Mariela A. Agotegaray

Significant anti-inflammatory properties of a copper(II) fenoprofenate complex compared with its parent drug: Physical and chemical characterization of the complex

The synthesis, physicochemical characterization, anti-inflammatory properties and catecholase mimetic activity of the dinuclear complex of copper(II) with the non-steroidal anti-inflammatory drug Fenoprofen [2-(3-phenoxyphenyl)propionic acid] with formula [Cu2(fen)4(dmf)2] (fen = fenoprofenate anion, dmf = N,N-dimethylformamide) have been investigated. Results of spectroscopic analysis (FTIR and EPR) as well as thermogravimetric and differential thermal analysis data obtained for the solid complex are in good agreement with its dinuclear structure. Electronic spectra of the product are also reported and discussed. The complex was tested for anti-inflammatory properties in comparison to the parent drug, Fenoprofen calcium salt. Oral administration of the dinuclear compound inhibited development of carrageenan-induced oedema in mice; this inhibition was higher than that observed for the parent drug. The kinetic study of the catecholase mimetic activity was carried out spectrophotometrically by monitoring the oxidative transformation of 3,5-di-tert-butylcatechol into the corresponding light-absorbing o-quinone. Kinetic parameters were determined employing the Michaelis-Menten model, showing that the new complex presents catechol oxidase mimetic activity.

Enhanced Analgesic Properties and Reduced Ulcerogenic Effect of a Mononuclear Copper(II) Complex with Fenoprofen in Comparison to the Parent Drug: Promising Insights in the Treatment of Chronic Inflammatory Diseases

Analgesic and ulcerogenic properties have been studied for the copper(II) coordination complex of the nonsteroidal anti-inflammatory drug Fenoprofen and imidazole [Cu(fen)2(im)2] (Cu: copper(II) ion; fen: fenoprofenate anion from Fenoprofen, im: imidazole). A therapeutic dose of 28 mg/kg was tested for [Cu(fen)2(im)2] and 21 mg/kg was employed for Fenoprofen calcium, administered by oral gavage in female mice to compare the therapeutic properties of the new entity. The acetic acid induced writhing test was employed to study visceral pain. The percentage of inhibition in writhing and stretching was 78.9% and 46.2% for the [Cu(fen)2(im)2] and Fenoprofen calcium, respectively. This result indicates that the complex could be more effective in diminishing visceral pain. The formalin test was evaluated to study the impact of the drugs over nociceptive and inflammatory pain. The complex is a more potent analgesic on inflammatory pain than the parent drug. Ulcerogenic effects were evaluated using a model of gastric lesions induced by hypothermic-restraint stress. Fenoprofen calcium salt caused an ulcer index of about 79 mm2 while the one caused by [Cu(fen)2(im)2] was 22 mm2. The complex diminished the development of gastric mucosal ulcers in comparison to the uncomplexed drug. Possible mechanisms of action related to both therapeutic properties have been discussed.

Influence of chitosan coating on magnetic nanoparticles in endothelial cells and acute tissue biodistribution

Abstract Chitosan coating on magnetic nanoparticles (MNPs) was studied on biological systems as a first step toward the application in the biomedical field as drug-targeted nanosystems. Composition of MNPs consists of magnetite functionalized with oleic acid and coated with the biopolymer chitosan or glutaraldehyde-cross-linked chitosan. The influence of the biopolymeric coating has been evaluated by in vitro and in vivo assays on the effects of these MNPs on rat aortic endothelial cells (ECs) viability and on the random tissue distribution in mice. Results were correlated with the physicochemical properties of the nanoparticles. Nitric oxide (NO) production by ECs was determined, considering that endothelial NO represents one of the major markers of ECs function. Cell viability was studied by MTT assay. Different doses of the MNPs (1, 10 and 100 μg/mL) were assayed, revealing that MNPs coated with non-cross-linked chitosan for 6 and 24 h did not affect neither NO production nor cell viability. However, a significant decrease in cell viability was observed after 36 h treatment with the highest dose of this nanocarrier. It was also revealed that the presence and dose of glutaraldehyde in the MNPs structureimpact on the cytotoxicity. The study of the acute tissue distribution was performed acutely in mice after 24 h of an intraperitoneal injection of the MNPs and sub acutely, after 28 days of weekly administration. Both formulations greatly avoided the initial clearance by the reticuloendothelial system (RES) in liver. Biological properties found for N1 and N2 in the performed assays reveal that chitosan coating improves biocompatibility of MNPs turning these magnetic nanosystems as promising devices for targeted drug delivery.

Dinuclear copper(II) complexes of Fenoprofen: synthesis, spectroscopic, thermal, and SOD-mimic activity studies

Three dinuclear copper(II) complexes with the anti-inflammatory drug Fenoprofen [Hfen, 2-(3-phenoxyphenyl)propionic acid] and nitrogen donors of general formula [Cu2(fen)4(L)] n were prepared from [Cu2(fen)4(dmf)2]·2H2O (1) [dmf = N,N′-dimethylformamide; L = 4,4′-bipyridine (2), pyrazine (3), and 2,5-dimethylpyrazine (4)]. The new complexes were characterized by chemical analysis, spectroscopic, and thermogravimetric techniques. Antioxidant properties of 1–4 were evaluated for superoxide-dismutase-mimic activity employing the XTT method. Complex 2 presented the highest antioxidant activity (IC50 = 0.260 µmol L−1). Anti-inflammatory properties of 2 were evaluated employing carrageenan-induced paw edema in mice, revealing that the Fenoprofen–copper(II) complex containing 4,4′-bipyridine does not present enhanced anti-inflammatory activity compared to the uncomplexed parent drug Fenoprofen calcium salt.

Crystal structure and spectroscopic properties of polymeric adducts of the tetra-μ-haloaspirinate-dicopper(II)

Eight new copper(II) complexes with halo-aspirinate anions have been synthesized: [Cu2(Fasp)4(MeCN)2] · 2MeCN (1), [Cu2(Clasp)4(MeCN)2] · 2MeCN (2), [Cu2(Brasp)4(MeCN)2] · 2MeCN (3), {[Cu2(Fasp)4(Pyrz)] · 2MeCN} n (4), {[Cu2(Clasp)4(Pyrz)] · 2MeCN} n (5), [Cu2(Brasp)4(Pyrz)] n (6), [Cu2(Clasp)4(4,4′-Bipy)] n (7), and [Cu2(Brasp)4(4,4′-Bipy)] n (8) (Fasp: fluor-aspirinate; Clasp: chloro-aspirinate; Brasp: bromo-aspirinate; MeCN: acetonitrile; Pyrz: pyrazine; 4,4′-Bipy: 4,4′-bipyridine). The crystal structure of two 2 and 4 have been determined by X-ray diffraction methods. All compounds have been studied employing elemental analysis, IR, and UV-Visible spectroscopic techniques. The results have been compared with previous data reported for complexes with similar structures.

Tetra­kis[μ-2-(3-phenoxy­phen­yl)propionato-κ2O:O′]bis­[(dimethyl­formamide-κO)copper(II)]

The title compound, [Cu2(C15H13O3)4(C3H7NO)2], is formed by the chelate coordination of four racemic fenoprofenate (fenoprofenate is 2,3-phenoxyphenyl propionate) anions and two dimethylformamide molecules to two copper(II) ions, building a paddle-wheel dinuclear molecule. The distorted square-pyramidal coordination of each CuII atom is made up of four O atoms of the four fenoprofenate units and another O atom from a dimethylformamide molecule. The two enantiomeric forms of the fenoprofenate anions are present in the complex, in an optically inactive centrosymmetric arrangement.

Future Perspectives on Silica-Coated Magnetic Nanoparticles in Biomedicine

The lack of enough knowledge about the biological impact of silica-coated magnetic nanoparticles makes these systems non well-explored devices. However, the potential they have in terms of biomedical applications is really huge. Therefore, several applications in medicine are waiting to be explored and developed for silica-coated magnetic nanoparticles.

Silica: Chemical Properties and Biological Features

Silicon dioxide, SiO2, is commonly known as silica. It may be found polymerized alone or in combination with other metals known as silicates.

Silica-coated Magnetic Nanoparticles

Nanotechnology is a scientific discipline involving multiple hard sciences such as chemistry, physic, biology, engineering, among others. The occurrence of novel properties when materials are reduced to nanosizes is the main reason for the scientific and technological interest in such discipline. In particular nanomedicine, that is nanotechnology applied to medicine, has suffered an exponential grow in the last decades. The possibility to target the drug to the diseased site, by avoiding side effects and lowering the required doses, strongly impulses the development of this kind of technology. Magnetic nanotechnology presents the additional advantage related to nanosystems that may be easily guided by the aid of an external magnetic field. This property improves the targeting capability and increases their potential in biomedical applications such as target drug delivery or MRI diagnostic. Iron oxides based nanosystems are currently the favorites to achieve these kinds of issues due to multiple reasons, but mainly to their low toxicity and biocompatibility. However, surface modification is often required to gain in stability, improve their physicochemical properties or even to raise the reactivity by means of functional groups incorporation. Silica appears as a highly attractive material to assess this objective. In the Introductory section the general aspects of nanotechnology and nanomedicine are highlighted. Principles of iron oxides nanoparticles and their silica coat are described.

Magnetic Nanoparticles as Drug Delivery Devices

Nano-size in combination with magnetic properties gave rise to novel nanomaterials with improved properties, especially with regard to biomedical applications. This chapter is devoted to show the strong relationship between the design of nanoparticles and the final properties able to define its efficiency to the desired applications.