 2,5-Bis(2-pyridyl)pyrazine: Synthesis, Spectral Analysis, and Single-Crystal and Powder X-ray Analyses.

Three zinc compounds, [ZnCl(2)(bppz)(dmf)] (1), [Zn(3)(OAc)(6)(bppz)(2)](H(2)O) (2), and [Zn(3)(Cl)(6)(bppz)(3)](H(2)O) (3), and two cadmium complexes, {[Cd(OAc)(2)(bppz)](H(2)O)(5)}(n)() (4) and [Cd(NO(3))(2)(bppz)](n)() (5), where bppz is 2,5-bis(2-pyridyl)pyrazine, have been synthesized and characterized spectroscopically and crystallographically. The mononuclear complex 1, C(17)H(17)Cl(2)N(5)OZn, crystallizes in the monoclinic space group P2(1)/c, with a = 8.654(1) Å, b = 9.500(1) Å, c = 22.997(1) Å, beta = 97.99(1) degrees, and Z = 4; R1 for 2356 observed reflections [I > 2sigma(I)] was 0.058. The zinc atom has a distorted square planar coordination sphere with the ligand bppz connected in a mono-bidentate manner. The remaining coordination sites are occupied by the chloride counterions and by an oxygen atom of a solvent molecule. The trinuclear zinc compound 2, C(40)H(38)N(8)O(12)Zn(3).H(2)O, crystallizes in the triclinic space group P&onemacr;, with a = 12.238(4) Å, b = 12.986(3) Å, c = 15.470(4) Å, alpha = 75.65(1) degrees, beta = 97.99(1) degrees, gamma = 65.98(1) degrees, and Z = 2; R1 for 4511 observed reflections [I > 2sigma(I)] was 0.07. This complex consists of a linear arrangement of three zinc atoms. The central zinc atom, located on a crystallographic inversion center, is connected by six bridging acetate groups to two symmetry-related zinc atoms. It has an almost perfect octahedral coordination environment. The outer symmetry-related zinc atoms are in a square pyramidal environment, and they coordinate to three acetate groups and to one bppz molecule in a mono-bidentate manner. Compound 3, C(42)H(30)Cl(6)N(12)Zn(3).1.25H(2)O, a cyclic zinc(II) trimer, crystallizes in the cubic space group Ia&thremacr;d, with a = 26.311(1) Å and Z = 16; R1 for 692 observed reflections [I > 2sigma(I)] was 0.038. This trinuclear complex has a perfect triangular arrangement of the zinc atoms. Each zinc atom is connected to the other two by a bppz molecule. The coordination about the metal is best described as a distorted octahedral with four long distances in the basal plane, to two chlorines and to two nitrogen atoms, and two short distances in the axial direction, to two nitrogen atoms. With Cd(II) two polymeric complexes, 4 and 5 were obtained. Compound 4, C(18)H(16)N(4)O(4)Cd.5H(2)O, crystallizes in the triclinic space group P&onemacr;, a = 9.045(1) Å, b = 10.438(1) Å, c = 12.719(1) Å, alpha = 100.48(1) degrees, beta = 95.05(1) degrees, gamma = 95.86(1) degrees, and Z = 2; R1 for 3694 observed reflections [I > 2sigma(I)] was 0.029. The analogous Cd(NO(3))(2) complex with bppz, 5, could only be obtained in microcrystalline form, and its structure was solved by the use of X-ray powder diffraction methods. Compound 5, C(14)H(10)N(6)O(6)Cd, crystallizes in the monoclinic space group C2/c, with a = 11.6601(3) Å, b = 11.9870(3) Å, c = 12.1453(3) Å, beta = 103.348(2) degrees, and Z = 4. In both 4 and 5 the cadmium atoms are bridged by the ligand bppz, so forming uniform one-dimensional coordination polymers. The cadmium ions exhibit the rare coordination number of 8, with two coordinated ligand molecules and two chelating acetate (4) or nitrate (5) groups.

Synthesis and X-ray Powder Structures of Nickel(II) and Copper(II) Coordination Polymers with 2,5-Bis(2-pyridyl)pyrazine.

The reaction of 2,5-bis(2-pyridyl)pyrazine (bppz) with nickel(II) sulfate in aqueous solution yielded a binuclear complex, [Ni(2)(bppz)(H(2)O)(8)](SO(4))(2).2H(2)O (1), whose structure was solved by single-crystal methods. The compound crystallizes in the monoclinic space group P2(1)/n with a = 8.372(2) Å, b = 18.301(2) Å, c = 17.197(2) Å, beta = 97.54(2) degrees, and Z = 4. The bppz ligand chelates the two octahedrally coordinated nickel atoms through its nitrogen donors. The four remaining coordination sites are occupied by water oxygen atoms. The binuclear [Ni(2)(bppz)(H(2)O)(8)](4+) cations are held together by hydrogen bonds involving sulfate anions and water molecules. Similar reactions with nickel(II) or copper(II) chloride in less polar solvents resulted in the formation of two new coordination polymers, {[Ni(2)Cl(2)(bppz)(H(2)O)(2)(CH(3)OH)(2)]Cl(2)}(n)() (2) and [Cu(2)Cl(4)(bppz)](n)() (3). These polymers could be obtained only in microcrystalline form. Their structures were determined ab initio from X-ray powder diffraction data. The complex {[Ni(2)Cl(2)(bppz)(H(2)O)(2)(CH(3)OH)(2)]Cl(2)}(n)() (2) belongs to the triclinic space group P&onemacr; with a = 8.7014(4) Å, b = 10.1465(5) Å, c = 8.0303(3) Å, alpha = 116.095(2) degrees, beta = 112.713(3) degrees, gamma = 64.056(3) degrees, and Z = 1. The octahedral coordination of the nickel atom is achieved by two nitrogens of the ligand bppz, two chloride ions, and two oxygens from the solvent molecules. The bridging nature of the chloride ions and the bis-bidentate ligands (bppz) leads to a one-dimensional polymer. The compound [Cu(2)Cl(4)(bppz)](n)() (3) crystallizes in the monoclinic space group C2/m with a = 13.9124(5) Å, b = 6.1844(2) Å, c = 10.1572(3) Å, beta = 112.952(3) degrees, and Z = 2. The copper atoms display a distorted octahedral geometry where four of the coordination sites are occupied by chloride ions and the remaining two by nitrogen atoms of bppz. The metal atoms are bridged by two chlorine atoms and the bppz ligands, forming a two-dimensional coordination polymer.