Mn(II)-Based MRI Contrast Agent Candidate for Vascular Imaging

Kálmán, Ferenc K.; Nagy, Viktória; Váradi, Balázs; Garda, Zoltán; Molnár, Enikő; Trencsényi, György; Kiss, János; Même, Sandra; Même, William; Tóth, Éva; Tircsó, Gyula

doi:10.1021/acs.jmedchem.0c00197

Cited by 52 publications

(64 citation statements)

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“…The incorporation of a rigid pyridyl unit to the macrocyclic unit afforded Mn(II) complexes with a coordinated water molecule, regardless of the arrangement of the acetate groups (cPC2A 2− or tPC2A 2− , Scheme 1) [19,20]. The latter ligands form rather stable and inert complexes with Mn(II) and can be considered promising building blocks for the preparation of contrast agent candidates [21,22]. Herein, we report a detailed study of the Mn(II) complex with tO2DO2A 2− , in which the two secondary amine nitrogen atoms of tDO2A 2− are replaced by harder oxygen donors.…”

Section: Introductionmentioning

confidence: 99%

Expanding the Ligand Classes Used for Mn(II) Complexation: Oxa-aza Macrocycles Make the Difference

et al. 2021

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We report two macrocyclic ligands based on a 1,7-diaza-12-crown-4 platform functionalized with acetate (tO2DO2A2−) or piperidineacetamide (tO2DO2AMPip) pendant arms and a detailed characterization of the corresponding Mn(II) complexes. The X−ray structure of [Mn(tO2DO2A)(H2O)]·2H2O shows that the metal ion is coordinated by six donor atoms of the macrocyclic ligand and one water molecule, to result in seven-coordination. The Cu(II) analogue presents a distorted octahedral coordination environment. The protonation constants of the ligands and the stability constants of the complexes formed with Mn(II) and other biologically relevant metal ions (Mg(II), Ca(II), Cu(II) and Zn(II)) were determined using potentiometric titrations (I = 0.15 M NaCl, T = 25 °C). The conditional stabilities of Mn(II) complexes at pH 7.4 are comparable to those reported for the cyclen-based tDO2A2− ligand. The dissociation of the Mn(II) chelates were investigated by evaluating the rate constants of metal exchange reactions with Cu(II) under acidic conditions (I = 0.15 M NaCl, T = 25 °C). Dissociation of the [Mn(tO2DO2A)(H2O)] complex occurs through both proton− and metal−assisted pathways, while the [Mn(tO2DO2AMPip)(H2O)] analogue dissociates through spontaneous and proton-assisted mechanisms. The Mn(II) complex of tO2DO2A2− is remarkably inert with respect to its dissociation, while the amide analogue is significantly more labile. The presence of a water molecule coordinated to Mn(II) imparts relatively high relaxivities to the complexes. The parameters determining this key property were investigated using 17O NMR (Nuclear Magnetic Resonance) transverse relaxation rates and 1H nuclear magnetic relaxation dispersion (NMRD) profiles.

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Section: Introductionmentioning

confidence: 99%

Expanding the Ligand Classes Used for Mn(II) Complexation: Oxa-aza Macrocycles Make the Difference

et al. 2021

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“…MR imaging is an indispensable part during tumor diagnosis and treatment. Among MRI contrast agents in researches, manganese (Mn 2+ ), a trace element to sustain life normal function, is a commonly used imaging probe [ 2 , 3 ]. Recently, researches have pointed out that Mn 2+ can activate stimulator of interferon genes (STING) pathway and played a crucial role in virus defense [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

A magnetic resonance nanoprobe with STING activation character collaborates with platinum-based drug for enhanced tumor immunochemotherapy

Yang

et al. 2021

J Nanobiotechnol

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Background Immunochemotherapy is a potent anti-tumor strategy, however, how to select therapeutic drugs to enhance the combined therapeutic effect still needs to be explored. Methods and results Herein, a magnetic resonance nanoprobe (MnP@Lip) with STING (Stimulator of INterferon Genes) activation character was synthesized and co-administered with platinum-based chemotherapeutics for enhanced immunochemotherapy. MnP@Lip nanoparticles was prepared by simple fabrication process with good reproducibility, pH-sensitive drug release behavior and biocompatibility. In vitro experiments elucidated that Mn2+ can promote the polarization of M0 and/or M2 macrophages to M1 phenotype, and promote the maturation of BMDC cells. Upon Mn2+ treatment, the STING pathway was activated in tumor cells, mouse lung epithelial cells, and immune cells. More importantly, anti-tumor experiments in vivo proved that MnP@Lip combined with platinum-based chemotherapeutics increased T cells infiltration in the tumor microenvironment, and inhibited tumor growth in the orthotopic therapeutic and postoperative tumor models. Conclusions This kind of therapeutic strategy that combined MnP@Lip nanoparticles with platinum-based chemotherapeutics may provide a novel insight for immunochemotherapy. Graphical Abstract

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“…28 The log K1 H value of 3,9-PC2A decreases significantly upon functionalization of the secondary NH group with biphenyl (BP) or ethylamine (EA) substituents (log K1 H = 10.45 and 11.34, respectively, vs. 12.25 in 3,9-PC2A). 21,22 The isomeric PC2A ligands were found to be less basic than the DO2A derivatives, as judged by the logKi H values (Table 1). However, the parent PCTA ligand appears to be even less basic, which can be related in part to the formation of a relatively stable complex with the Na + ions present at high concentration in the sample (originating for the ionic strength).…”

Section: Resultsmentioning

confidence: 98%

Complexation of Mn(II) by Rigid Pyclen Diacetates: Equilibrium, Ki-netic, Relaxometric, DFT and SOD Activity Studies.

Molnár¹,

Hamon²,

Barriada³

et al. 2020

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We report the Mn(II) complexes with two pyclen-based ligands (pyclen = 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene) functionalized with acetate pendant arms either at positions 3,6 (3,6-PC2A) or 3,9 (3,9-PC2A) of the macrocyclic fragment. The 3,6-PC2A ligand was synthesized in five steps from pyclen-oxalate by protecting one of the secondary amine groups of pyclen using Alloc protecting chemistry. The complex with 3,9-PC2A is characterized by a higher thermodynamic stability (logKMnL = 17.09(2) than the 3,6-PC2A analogue (logKMnL = 15.53(1), 0.15 M NaCl). Both complexes contain a water molecule coordinated to the metal ion, which results in relatively high 1H relaxivities (r1p = 2.72 and 2.91 mM-1 s -1 for the complexes with 3,6- and 3,9-PC2A, respectively, 25 ºC, 0.49 T). The coordinated water molecule displays fast exchange kinetics with the bulk in both cases; the rates (kex 298) are 140106 and 126106 s -1 for [Mn(3,6-PC2A)] and [Mn(3,9- PC2A)], respectively. The two complexes were found to be remarkably inert with respect to their dissociation, with halflives of 63 and 21 h, respectively, at pH 7.4 in the presence of excess Cu(II). The r1p values recorded in blood serum remain constant at least over a period of 120 h. Cyclic voltammetry experiments show irreversible oxidation features shifted to higher potentials with respect to [Mn(EDTA)]2- and [Mn(PhDTA)]2- , indicating that the PC2A complexes reported here have a lower tendency to stabilize Mn(III). The superoxide dismutase activity of the Mn(II) complexes was tested using the xanthine/xanthine oxidase/NBT assay at pH 7.8. The Mn(II) complexes of 3,6-PC2A and 3,9-PC2A are capable to assist the decomposition of superoxide anion radical. The kinetic rate constant of the complex of 3,9-PC2A is smaller by one order of magnitude than that of 3,6-PC2A.

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Mn(II)-Based MRI Contrast Agent Candidate for Vascular Imaging

Cited by 52 publications

References 44 publications

Expanding the Ligand Classes Used for Mn(II) Complexation: Oxa-aza Macrocycles Make the Difference

Expanding the Ligand Classes Used for Mn(II) Complexation: Oxa-aza Macrocycles Make the Difference

A magnetic resonance nanoprobe with STING activation character collaborates with platinum-based drug for enhanced tumor immunochemotherapy

Complexation of Mn(II) by Rigid Pyclen Diacetates: Equilibrium, Ki-netic, Relaxometric, DFT and SOD Activity Studies.

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