Preparation of core-crosslinked linear-dendritic copolymer micelles with enhanced stability and their application for drug solubilisation

In this study we explore the preparation of core-crosslinked micelles of linear-dendritic methoxy-poly(ethylene glycol) (MPEG)-copoly(ester-sulfide) (PES) polymers to improve the stability of such polymeric micelle systems against premature disintegration and drug release. A series of MPEG-PES copolymers were synthesised via stepwise reactions of acetylation and thiol-ene photoreaction. Surface tension measurement showed that the copolymers with ethenyl surface groups could self-associate in dilute aqueous solutions to form micelles. Crosslinking within the micelle cores in the presence of dithioerythritol (DTT) linker was initiated under UV radiation. The formation of core-crosslinked micelles was confirmed by HPLC in combination with charged aerosol detection (CAD). The copolymers were found to readily hydrolyse under acidic conditions due to the ester-containing dendrons. Drug solubilisation capacities of the micellar solutions were determined using griseofulvin as a poorly water-soluble model drug. The solubility of griseofulvin showed a 10-fold enhancement in 1% w/v micelle solution and increased with the concentration of the copolymers. Drug release studies indicated that a more sustained release of griseofulvin was achieved for the core-crosslinked micelles compared to the non-crosslinked micelles, attributable to greater stability of the crosslinked core structure. The findings of this study present a new pathway towards developing biodegradable polymeric nanocarriers

Source-level runtime validation through interval temporal logic

The high degree of software complexity achievable through current software development practices makes software more prone to failure. A number of work and work practices has evolved in order to reduce risks related to software correctness and reliability. One of which is validation, which monitors the system execution at runtime and verifies that the system states entered are valid according to the behavioural specification. This paper describes a framework providing an assertion like validation environment for integrating software properties specified in interval temporal logic. The framework consists in three parts. The first part provides a mechanism for converting the human readable assertion to a symbolic automata, which is then used by the second part of the framework that performs the validation.peer-reviewe

Runtime validation using interval temporal logic

Formal specifications are one of the design choices in reactive and/or real-time systems as a number of notations exist to formally define parts of the system. However, defining the system formally is not enough to guarantee correctness thus the specifications are used as execution monitors over the system. A number of projects are around that provides a framework to define execution monitors in Interval Temporal Logic (ITL), such as Temporal-Rover, EAGLE Flier, and D3CA framework. This paper briefly describes the D3CA framework, consisting in the adaptation of Quantified Discrete-Time Duration Calculus to monitoring assertions. The D3CA framework uses the synchronous data-flow programming language Lustre as a generic platform for defining the notation. Additionally, Lustre endows the framework with the ability to predetermine the space and time requirements of the monitoring system. After defining the notation framework the second part of the paper presents two case studies - a mine pump and an answering machine. The case studies illustrate the power endowed by using ITL observers in a reactive or event-driven system.peer-reviewe

The Effects of Red-Grape Seed and Pomace-Flour Dietary Supplementation on Broiler Chickens

Wine by-products, generated in large quantities and wasted with serious environmental and economic consequences, are an exceptional alternative to conventional and non-sustainable food sources. The aim of the study was to understand if these by-products could be reused in feed for broiler chickens, improving certain blood parameters important in immune responses, by testing different concentrations and administration times. The effects of the grape-seed and pomace flour of red-wine waste were evaluated. Three different diets were tested containing pomace (0%, 3%, and 6%), grape seeds (0%, 3%, and 6%), and a mix of pomace and grape seeds (0 and 3%) for 7, 21, and 42 days. Esterase, alkaline phosphatase, and peroxidase activity, along with glucose, reactive oxygen species, and glutathione levels, were evaluated in blood samples. The results showed significant changes in the parameters analyzed, especially after 21 and 42 days of administration. All diets administered showed significant effects based on exposure time and by-product concentration used. The greatest effects seem to have come from grape-seed flour. All the by-products of wine production analyzed in this study showed important antioxidant activities and can be included in the food context of farm animals in different growth phases at different concentrations

Natural and Synthetic Polymers as Inhibitors of Drug Efflux Pumps

Inhibition of efflux pumps is an emerging approach in cancer therapy and drug delivery. Since it has been discovered that polymeric pharmaceutical excipients such as Tweens® or Pluronics® can inhibit efflux pumps, various other polymers have been investigated regarding their potential efflux pump inhibitory activity. Among them are polysaccharides, polyethylene glycols and derivatives, amphiphilic block copolymers, dendrimers and thiolated polymers. In the current review article, natural and synthetic polymers that are capable of inhibiting efflux pumps as well as their application in cancer therapy and drug delivery are discussed

Solubility enhancement of paclitaxel using a linear-dendritic block copolymer

The solubilising capacities of micelles of a linear-dendritic copolymer (BE-PAMAM), formed by conjugating the poly(butylene oxide) (B)–poly(ethylene oxide) (E) block copolymer B16E42 (BE) with a G2 PAMAM dendrimer, have been compared with those of the diblock copolymer B16E42 for the anti-cancer drug paclitaxel. The BE-PAMAM copolymer showed a greater solubility enhancement than BE under equivalent conditions. Drug-loading efficiency was improved using a solvent-loading method compared with the conventional solution-loading method. The solubility of paclitaxel was increased 3700-fold by micellar encapsulation in a 2% (w/v) BE–PAMAM copolymer solution at 37 °C using this solubilisation technique. Dynamic light scattering and transmission electron microscopy studies indicated a transition of spherical to worm-like micelles of the BE copolymer induced by the encapsulation of drug molecules. A sustained release of encapsulated drug was observed, with approximately 80% and 60% paclitaxel being released from 2% (w/v) solutions of BE and BE-PAMAM respectively after 24 h of dialysis at 37 °C

RNAi-combined nano-chemotherapeutics to tackle resistant tumors

The merger of nanotechnology and combination chemotherapy has shown notable promise in the therapy of resistant tumors. The latest scientific attention encompasses the engagement of anticancer drugs in combination with small interfering (si)RNAs, such as VEGF, XLAP, PGP, MRP-1, BCL-2 and cMyc, to name but a few. siRNAs have shown immense promise to knockout drug resistance genes as well as to recover the sensitivity of resistant tumors to anticancer therapy. The nanotechnology approach could also protect siRNA against RNAse degradation as well as prevent off-target effects. In this article, we discuss the approaches that have been used to deliver of siRNA in combination with chemotherapeutic drugs to treat resistant tumors. We also discuss the stipulations that must be considered in formulating a nanotechnology-assisted siRNA-drug cancer therapy

PAMAM dendrimers as aerosol drug nanocarriers for pulmonary delivery via nebulization

Polyamidoamine (PAMAM) dendrimers were evaluated as nanocarriers for pulmonary delivery of the model poorly soluble anti-asthma drug beclometasone dipropionate (BDP) using G3, G4 and G4(12) dendrimers. BDP-loaded dendrimers were characterized for drug solubility, in vitro drug release and aerosolization properties using three nebulizers: Pari LC Sprint (air-jet), Aeroneb Pro (actively vibrating-mesh) and Omron MicroAir (passively vibrating-mesh) nebulizers. Solubilization of BDP using dendrimers was increased by increasing the dendrimer generation and by using higher pH media. In vitro release studies showed that BDP when complexed with dendrimers exhibited a sustained release, and for all dendrimer formulations less than 35% of the drug was released after 8 h. Nebulization studies revealed that aerosol performance was dependent on nebulizer rather than dendrimer generation. Nebulization output values for the Pari (air-jet) and Aeroneb Pro (active mesh) nebulizers were in the range of 90–92% and 85–89% respectively compared to 57–63% for the Omron (passive mesh) nebulizer. The size of the droplets generated from the jet nebulizer was slightly smaller and aerosol polydispersity was lower compared to both mesh devices. The “fine particle fraction (FPF)” of the aerosols was in the following order: Pari (air-jet) > Aeroneb Pro (active mesh) > Omron (passive mesh). This study demonstrates that BDP-dendrimers have potential for pulmonary inhalation using air-jet and vibrating-mesh nebulizers. Moreover, the aerosol characteristics are influenced by nebulizer design rather than dendrimer generation

Análisis de la molienda de expeller de soja evaluando la performance de diferentes tipos de molinos

El objetivo del presente trabajo es analizar la performance del proceso de molienda y tamizado de expeller de soja, subproducto de la extracción de aceite por el método de extrusado-prensado, para su posterior utilización en la obtención de productos proteicos. La molienda se realiza con tres molinos diferentes: de bolas (impacto), de rodillos (cizalla y compresión) y de cuchillas (cizalla), bajo diferentes condiciones de operación. El análisis de tamizado se realiza utilizando la serie de tamices ASTM Nº 5, 6, 10, 12, 25, 30 y ciego. Los productos obtenidos se clasifican en finos, medios, y gruesos, analizándose así los rendimientos de cada fracción en cada molino. Al ser la fracción de interés la correspondiente a las partículas de tamaño medio, se concluye que los molinos de cuchillas y de rodillos son más adecuados debido a que se alcanzan rendimientos superiores al 55% cuando se los opera con una sola pasada. Asimismo, se calculan y reportan las energías específicas desarrolladas en las moliendas con la Ley de Bond para exponer una comparativa.The objective of this work is to analyze the performance of a milling and grinding process for soybean expeller, which is a by-product of the oil extraction by means of the extruding-pressing method, for its later use in obtaining protein products. Milling is done with three different mills: balls (impact), rollers (shear and compression) and blades (shear), under different operating conditions. The analysis of the grinding operation is done using the ASTM sieve series Nº 5, 6, 10, 12, 25, 30 and pan. The obtained products are classified in fine, medium and large, thus analyzing the yields of each fraction in each mill. Being the interest’s fraction the corresponding to medium sized particles, it is concluded that the roller and blades mills are the most adequate once since yields greater than 55% are achieved when operated with a single pass. Also, the specific energies developed for the milling were calculated with the Bond’s Law for comparison purposes.EEA OliverosFil: D'Emanuele Ares, Carolina. Universidad Tecnológica Nacional. Regional Rosario. Centro de Aplicaciones Informáticas y Modelado en Ingeniería; Argentina. Universidad Tecnológica Nacional. Facultad Regional Rosario; ArgentinaFil: Accoroni, Cecilia. Universidad Tecnológica Nacional. Regional Rosario. Centro de Aplicaciones Informáticas y Modelado en Ingeniería; Argentina. Universidad Tecnológica Nacional. Facultad Regional Rosario; Argentina. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Oliveros. Agencia de Extensión Rural Totoras; ArgentinaFil: Ferigutti, Leonardo. Universidad Tecnológica Nacional. Regional Rosario. Centro de Aplicaciones Informáticas y Modelado en Ingeniería; Argentina. Universidad Tecnológica Nacional. Facultad Regional Rosario; ArgentinaFil: Godoy, Ezequiel. Universidad Tecnológica Nacional. Regional Rosario. Centro de Aplicaciones Informáticas y Modelado en Ingeniería; Argentina. Universidad Tecnológica Nacional. Facultad Regional Rosario; ArgentinaFil: Reinheimer, Maria Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Tecnológica Nacional. Regional Rosario. Centro de Aplicaciones Informáticas y Modelado en Ingeniería; Argentin