Molecular MR Imaging of Liver Fibrosis: A Feasibility Study Using Rat and Mouse Models

Background & Aims: Liver biopsy, the current clinical gold standard for fibrosis assessment, is invasive and has sampling errors, and is not optimal for screening, monitoring, or clinical decision-making. Fibrosis is characterized by excessive accumulation of extracellular matrix proteins including type I collagen. We hypothesize that molecular magnetic resonance imaging (MRI) with a probe targeted to type I collagen could provide a direct and non-invasive method of fibrosis assessment. Methods: Liver fibrosis was induced in rats with diethylnitrosamine and in mice with carbon tetrachloride. Animals were imaged prior to and immediately following i.v. administration of either collagen-targeted probe EP-3533 or non-targeted control Gd-DTPA. Magnetic resonance (MR) signal washout characteristics were evaluated from T1 maps and T1-weighted images. Liver tissue was subjected to pathologic scoring of fibrosis and analyzed for gadolinium and hydroxyproline. Results: EP-3533-enhanced MR showed greater signal intensity on delayed imaging (normalized signal enhancement mice: control = 0.39 ± 0.04, fibrotic = 0.55 ± 0.03, p <0.01) and slower signal washout in the fibrotic liver compared to controls (liver t1/2 = 51.3 ± 3.6 vs. 42.0 ± 2.5 min, p <0.05 and 54.5 ± 1.9 vs. 44.1 ± 2.9 min, p <0.01 for fibrotic vs. controls in rat and mouse models, respectively). Gd-DTPA-enhanced MR could not distinguish fibrotic from control animals. EP-3533 gadolinium concentration in the liver showed strong positive correlations with hydroxyproline levels (r = 0.74 (rats), r = 0.77 (mice)) and with Ishak scoring (r = 0.84 (rats), r = 0.79 (mice)). Conclusions: Molecular MRI of liver fibrosis with a collagen-specific probe identifies fibrotic tissue in two rodent models of disease

Titanium(IV) Citrate Speciation and Structure under Environmentally and Biologically Relevant Conditions

The water-soluble complexes of Ti(IV) with citrate are of interest in environmental, biological, and materials chemistry. The aqueous solution speciation is revealed by spectropotentiometric titration. From pH 3−8, given at least three equivalents of ligand, 3:1 citrate/titanium complexes predominate in solution with successive deprotonation of dangling carboxylates as the pH increases. In this range and under these conditions, hydroxo- or oxo-metal species are not supported by the data. At ligand/metal ratios between 1:1 and 3:1, the data are difficult to fit, and are consistent with the formation of such hydroxo- or oxo- species. Stability constants for observed species are tabulated, featuring log β-values of 9.18 for the 1:1 complex [Ti(Hcit)]+, and 16.99, 20.41, 16.11, and 4.07 for the 3:1 complexes [Ti(H2cit)3]2-, [Ti(H2cit)(Hcit)2]4-, [Ti(Hcit)2(cit)]6-, and [Ti(cit)3]8-, respectively (citric acid = H4cit). Optical spectra for the species are reported. The complexes exhibit similar yet distinct spectra, featuring putative citrate-to-Ti(IV) charge-transfer absorptions (λmax ≈ 250−310 nm with ε ≈ 5000−7000 M-1 cm-1). The prevailing 3:1 citrate/titanium ratio in solution is supported by electrospray mass spectrometry data. The X-ray crystal structure of a fully deprotonated tris-citrate complex Na8[Ti(C6H4O7)3]·17H2O (1) (or Na8[Ti(cit)3]·17H2O) that crystallizes from aqueous solution at pH 7−8 is reported. Compound 1 crystallizes in the triclinic space group P1̄, with a = 11.634(2) Å, b = 13.223(3) Å, c = 13.291(3) Å, V = 1982.9(7) Å3, and Z = 2

Correction to Titanium(IV) Complexes with <i>N</i>,<i>N</i>′‑Dialkyl-2,3-dihydroxyterephthalamides and 1‑Hydroxy-2(1<i>H</i>)‑pyridinone as Siderophore and Tunichrome Analogues

Correction to Titanium(IV) Complexes with N,N′‑Dialkyl-2,3-dihydroxyterephthalamides and 1‑Hydroxy-2(1H)‑pyridinone as Siderophore and Tunichrome Analogue

Titanium(IV) Complexes with <i>N</i>,<i>N</i>′-Dialkyl-2,3-dihydroxyterephthalamides and 1-Hydroxy-2(1<i>H</i>)-pyridinone as Siderophore and Tunichrome Analogues

The aqueous chemistry of Ti(IV) with biological ligands siderophores and tunichromes is modeled by using N,N′-dialkyl-2,3-dihydroxyterephthalamides (alTAMs), analogues of catecholamide-containing biomolecules, and 1-hydroxy-2(1H)-pyridinone (1,2-HOPO), an analogue of hydroxamate-containing biomolecules. Both types of ligands stabilize Ti(IV) with respect to hydrolytic precipitation, and afford tractable complexes. Complexes with the methyl derivative of alTAM, meTAM, are characterized by using mass spectrometry and UV/vis spectroscopy. Complexes with etTAM are characterized by the same techniques as well as X-ray crystallography, cyclic voltammetry, and spectropotentiomeric titration. The ESI mass spectra of these complexes in water show both 1:2 and 1:3 metal/ligand species. The X-ray crystal structure of a 1:2 complex, K2[Ti(etTAM)2(OCH3)2]·2CH3OH (1), is reported. The midpoint potential for reduction of 1 dissolved in solution is −0.98 V. A structure for a 1:3 Ti/etTAM species, Na2[Ti(etTAM)3] demonstrates the coordination and connectivity in that complex. Spectropotentiometric titrations in water reveal three metal-containing species in solution between pH 3 and 10. 1,2-HOPO supports Ti(IV) complexes that are stable and soluble in aqueous solution. The bis-HOPO complex [Ti(1,2-HOPO)2(OCH3)2] (5) was characterized by X-ray crystallography and by mass spectrometry in solution, and the tris-HOPO dimer [(1,2-HOPO)3TiOTi(1,2-HOPO)3] (6) was characterized by X-ray crystallography. Taken together, these experiments explore the characteristics of complexes that may form between siderophores and tunichromes with Ti(IV) in biology and in the environment, and guide efforts toward new, well characterized aqueous Ti(IV) complexes. By revealing the identities and some characteristics of complexes that form under a variety of conditions, these studies further our understanding of the complicated nature of aqueous titanium coordination chemistry

Aqueous Spectroscopy and Redox Properties of Carboxylate-Bound Titanium

The aqueous chemistry of Ti(III) and Ti(IV) in two different chemical environments is investigated given its relevance to environmental, materials, and biological chemistry. Complexes of titanium with the carboxylate ligands citrate and oxalate, found ubiquitously in Nature, were synthesized. The redox properties were studied by using cyclic voltammetry. All the titanium citrate redox couples are quasi-reversible. Electrospray mass spectrometry of the Ti(III) citrate solution shows the presence of a 1:2 Ti/cit complex in solution, in contrast to the predominant 1:3 Ti/cit complex with Ti(IV). The change in the coordination of the ligand to the metal on reduction may explain the quasi-reversible behavior of the electrochemistry. The redox potentials for Ti(IV) citrate in water vary with pH. At pH 7, the approximate E1/2 is less than −800 mV. This stated change in redox properties is considered in light of the previously reported Ti(IV) citrate solution speciation. Analogous speciation behavior is suggested from the EPR spectroscopy of Ti(III) citrate aqueous solutions. The g tensors are deduced for several pH-dependent species from the simulated data. The X-ray crystal structure of a TiIII2 oxalate dimer Ti2(μ-C2O4)(C2O4)2(H2O)6·2H2O (3), which crystallizes from water below pH 2, is reported. Complex 3 crystallizes in a monoclinic P21/c space group with a = 9.5088(19) Å, b = 6.2382(12) Å, c = 13.494(3) Å, V = 797.8(3) Å3, and Z = 2. The infrared spectroscopy, EPR spectroscopy, and cyclic voltammetry on complex 3 are reported. The cyclic voltammetry shows an irreversible redox couple ∼−196 mV which likely corresponds to the TiIV2/TiIIITiIV couple. The EPR spectroscopy on solid complex 3 shows a typical S = 1 triplet-state spectrum. The solid follows non-Curie behavior, and the antiferromagnetic coupling between the two metal centers is determined to be −37.2 cm-1. However, in solution the complex follows Curie behavior and supports a TiIIITiIV oxidation state for the dimer