The role of Eudragit® as a component of hydrogel formulations for medical devices.

Over the last decade, significant progress has been made in developing hydrogels as medical devices. By physically cross-linking pharmaceutically approved polymers into three-dimensional matrices, we can ensure their biocompatibility and facilitate their seamless transition from the laboratory to clinical applications. Moreover, the reversible nature of their physical cross-links allows hydrogels to dissolve in the presence of external stimuli. Particularly, their high degree of hydration, high molecular weight, and superior flexibility of the polymer chains facilitate their interaction with complex biological barriers (e.g., mucus layer), making them ideal candidates for mucosal drug delivery. However, fine-tuning the composition of the hydrogel formulations is of great importance to optimize the performance of the medical device and its therapeutic cargo. Herein, we investigated the influence of different Eudragits® on the properties of hydrogels based on polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), and polyethylene glycol (PEG), which were originally proposed as ocular inserts in previous reports. Our research aims to determine the effects that including different Eudragits® have on the structure and protein ocular delivery ability of various hydrogel formulations. Properties such as matrix stability, protein encapsulation, release kinetics, mucoadhesion, and biocompatibility have been analyzed in detail. Our study represents a guideline of the features that Eudragits® have to exhibit to endow hydrogels with good adhesion to the eye's conjunctiva, biocompatibility, and structural strength to cope with the ocular biointerface and allow sustained protein release. This work has important implications for the design of new hydrogel materials containing Eudragits® in their composition, particularly in mucosal drug delivery.

Synthesis and biological characterization of organoruthenium complexes with 8-hydroxyquinolines.

In this study we report the synthesis, characterization and a thorough biological evaluation of twelve organoruthenium-8-hydroxyquinolinato (Ru-hq) complexes. The chosen hqH ligands bear various halogen atoms in different positions which enables to study effect of the substituents on physico-chemical and biological properties. The determined crystal structures of novel complexes expectedly show the cymene ring, a bidentately coordinated deprotonated hq and a halide ligand (chlorido or iodido) coordinated to the ruthenium central ion. In previous studies the anticancer potential of organoruthenium complex with 8-hydroxyquinoline ligand clioquinol was well established and we have decided to perform an extended biological evaluation (antibacterial and antitumor activity) of the whole series of halo-substituted analogs. Beside the cytotoxic potential of studied compounds also the effect of two selected complexes (9 and 10) on apoptosis induction in MG-63 and A549 cells was also studied via externalization of phosphatidylserine at the outer plasma membrane leaflet. Both selected complexes that gave best preliminary cytotoxicity results contain bromo substituted hq ligands. Apoptosis induction results are in agreement with the cell viability assays suggesting the higher and more selective anticancer activity of complex 10 in comparison to complex 9 on MG-63 cells.

Copper(II) Complexes with Saccharinate and Glutamine as Antitumor Agents: Cytoand Genotoxicity in Human Osteosarcoma Cells.

BACKGROUND: Copper has shown to be useful in disorders with an inflammation origin such as cancer [1-3]. It has previously shown that Casiopeínas® interact with DNA and promote the disruption by a mechanism related to the increase in the level of free radicals [4-6] which confers antineoplastic potential. Objetive: The aim of the present work was to study the antitumor effects of a series of Cu(II) complexes with saccharinate (sac) and glutamate (gln): [Cu(sac)2(H2O)4].2H2O (Cu-sac), [Cu(gln)2] (Cu-gln) and Na2[Cu(sac)2 (gln)2].H2O (Cu-sac-gln). METHODS: We have investigated the action of these compounds on cell viability on human osteosarcoma cells MG-63. In particular, we pay special attention to the cyto and genotoxicity actions of these complexes and to the association to oxidative stress. RESULTS: The three complexes: Cu-sac, Cu-gln and Cu-sac-gln caused a decline in cell viability. The half-maximal inhibitory concentration in MG-63 cells for Cu-sac-gln is 170 µM, showing the strongest antiproliferative effect. Moreover, only Cu-sac-gln caused a decrease of the mitochondrial activity from 100 µM. Our results indicate that the copper(II) complexes studied here produce DNA damage and suggest that the rise of reactive oxygen species (ROS) is the central mechanism action. Genotoxicity studied by the Cytokinesis-block micronucleus (MN) assay and the Single cell gel electrophoresis (comet assay) could be observed in MG-63 cells treated with Cu-sac-gln from 100 and 50 µM, respectively. Cu-sac and Cu-gln also induced DNA damage; however their effect was definitively weaker. The generation of reactive oxygen species increased from 50 µM of Cu-sac-gln and Cu-sac and only from 250 µM of Cugln, as well as a reduction of the GSH/GSSG ratio from 50 µM. When cells were treated with several concentrations of the complexes in addition to a combination of 50 µM of vitamin C plus 50 µM of vitamin E, a total recovery in cell survival was obtained for Cu-gln in the whole range of tested concentrations while only a partial viability recovery was obtained from 250 µM of Cu-sac and Cu-sac-gln. CONCLUSION: Overall, our results point to a differential cyto- and genotoxicity of the three copper(II) complexes and demonstrate that the complexation with both ligands confers the most potent antitumor action in human osteosarcoma cells.

In vitro and in vivo antitumor effects of the VO-chrysin complex on a new three-dimensional osteosarcoma spheroids model and a xenograft tumor in mice.

Osteosarcoma (OS) is the most common primary tumor of bone, occurring predominantly in the second decade of life. High-dose cytotoxic chemotherapy and surgical resection have improved prognosis, with long-term survival for patients with localized disease. Vanadium is an ultra-trace element that after being absorbed accumulates in bone. Besides, vanadium compounds have been studied during recent years to be considered as representative of a new class of non-platinum antitumor agents. Moreover, flavonoids are a wide family of polyphenolic compounds that display many interesting biological effects. Since coordination of ligands to metals can improve the pharmacological properties, we report herein, for the first time, the in vitro and in vivo effects of an oxidovanadium(IV) complex with the flavonoid chrysin on the new 3D human osteosarcoma and xenograft osteosarcoma mice models. The pharmacological results show that VOchrys inhibited the cell viability affecting the shape and volume of the spheroids and VOchrys suppressed MG-63 tumor growth in the nude mice without inducing toxicity and side effects. As a whole, the results presented herein demonstrate that the antitumor action of the complex was very promissory on human osteosarcoma models, whereby suggesting that VOchrys is a potentially good candidate for future use in alternative antitumor treatments.