Investigation on Filaments for 3D Printing of Nasal Septum Cartilage Implant.

Septoplasty is a widely used method in treating deviated septum. Although it is successfully implemented, there are problems with excessive bleeding, septal perforation, or infections. The use of anatomically shaped implants could help overcome these problems. This paper focuses on assessing the possibility of the usage of a nasal septum cartilage implant 3D printed from various market-available filaments. Five different types of laments were used, two of which claim to be suitable for medical use. A combination of modeling, mechanical (bending, compression), structural (FTIR), thermal (DSC, MFR), surface (contact angle), microscopic (optical), degradation (2 M HCl, 5 M NaOH, and 0.01 M PBS), printability, and cell viability (MTT) analyses allowed us to assess the suitability of materials for manufacturing implants. Bioflex had the most applicable properties among the tested materials, but despite the overall good performance, cell viability studies showed toxicity of the material in MTT test. The results of the study show that selected filaments were not suitable for nasal cartilage implants. The poor cell viability of Bioflex could be improved by surface modification. Further research on biocompatible elastic materials for 3D printing is needed either by the synthesis of new materials or by modifying existing ones.

GdIII and GaIII complexes with a new tris-3,4-HOPO ligand as new imaging probes: complex stability, magnetic properties and biodistribution.

The development of metal-based multimodal imaging probes is a highly challenging field in coordination chemistry. In this context, we have developed a bifunctional hexadentate tripodal ligand (H3L2) with three 3,4-HOPO moieties attached to a flexible tetrahedral carbon bearing a functionalizable nitro group. Complexes formed with different metal ions have potential interest for diagnostic applications, namely magnetic resonance imaging (MRI) and positron emission tomography (PET). The capacity of the ligand to coordinate GdIII and GaIII was studied and the thermodynamic stability constants of the respective complexes were determined by potentiometry and spectrophotometry. The ligand forms stable 1 : 1 ML complexes though with considerably higher affinity for GaIII than for GdIII (pGa = 26.2 and pGd = 14.3 at pH 7). The molecular dynamics simulations of the GdIII complex indicate that two water molecules can coordinate the metal ion, thus providing efficient paramagnetic enhancement of water proton relaxation. The relaxation and the water exchange properties of the GdIII chelate, assessed by a combined 17O NMR and 1H NMRD study, showed associative activated water exchange with a relatively low rate constant, k298ex = (0.82 ± 0.11) × 107 s-1, and some aggregation tendency. Biodistribution studies of the 67Ga-L2 complex suggested good in vivo stability and quick renal clearance. Further anchoring of this ligand with specific biotargeting moieties might open future prospectives for applications of labelled conjugates in both MRI and 68Ga-PET diagnostic imaging.

Novel Donepezil-Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders, characterized by multiple pathological features. Therefore, multi-target drug discovery has been one of the most active fields searching for new effective anti-AD therapies. Herein, a series of hybrid compounds are reported which were designed and developed by combining an aryl-sulfonamide function with a benzyl-piperidine moiety, the pharmacophore of donepezil (a current anti-AD acetylcholinesterase AChE inhibitor drug) or its benzyl-piperazine analogue. The in vitro results indicate that some of these hybrids achieve optimized activity towards two main AD targets, by displaying excellent AChE inhibitory potencies, as well as the capability to prevent amyloid-ß (Aß) aggregation. Some of these hybrids also prevented Aß-induced cell toxicity. Significantly, drug-like properties were predicted, including for blood-brain permeability. Compound 9 emerged as a promising multi-target lead compound (AChE inhibition (IC50 1.6 µM); Aß aggregation inhibition 60.7%). Overall, this family of hybrids is worthy of further exploration, due to the wide biological activity of sulfonamides.

Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease.

A series of multi-target-directed ligands (MTDLs), obtained by attachment of a hydroxyphenylbenzimidazole (BIM) unit to donepezil (DNP) active mimetic moiety (benzyl-piperidine/-piperazine) was designed, synthesized, and evaluated as potential anti-Alzheimer's disease (AD) drugs in terms of biological activity (inhibition of acetylcholinesterase (AChE) and ß-amyloid (Aß) aggregation), metal chelation, and neuroprotection capacity. Among the DNP-BIM hybrids studied herein, the structural isomerization did not significantly improve the biological properties, while some substitutions, namely fluorine atom in each moiety or the methoxy group in the benzyl ring, evidenced higher cholinergic AChE activity. All the compounds are able to chelate Cu and Zn metal ions through their bidentate BIM moieties, but compound 5, containing a three-dentate chelating unit, is the strongest Cu(II) chelator. Concerning the viability on neuroblastoma cells, compounds 9 and 10 displayed the highest reduction of Aß-induced cell toxicity. In silico calculations of some pharmacokinetic descriptors indicate that all the compounds but the nitro derivatives have good potential oral-bioavailability. Overall, it can be concluded that most of the studied DNP-BIM conjugates showed quite good anti-AD properties, therefore deserving to be considered in further studies with the aim of understanding and treating AD.

Serological characterization of the enterobacterial common antigen substitution of the lipopolysaccharide of Yersinia enterocolitica O : 3.

Enterobacterial common antigen (ECA) is a polysaccharide present in all members of Enterobacteriaceae anchored either via phosphatidylglycerol (PG) or LPS to the outer leaflet of the outer membrane (ECAPG and ECALPS, respectively). Only the latter form is ECA-immunogenic. We previously demonstrated that Yersinia enterocolitica O : 3 and its rough (O-specific polysaccharide-negative) mutants were ECA-immunogenic, suggesting that they contained ECALPS; however, it was not known which part of the LPS core region was involved in ECA binding. To address this, we used a set of three deep-rough LPS mutants for rabbit immunization. The polyvalent antisera obtained were: (i) analysed for the presence of anti-LPS and anti-ECA antibodies; (ii) treated with caprylic acid (CA) to precipitate IgM antibodies and protein aggregates; and (iii) adsorbed with live ECA-negative bacteria to obtain specific anti-ECA antisera. We demonstrated the presence of antibodies specific for both ECAPG and ECALPS in all antisera obtained. Both CA treatment and adsorption with ECA-negative bacteria efficiently removed anti-LPS antibodies, resulting in specific anti-ECA sera. The LPS of the ECALPS-positive deepest-rough mutant contained only lipid A and 3-deoxy-d-manno-oct-2-ulosonic acid (Kdo) residues of the inner core, suggesting that ECALPS was linked to the Kdo region of LPS in Y. enterocolitica O : 3.