High spin Fe(III)-doped nanostructures as T1 MR imaging probes

Magnetic Resonance Imaging (MRI) T1 contrast agents based on Fe(III) as an alternative to Gd-based compounds have been under intense scrutiny in the last 6-8 years and a number of nanostructures have been designed and proposed for in vivo diagnostic and theranostic applications. Excluding the large family of superparamagnetic iron oxides widely used as T2 -MR imaging agents that will not be covered by this review, a considerable number and type of nanoparticles (NPs) have been employed, ranging from amphiphilic polymer-based NPs, NPs containing polyphenolic binding units such as melanin-like or polycatechols, mixed metals such as Fe/Gd or Fe/Au NPs and perfluorocarbon nanoemulsions. Iron(III) exhibits several favorable magnetic properties, high biocompatibility and improved toxicity profile that place it as the paramagnetic ion of choice for the next generation of nanosized MRI and theranostic contrast agents. An analysis of the examples reported in the last decade will show the opportunities for relaxivity and MR-contrast enhancement optimization that could bring Fe(III)-doped NPs to really compete with Gd(III)-based nanosystems. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Diagnostic Tools > Diagnostic Nanodevices Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

Effect of hydration equilibria on the relaxometric properties of Gd(III) complexes: new insights into old systems

[Abstract]: We present a detailed relaxometric and computational investigation of three Gd(III) complexes that exist in solution as an equilibrium of two species with a different number of coordinated water molecules: [Gd(H2O)q]3+ (q = 8, 9), [Gd(EDTA)(H2O)q]− and [Gd(CDTA)(H2O)q]− (q = 2, 3). 1H nuclear magnetic relaxation dispersion (NMRD) data were recorded from aqueous solutions of these complexes using a wide Larmor frequency range (0.01–500 MHz). These data were complemented with 17O transverse relaxation rates and chemical shifts recorded at different temperatures. The simultaneous fit of the NMRD and 17O NMR data was guided by computational studies performed at the DFT and CASSCF/NEVPT2 levels, which provided information on Gd⋯H dis-tances, 17O hyperfine coupling constants and the zero-field splitting (ZFS) energy, which affects electronic relaxation. The hydration equilibrium did not have a very im-portant effect in the fits of the experimental data for [Gd(H2O)q]3+ and [Gd(CDTA)(H2O)q]−.A. N. acknowledges Università del Piemonte Orientale for the PhD grant. C. P.-I. thanks Ministerio de Ciencia e Innovación (grants PID2019-104626GB-I00 and PID2022-138335NB-I00) and Xunta de Galicia (grant ED431C 2023/33) for generous financial support. C. P.-I. also thanks Centro de Supercomputación de Galicia (CESGA) for providing the computer facilities.Xunta de Galicia; ED431C 2023/3

Optimizing the relaxivity of MRI probes at high magnetic field strengths with binuclear GdIIIComplexes

The key criteria to optimize the relaxivity of a Gd(III) contrast agent at high fields (defined as the region 65 1.5 T) can be summarized as follows: (i) the occurrence of a rotational correlation time \u3c4R in the range of ca. 0.2\u20130.5 ns; (ii) the rate of water exchange is not critical, but a \u3c4M < 100 ns is preferred; (iii) a relevant contribution from water molecules in the second sphere of hydration. In addition, the use of macrocycle-based systems ensures the formation of thermodynamically and kinetically stable Gd(III) complexes. Binuclear Gd(III) complexes could potentially meet these requirements. Their efficiency depends primarily on the degree of flexibility of the linker connecting the two monomeric units, the absence of local motions and the presence of contribution from the second sphere water molecules. With the aim to maximize relaxivity (per Gd) over a wide range of magnetic field strengths, two binuclear Gd(III) chelates derived from the well-known macrocyclic systems DOTA-monopropionamide and HPDO3A (Gd2L1 and Gd2L2, respectively) were synthesized through a multistep synthesis. Chemical Exchange Saturation Transfer (CEST) experiments carried out on Eu2L2 at different pH showed the occurrence of a CEST effect at acidic pH that disappears at neutral pH, associated with the deprotonation of the hydroxyl groups. Then, a complete 1H and 17O NMR relaxometric study was carried out in order to evaluate the parameters that govern the relaxivity associated with these complexes. The relaxivities of Gd2L1 and Gd2L2 (20 MHz, 298 K) are 8.7 and 9.5 mM 121 s 121, respectively, +77% and +106% higher than the relaxivity values of the corresponding mononuclear GdDOTAMAP-En and GdHPDO3A complexes. A significant contribution of second sphere water molecules was accounted for the strong relaxivity enhancement of Gd2L2. MR phantom images of the dinuclear complexes compared to GdHPDO3A, recorded at 7 T, confirmed the superiority of Gd2L2. Finally, ab initio (DFT) calculations were performed to obtain information about the solution structure of the dinuclear complexes

17O and 1H relaxometric and DFT study of hyperfine coupling constants in [Mn(H2O)6]2+

[Abstract] Nuclear Magnetic Relaxation Dispersion (NMRD) profiles and 17O NMR chemical shifts and transverse relaxation rates of aqueous solutions of [Mn(H2O)6]2+ were recorded to determine the parameters governing the relaxivity in this complex and the 17O and 1H hyperfine coupling constants (HFCCs). The analysis of the NMRD and 17O NMR data provided a water exchange rate of kex298 = 28.2 × 106 s−1, and AO/ħ and AH/ħ hyperfine coupling constants of −34.6 and 5.4 rad s−1, respectively. DFT calculations (TPSSh model) performed on the [Mn(H2O)6]2+ and [Mn(H2O)6]2+·12H2O systems were used to evaluate theoretically the 17O and 1H HFCCs responsible for the 17O NMR chemical shifts and the scalar contributions to 17O and 1H NMR relaxation rates. The use of a mixed cluster–continuum approach with the explicit inclusion of second-sphere water molecules is critical for an accurate calculation of HFCCs of coordinated water molecules. The impact of complex dynamics on the calculated HFCCs was evaluated with the use of molecular dynamics simulations within the atom-centered density matrix propagation (ADMP) approach. These molecular dynamics simulations show that the Aiso values are critically affected by the distance between the oxygen atom of the coordinated water molecule and the MnII ion, as well as by the orientation of the water molecule plane with respect to the Mn–O vector. The substantial scalar contribution to relaxivity observed for [Mn(H2O)6]2+ is related to a combination of a slow water exchange rate and a slow electron spin relaxation.Xunta de Galicia; EM2012/08

GdDOTAGA(C18)2: an efficient amphiphilic Gd(iii) chelate for the preparation of self-assembled high relaxivity MRI nanoprobes

A new amphiphilic GdDOTA-like complex functionalized with two octadecyl chains was synthesised and incorporated into the bilayer of liposomes and dendrimersomes. (1)H NMR relaxometric studies and in vivo MRI experiments on mice bearing a syngeneic melanoma tumour have shown a great improvement in performance

Inequality and finance in a rent economy

The present paper aims at offering a contribution to the understanding of the interactions between finance and inequality. We investigate the ways through which income and wealth inequality may have influenced the development of modern financial systems in advanced economies, the US economy first and foremost, and how modern financial systems have then fed back on income and wealth distribution. We focus in particular on securitization and on the production of complex structured financial products. We analyse this topic by elaborating a simulated hybrid Agent-Based Stock-Flow-Consistent (AB-SFC) macroeconomic model, encompassing heterogeneous (i.e. households) and aggregate sectors. Our findings suggest that the increase in economic growth, favoured by the higher level of credit supply coming with securitization, may determine a more unequal and financially unstable economic system

Surprising Complexity of the [Gd(AAZTA)(H2O)2]− Chelate Revealed by NMR in the Frequency and Time Domains

[Abstract] Typically, Ln(III) complexes are isostructural along the series, which enables studying one particular metal chelate to derive the structural features of the others. This is not the case for [Ln(AAZTA)(H2O)x]− (x = 1, 2) systems, where structural variations along the series cause changes in the hydration number of the different metal complexes, and in particular the loss of one of the two metal-coordinated water molecules between Ho and Er. Herein, we present a 1H field-cycling relaxometry and 17O NMR study that enables accessing the different exchange dynamics processes involving the two water molecules bound to the metal center in the [Gd(AAZTA)(H2O)2]− complex. The resulting picture shows one Gd-bound water molecule with an exchange rate ∼6 times faster than that of the other, due to a longer metal–water distance, in accordance with density functional theory (DFT) calculations. The substitution of the more labile water molecule with a fluoride anion in a diamagnetic-isostructural analogue of the Gd-complex, [Y(AAZTA)(H2O)2]−, allows us to follow the chemical exchange process by high-resolution NMR and to describe its thermodynamic behavior. Taken together, the variety of tools offered by NMR (including high-resolution 1H, 19F NMR as a function of temperature, 1H longitudinal relaxation rates vs B0, and 17O transverse relaxation rates vs T) provides a complete description of the structure and exchange dynamics of these Ln-complexes along the series.This research was supported by the Università del Piemonte Orientale (Ricerca locale FAR2019). F.C., L.T., and M.B. acknowledge the financial support from the Ministero dell’Università e della Ricerca (PRIN 2017A2KEPL project “Rationally designed nanogels embedding paramagnetic ions as MRI probes”). This work was carried out within the framework of the COST CA15209 Action “European Network on NMR Relaxometry”Italia. Ministero dell'Università e della Ricerca; PRIN-2017A2KEP