Novel biomimetic nanocomposite for investigation of drug metabolism

In vitro mimicking of hepatic drug metabolism is a key issue in early-stage drug discovery. Synthetic metalloporphyrins show structural similarity with the heme type prosthetic group of cytochrome P450 as primary hepatic enzyme in oxidative drug biotransformation. Therefore, they can catalyze these oxidations. Concerning economical aspects and the poor stability of metalloporphyrin, their immobilization onto or into solid carriers can be promising solution. This study presents a novel immobilized metalloporphyrin nanocomposite system and its potential use as biomimetic catalysts. The developed two-step immobilization procedure consists of two main steps. First, the ionic binding of meso-tetra (parasulphonatophenyl) iron porphyrin onto functionalized magnetic nanoparticles is established, followed by embedding the nanoparticles into polylactic acid nanofibers by electrospinning technique. Due to the synergistic morphological and chemo-structural advantages of binding onto nanoparticles and embedding in polymeric matrices the biomimetic efficiency of metalloporphyrin can be remarkably enhanced, while substrate conversion value was tenfold larger than which could be achieved with classic human liver microsomal system

Modular Synthesis of γ-Valerolactone-based Ionic Liquids and Their Application as Alternative Media for Copper-catalyzed Ullmann-type Coupling Reactions

A convenient procedure was developed for the manufacturing of partially bio-ionic liquids (ILs) from renewable γ- valerolactone (GVL) and cheap and readily available tetraalkylphosphonium bromides with excellent (>99%) yields. The novel ionic liquids were characterized by their temperature dependent vapor pressure, density, viscosity, and conductivity. We have proven that these ILs can be a useful medium for copper-catalyzed Ullmann-type coupling reactions without the use of any ligand or additive, representing an environmentally benign tool for the synthesis of various amines. Twenty cross-coupling products were isolated with good to excellent yields (50−87%)

Long-Term Aging of Concentrated Aqueous Graphene Oxide Suspensions Seen by Rheology and Raman Spectroscopy

Today, graphene oxide (GO) has gained well-deserved recognition, with its applications continuing to increase. Much of the processing of GO-based devices occurs in a dispersed form, which explains the commercialization of GO suspensions. Aging of these suspensions can, however, affect the shelf life and thus their application potential. Aging of GO preparations is often acknowledged, but no longer-term systematic study has been reported on the alteration of GO suspensions. This paper investigates high-concentration (10 mg/mL) aqueous GO suspensions over a 2-year time scale. In addition to steady shear tests, the dynamic behavior of the suspensions was studied in more detail by transient shear and frequency sweep measurements. Both the viscosity and the dynamic moduli increased with age, particularly within the first year. The results of the complementary Raman spectroscopic studies indicate that the change in the rheological behavior with aging results from a slow oxidation process occurring in the highly acidic aqueous medium during the relatively long-term storage. The (over)oxidized layers peel off spontaneously or are removed by high shear stress, resulting in increased viscosity, as it was corroborated by XRD and XPS

In situ gelation of thiolated poly(aspartic acid) derivatives through oxidant-free disulfide formation for ophthalmic drug delivery

Efficient topical treatment of ocular diseases requires a prolonged residence time of drug formulations. An in situ gelling, mucoadhesive system can provide improved residence time while keeps the installation of the formulation easy and accurate due to its low initial viscosity. We synthesized a two-component, biocompatible water-based liquid formulation showing in situ gelation. S protected, preactivated derivatives of thiolated poly(aspartic acid) (PASP-SS-MNA) were synthesized by coupling of the free thiol groups of thiolated poly(aspartic acid) (PASP-SH) with 6-mercaptonicotinic acid (MNA). The amount of protecting groups was found to be 242, 341 and 530 µmol/g depending on the degree of thiolation of PASP. The interaction between PASP-SS-MNA and mucin was proven indicating the mucoadhesive properties. Disulfide cross-linked hydrogels were formed in situ without an oxidizing agent by mixing the aqueous solutions of PASP-SS-MNA and PASP-SH. The gelation time was controlled between 1 and 6 min, while the storage modulus was as high as 4 to 16 kPa depending on the composition. Swelling experiments showed that hydrogels with no residual thiol groups are stable in phosphate-buffered saline at pH = 7.4 whereas the presence of free thiol groups leads to the dissolution of the hydrogel with a rate depending on the excess of thiol groups. Biological safety of the polymers and 6-mercaptonicotinic acid was confirmed on Madin-Darby Canine Kidney cell line. Furthermore, a prolonged release, compared to a conventional liquid formulation, of ofloxacin was observed at pH = 7.4, supporting the potential of the developed biopolymers in ophthalmic drug delivery

Ecotoxicity Assessment of Graphene Oxide by Daphnia magna through a Multimarker Approach from the Molecular to the Physiological Level including Behavioral Changes

The extensive use of engineered nanomaterials, such as graphene oxide (GO), is stimulating research about its potential environmental impacts on the aquatic ecosystem. This study is aimed to comprehensively assess the acute toxicity of a well-characterized GO suspension to Daphnia magna. Conventional ecotoxicological endpoints (lethality, immobilization) and more sensitive, sublethal endpoints (heartbeat rate, feeding activity, and reactive oxygen species (ROS)) production were used. The possible normalization of the heartbeat rate and feeding activity in clean test medium was also investigated. The fate, time-dependent, and concentration-dependent aggregation behaviour of GO was followed by dynamic light scattering, UV-Vis spectroscopy, and zeta potential measurement methods. The EC20 value for immobilization was 50 mg/L, while, for physiological and behavioural endpoints, it ranged from 8.1 mg/L (feeding activity) to 14.8 mg/L (immobilization). The most sensitive endpoint was the ROS production with EC20 = 4.78 mg/L. 24-h recovery experiments revealed that feeding activity was restored only up to a certain level at higher concentrations, indicating that the potential environmental health effects of GO cannot be neglected. Alterations of normal physiology (heart rate) and feeding activity may be associated with increased risk of predation and reproductive decline, highlighting that GO may have impacts on population and food web dynamics in aquatic ecosystems

Liver-on-a-Chip‒Magnetic nanoparticle bound synthetic metalloporphyrin-catalyzed biomimetic oxidation of a drug in a magnechip reactor

Biomimetic oxidation of drugs catalyzed by metalloporphyrins can be a novel and promising way for the effective and sustainable synthesis of drug metabolites. The immobilization of 5,10,15,20-tetrakis(2,3,4,5,6-pentafluorophenyl)iron(II) porphyrin (FeTPFP) and 5,10,15,20‐tetrakis‐(4‐sulfonatophenyl)iron(II) porphyrin (FeTSPP) via stable covalent or rapid ionic binding on aminopropyl-functionalized magnetic nanoparticles (MNPs-NH2) were developed. These immobilized catalysts could be efficiently applied for the synthesis of new pharmaceutically active derivatives and liver related phase I oxidative major metabolite of an antiarrhythmic drug, amiodarone integrated in a continuous-flow magnetic chip reactor (Magnechip)