Contribution of non-ionic interactions on bile salt sequestration by chitooligosaccharides: potential hypocholesterolemic activity

Chitooligosaccharides have been suggested as cholesterol reducing ingredients mostly due to their ability to sequestrate bile salts. The nature of the chitooligosaccharides-bile salts binding is usually linked with the ionic interaction. However, at physiological intestinal pH range (6.4 to 7.4) and considering chitooligosaccharides pKa, they should be mostly uncharged. This highlights that other type of interaction might be of relevance. In this work, aqueous solutions of chitooligosaccharides with an average degree of polymerization of 10 and 90 % deacetylated, were characterized regarding their effect on bile salt sequestration and cholesterol accessibility. Chitooligosaccharides were shown to bind bile salts to a similar extent as the cationic resin colestipol, both decreasing cholesterol accessibility as measured by NMR at pH 7.4. A decrease in the ionic strength leads to an increase in the binding capacity of chitooligosaccharides, in agreement with the involvement of ionic interactions. However, when the pH is decreased to 6.4, the increase in charge of chitooligosaccharides is not followed by a significant increase in bile salt sequestration. This corroborates the involvement of non-ionic interactions, which was further supported by NMR chemical shift analysis and by the negative electrophoretic mobility attained for the bile salt-chitooligosaccharide aggregates at high bile salt concentrations. These results highlight that chitooligosaccharides non-ionic character is a relevant structural feature to aid in the development of hypocholesterolemic ingredients.publishe

Gallium(III) chelates of mixed phosphonate-carboxylate triazamacrocyclic ligands relevant to nuclear medicine: structural, stability and in vivo studies

Three triaza macrocyclic ligands, H6NOTP (1,4,7-triazacyclononane-N,N′,N″-trimethylene phosphonic acid), H4NO2AP (1,4,7-triazacyclononane-N-methylenephosphonic acid-N′,N″-dimethylenecarboxylic acid), and H5NOA2P (1,4,7-triazacyclononane-N,N′-bis(methylenephosphonic acid)-N″-methylene carboxylic acid), and their gallium(III) chelates were studied in view of their potential interest as scintigraphic and PET (Positron Emission Tomography) imaging agents. A 1H, 31P and 71Ga multinuclear NMR study gave an insight on the structure, internal dynamics and stability of the chelates in aqueous solution. In particular, the analysis of 71Ga NMR spectra gave information on the symmetry of the Ga3+ coordination sphere and the stability of the chelates towards hydrolysis. The 31P NMR spectra afforded information on the protonation of the non-coordinated oxygen atoms from the pendant phosphonate groups and on the number of species in solution. The 1H NMR spectra allowed the analysis of the structure and the number of species in solution. 31P and 1H NMR titrations combined with potentiometry afforded the measurement of the protonation constants (log KHi) and the microscopic protonation scheme of the triaza macrocyclic ligands. The remarkably high thermodynamic stability constant (log KGaL =34.44 (0.04) and stepwise protonation constants of Ga (NOA2P)2− were determined by potentiometry and 69Ga and 31P NMR titrations. Biodistribution and gamma imaging studies have been performed on Wistar rats using the radiolabeled 67Ga(NO2AP)− and 67Ga (NOA2P)2−chelates, having both demonstrated to have renal excretion. The correlation of the molecular properties of the chelates with their pharmacokinetic properties has been analysed.The authors thank the financial support from the Fundação para a Ciência e Tecnologia (F.C.T., Portugal, projects RREQ/481/QUI/2006 and RECI/QEQ-QFI/0168/2012), the Rede Nacional de RMN (RNRMN), the Hungarian Scientific Research Fund (OTKA grants K-109029 and K-120224), the János Bolyai Research Scholarship (Gy.T.) of the Hungarian Academy of Sciences and the EU COST Action TD1004 “Theragnostics Imaging and Therapy”. The research was also supported by the EU and co-financed by the European Regional Development Fund (FEDER) under the projects CENTRO-07-CT62-FEDER) and GINOP-2.3.2-15-2016-00008.info:eu-repo/semantics/publishedVersio

Dual imaging gold nanoplatforms for targeted radiotheranostics

Gold nanoparticles (AuNPs) are interesting for the design of new cancer theranostic tools, mainly due to their biocompatibility, easy molecular vectorization, and good biological half-life. Herein, we report a gold nanoparticle platform as a bimodal imaging probe, capable of coordinating Gd3+ for Magnetic Resonance Imaging (MRI) and 67Ga3+ for Single Photon Emission Computed Tomography (SPECT) imaging. Our AuNPs carry a bombesin analogue with anity towards the gastrin releasing peptide receptor (GRPr), overexpressed in a variety of human cancer cells, namely PC3 prostate cancer cells. The potential of these multimodal imaging nanoconstructs was thoroughly investigated by the assessment of their magnetic properties, in vitro cellular uptake, biodistribution, and radiosensitisation assays. The relaxometric properties predict a potential T1-and T2-MRI application. The promising in vitro cellular uptake of 67Ga/Gd-based bombesin containing particles was confirmed through biodistribution studies in tumor bearing mice, indicating their integrity and ability to target the GRPr. Radiosensitization studies revealed the therapeutic potential of the nanoparticles. Moreover, the DOTA chelating unit moiety versatility gives a high theranostic potential through the coordination of other therapeutically interesting radiometals. Altogether, our nanoparticles are interesting nanomaterial for theranostic application and as bimodal T1-and T2-MRI / SPECT imaging probes.This research was funded by FCT (Portuguese Foundation for Science and Technology), grant numbers EXCL/QEQ-MED/0233/2012, UID/Multi/04349/2013 and PTDC/MED-QUI/29649/2017. CFGCG and MMCAC thank FCT and FEDER through the COMPETE Program for funding the CQC (UID/QUI/00313/2013 and PEst-OE/QUI/UI0313/2014). P.L-L. thanks Ministry of Economy, Industry and Competitiviy for SAF2017-83043-R, and Comunity of Madrid, FEDER and FSE for S2017/BMD-368

Hydroxy double salts intercalated with Mn(II) complexes as potential contrast agents

A series of Mn(II) aminophosphonate complexes were successfully synthesized and intercalated into the hydroxy double salt [Zn5(OH)8]Cl2·yH2O. Complex incorporation led to an increase in the interlayer spacing from 7.8 to 10–12 Å. Infrared spectroscopy showed the presence of the characteristic vibration peaks of the Mn(II) complexes in the intercalates' spectra, indicating successful incorporation. The complex-loaded composites had somewhat lower proton relaxivities than the pure complexes. Nevertheless, these intercalates may have use as MRI contrast agents for patients with poor kidney function, where traditional Gd(III)-based contrast agents cause severe renal failure

Paramagnetic NMR Lanthanide Induced Shifts for Extracting Solution Structures

This chapter focuses on the use and limitations of the model-free methods in axial paramagnetic supramolecular mono- and polymetallic lanthanide-containing complexes. A comprehensive survey of the systems with three- and fourfold symmetry, for which these techniques have been applied, is proposed together with a detailed discussion of the limitations of Bleaney's approach for the modelling of paramagnetic anisotropies and the detection of the structural changes along the lanthanide series. The structural changes are usually observed for flexible complexes, in which dynamic motions produce significant distortions whose magnitude is controlled by the strength of the R–ligand interactions ([R(L3)3]3+, [R(L7–2H)3]3-). On the other hand, the considerable rigidity imposed by podand ([R(L4)3]3+), non-covalent podand [RM(L5)3]5/6+, or macrobicyclic ([R(L6)3]3+) ligands ensures well-defined coordination sites and isostructurality along the complete lanthanide series

Oxide nanoparticles for bio-imaging

Iron oxide nanoparticles (IONPs) have been studied extensively as platforms for bio-imaging applications. This is the result of their strong Magnetic Resonance Imaging (MRI) contrast enhancement effects which brought them to clinical use, their recent development as Magnetic Particle Imaging (MPI) probes and their versatility for multimodality imaging applications. In this chapter we first describe their main synthetic methodologies, their characterization techniques and the physico-chemical properties, in vivo biodistribution, excretion, toxicity and degradation processes that are at the basis of their imaging applications. The contrast mechanisms used by IONPs in MRI and MPI are described, and are illustrated by typical examples of their use for in vivo pre-clinical single modality and multimodality molecular imaging applications. Perspectives on their use in theranostic and potential clinical developments are also discussed

Molecular Probes for Magnetic Resonance Imaging of Amyloid β Peptides

International audienc

A semi-empirical method for the estimation of the hydration number of Mn(II)-complexes

A semi-empirical equation to estimate the hydration number of Mn(II) complexes was derived from a database of 49 previously published 1H longitudinal Nuclear Magnetic Relaxation Dispersion profiles. This equation has the longitudinal 1H relaxivity and the molecular weight of the Mn(II) complex under consideration as parameters.BT/Biocatalysi

MRI Contrast Agents in Glycobiology

Molecular recognition involving glycoprotein-mediated interactions is ubiquitous in both normal and pathological natural processes. Therefore, visualization of these interactions and the extent of expression of the sugars is a challenge in medical diagnosis, monitoring of therapy, and drug design. Here, we review the literature on the development and validation of probes for magnetic resonance imaging using carbohydrates either as targeting vectors or as a target. Lectins are important targeting vectors for carbohydrate end groups, whereas selectins, the asialoglycoprotein receptor, sialic acid end groups, hyaluronic acid, and glycated serum and hemoglobin are interesting carbohydrate targets.BT/Biocatalysi

The chemical consequences of the gradual decrease of the ionic radius along the Ln-series

In the periodical system, the lanthanides (the 15 elements in the periodic table between barium and hafnium) are unique in the sense that their trivalent cations have their valence electrons hidden behind the 5s and 5p electrons. They show a gradual decrease in ionic radius with increasing atomic number (also known as the lanthanide contraction). The resulting steric effects determine to a large extent the geometries of complexes of these ions. Here, we discuss these effects, particularly upon the properties of the complexes in aqueous solution, for selected families of Ln3+-complexes of oxycarboxylate and aminocarboxylate ligands. The physical properties of the cations are very different, which is very useful for the elucidation of the configuration, conformation and the dynamics of the complexes by X-ray techniques, NMR spectroscopy, and optical techniques. Often the structural analysis is assisted by computational methods.</p