Amphiphilic Phosphorus Dendrons Associated with Anti-inflammatory siRNA Reduce Symptoms in Murine Collagen-Induced Arthritis.

Small interfering RNA (siRNA) holds promise for treating rheumatoid arthritis by inhibiting major cytokines such as tumor necrosis factor-α (TNF-α). We developed original cationic amphiphilic phosphorus dendrons to produce dendriplexes associated with TNF-α siRNA. The dendrons were made of 10 pyrrolidinium end groups and a C17 aliphatic chain. The dendriplexes demonstrated the ability to protect siRNA from nuclease degradation and to promote macrophage uptake. Moreover, they led to potent inhibition of TNF-α expression in the lipopolysaccharide-activated mouse macrophage cell line RAW264.7 in vitro model. A significant anti-inflammatory effect in the murine collagen-induced arthritis model was observed through arthritis scoring and histological observations. These results open up essential perspectives in using this original amphiphilic dendron to reduce the disease burden and improve outcomes in chronic inflammatory diseases.

The FcγRIIa-Syk Axis Controls Human Dendritic Cell Activation and T Cell Response Induced by Infliximab Aggregates.

The development of anti-drug Abs in response to biological products (BP) is a major drawback in the treatment of patients. Factors related to the patient, the treatment, and the product can influence BP immunogenicity. Among these factors, BP aggregates have been suggested to promote immunogenicity by acting as danger signals recognized by dendritic cells (DC) facilitating the establishment of an anti-BP CD4 T cell-dependent adaptive immune response leading to anti-drug Abs production. To date, little is known on the mechanism supporting the effect of aggregates on DCs and consequently on the T cell response. The aim of this work was to identify key signaling pathways involved in BP aggregate DC activation and T cell response. We generated aggregates by submitting infliximab (IFX), an immunogenic anti-TNF-α chimeric Ab, to heat stress. Our results showed that IFX aggregates were able to induce human monocyte-derived DC (moDC) maturation in a concentration-dependent manner. Aggregate-treated moDCs enhanced allogeneic T cell proliferation and IL-5, IL-9, and IL-13 production compared with native Ab-treated moDCs. We then investigated the implication of FcγRIIa and spleen tyrosine kinase (Syk) in DC activation and showed that they were both strongly implicated in moDC maturation induced by IFX aggregates. Indeed, we found that neutralization of FcγRIIa inhibited DC activation, and consequently, Syk inhibition led to a decrease in T cell proliferation and cytokine production in response to IFX aggregates. Taken together, our results bring new insight, to our knowledge, on how protein aggregates could induce DC and T cell activation via the FcγRIIa-Syk signaling pathway.

Highlighting the efficiency of ultrasound-based emulsifier-free emulsions to penetrate reconstructed human skin.

OBJECTIVE: The cosmetic industry endeavours to strengthen the greener and safer claims of processes to respond to the high demand from customers for natural and environmentally friendly products. High-frequency ultrasonication technology (HFUT) is a physical process enabling the stabilization of emulsions without requiring additional ingredients, such as emulsifying surfactants (ES) to be introduced into the formulations. In this study, key formulation characteristics of an emulsion synthesized by HFUT and a reference emulsion (RE) were compared, as well as the permeation kinetics of caffeine, used as a model active cosmetic ingredient, from both types of emulsions. METHODS: The pH, droplet size and viscosity of emulsions prepared by the HFUT and the RE were determined and compared. The permeation of caffeine from the HFUT emulsion and the RE applied to the surface of reconstructed human epidermis (RHE) models was compared. RESULTS: The ES-free formulations prepared by HFUT displayed a nearly 2-fold lower average droplet size and over 3-fold greater viscosity, compared to the RE. Despite these differences, the absence of ES in the HFUT emulsion did not significantly alter the permeation kinetics of caffeine through RHE. The caffeine steady-state flux, lag time and permeability coefficients differed by 20%-30% only. CONCLUSION: This study demonstrates the potential of the HFUT to yield topical cosmetic products with lower requirements ingredients-wise, without losing efficacy, supporting the possible implementation of the technology in the cosmetic industry.

OBJECTIF: l'industrie cosmétique œuvre à renforcer les revendications plus écologiques et plus sûres des processus pour répondre à la forte demande des clients de produits naturels et plus respectueux de l'environnement. La technologie d'ultrasons à haute fréquence (High-Frequency Ultrasonication Technology, HFUT) est un processus physique permettant de stabiliser les émulsions sans qu'il soit nécessaire d'ajouter des ingrédients supplémentaires, tels que des surfactants émulsifiants, aux formulations. Dans cette étude, les principales caractéristiques de formulation d'une émulsion synthétisée par HFUT et d'une émulsion de référence ont été comparées, ainsi que la cinétique de perméation de la caféine, utilisée comme ingrédient cosmétique actif modèle, dans les deux types d'émulsion. MÉTHODES: le pH, la taille des gouttelettes, et la viscosité de l'émulsion préparée par HFUT et de l'émulsion de référence ont été déterminés et comparés. La perméation de la caféine de l'émulsion HFUT et de l'émulsion de référence appliquées à la surface de modèles d'épiderme humain reconstruit a été comparée. RÉSULTATS: la formulation sans surfactants émulsifiants préparée par HFUT présentait une taille moyenne de gouttelettes presque 2 fois plus faible et une viscosité plus de 3 fois supérieure comparée à l'émulsion de référence. Malgré ces différences, l'absence de surfactants émulsifiants dans l'émulsion HFUT n'a pas significativement modifié la cinétique de perméation de la caféine dans l'épiderme humain reconstruit. Le flux à l'état d'équilibre de la caféine, le temps de latence et les coefficients de perméabilité différaient de 20 à 30 % uniquement. CONCLUSION: cette étude démontre le potentiel de la technologie HFUT à générer des produits cosmétiques topiques possédant des exigences plus faibles en termes d'ingrédients, sans perte d'efficacité, soutenant la mise en œuvre éventuelle de la technologie dans l'industrie cosmétique.

ß-Glucan Grafted Microcapsule, a Tool for Studying the Immunomodulatory Effect of Microbial Cell Wall Polysaccharides.

ß-(1,3)-Glucan is one of the antigenic components of the bacterial as well as fungal cell wall. We designed microcapsules (MCs) ligated with ß-(1,3)-glucan, to study its immunomodulatory effect. The MCs were obtained by interfacial polycondensation between diacyl chloride (sebacoyl chloride and terephtaloyl chloride) and diethylenetriamine in organic and aqueous phases, respectively. Planar films were first designed to optimize monomer compositions and to examine the kinetics of film formation. MCs with aqueous fluorescent core were then obtained upon controlled emulsification-polycondensation reactions using optimized monomer compositions and adding fluorescein into the aqueous phase. The selected MC-formulation was grafted with Curdlan, a linear ß-(1,3)-glucan from  Agrobacterium species or branched ß-(1,3)-glucan isolated from the cell wall of Aspergillus fumigatus. These ß-(1,3)-glucan grafted MCs were phagocytosed by human monocyte-derived macrophages, and stimulated cytokine secretion. Moreover, the blocking of dectin-1, a ß-(1,3)-glucan recognizing receptor, did not completely inhibit the phagocytosis of these ß-(1,3)-glucan grafted MCs, suggesting the involvement of other receptors in the recognition and uptake of ß-(1,3)-glucan. Overall, grafted MCs are a useful tool for the study of the mechanism of phagocytosis and immunomodulatory effect of the microbial polysaccharides.

Bare and Sterically Stabilized PLGA Nanoparticles for the Stabilization of Pickering Emulsions.

Pickering emulsions were formulated using biodegradable and biocompatible poly(lactic- co-glycolic acid) (PLGA) nanoparticles (NPs) prepared without surfactants or any other polymer than PLGA. A pharmaceutical and cosmetic oil (Miglyol) was chosen as the oil phase at a ratio of 10% w/w. These emulsions were then compared with emulsions using the same oil but formulated with well-described PLGA-poly(vinyl alcohol) (PVA) NPs, i.e., with PVA as NP stabilizers. Strikingly, the emulsions demonstrated very different structures at macroscopic, microscopic, and interfacial scales, depending on the type of NPs used. Indeed, the emulsion layer was significantly thicker when using PLGA NPs rather than PLGA-PVA NPs. This was attributed to the formation and coexistence of multiple water-in-oil-in-water (W/O/W) and simple oil-in-water (O/W) droplets, using a single step of emulsification, whereas simple O/W emulsions were obtained with PLGA-PVA NPs. The latter NPs were more hydrophilic than bare PLGA NPs because of the presence of PVA at their surface. Moreover, PLGA NPs only slightly lowered the oil/water interfacial tension whereas the decrease was more pronounced with PLGA-PVA NPs. The PVA chains at the PLGA-PVA NP surface could probably partially desorb from the NPs and adsorb at the interface, inducing the interfacial tension decrease. Finally, independent of their composition, NPs were adsorbed at the oil/water interface without influencing its rheological behavior, possibly due to their mobility at their interface. This work has direct implications in the formulation of Pickering emulsions and stresses the paramount influence of the physicochemical nature of the NP surface into the stabilization of these systems.

Comb-Like Fluorophilic-Lipophilic-Hydrophilic Polymers for Nanocapsules as Ultrasound Contrast Agents.

Imaging the enhanced permeation and retention effect by ultrasound is hindered by the large size of commercial ultrasound contrast agents (UCAs). To obtain nanosized UCAs, triblock copolymers of poly(ethylene glycol)-polylactide-poly(1 H,1 H,2 H,2 H-heptadecafluorodecyl methacrylate) (PEG-PLA-PFMA) with distinct numbers of perfluorinated pendant chains (5, 10, or 20) are synthesized by a combination of ring-opening polymerization and atom transfer radical polymerization. Nanocapsules (NCs) containing perfluorooctyl bromide (PFOB) intended as UCAs are obtained with a 2-fold increase in PFOB encapsulation efficiency in fluorinated NCs as compared with plain PEG-PLA NCs thanks to fluorous interactions. NC morphology is strongly influenced by the number of perfluorinated chains and the amount of polymer used for formulation, leading to peculiar capsules with several PFOB cores at high PEG-PLA-PFMA20 amount and single-cored NCs with a thinner shell at low fluorinated polymer amount, as confirmed by small-angle neutron scattering. Finally, fluorinated NCs yield higher in vitro ultrasound signal compared with PEG-PLA NCs, and no in vitro cytotoxicity is induced by fluorinated polymers and their degradation products. Our results highlight the benefit of adding comb-like fluorinated blocks in PEG-PLA polymers to modify the nanostructure and enhance the echogenicity of nanocapsules intended as UCAs.

Ethosomes and organogels for cutaneous administration of crocin.

The present study describes the production and characterization of phosphatidylcholine based ethosomes and organogels, as percutaneous delivery systems for crocin. Crocin presence did not influence ethosome morphology, while the drug slightly increased ethosome mean diameter. Importantly, the poor chemical stability of crocin has been found to be long controlled by organogel. To investigate the performance of phosphatidylcholine lipid formulations as crocin delivery system, in vivo studies, based on tape stripping and skin reflectance spectrophotometry, were performed. Tape stripping results suggested a rapid initial penetration of crocin exerted by the organogel, probably due to a strong interaction between the peculiar supramolecular aggregation structure of phospholipids in the vehicle and the lipids present in the stratum corneum and a higher maintenance of crocin concentration in the case of ethosomes, possibly because of the formation of a crocin depot in the stratum corneum. Skin reflectance spectrophotometry data indicated that both vehicles promoted the penetration of crocin through the skin, with a more rapid anti-inflammatory effect exploited by ethosomes, attributed to an ethanol pronounced penetration enhancer effect and to the carrier system as a whole.

Match of Solubility Parameters Between Oil and Surfactants as a Rational Approach for the Formulation of Microemulsion with a High Dispersed Volume of Copaiba Oil and Low Surfactant Content.

PURPOSE: Aim was to formulate oil-in-water (O/W) microemulsion with a high volume ratio of complex natural oil, i.e. copaiba oil and low surfactant content. The strategy of formulation was based on (i) the selection of surfactants based on predictive calculations of chemical compatibility between their hydrophobic moiety and oil components and (ii) matching the HLB of the surfactants with the required HLB of the oil. METHOD: Solubility parameters of the hydrophobic moiety of the surfactants and of the main components found in the oil were calculated and compared. In turn, required HLB of oils were calculated. Selection of surfactants was achieved matching their solubility parameters with those of oil components. Blends of surfactants were prepared with HLB matching the required HLB of the oils. Oil:water mixtures (15:85 and 25:75) were the titrated with surfactant blends until a microemulsion was formed. RESULTS: Two surfactant blends were identified from the predictive calculation approach. Microemulsions containing up to 19.6% and 13.7% of selected surfactant blends were obtained. CONCLUSION: O/W microemulsions with a high volume fraction of complex natural oil and a reasonable surfactant concentration were formulated. These microemulsions can be proposed as delivery systems for the oral administration of poorly soluble drugs.

Texturing formulations for uranium skin decontamination.

CONTEXT: Since no specific treatment exists in case of cutaneous contamination by radionuclides such as uranium, a nanoemulsion comprising calixarene molecules, known for their good chelation properties, was previously designed. However, this fluid topical form may be not suitable for optimal application on the skin or wounds. OBJECTIVE: To develop a texturing pharmaceutical form for the treatment of wounded skins contaminated by uranium. MATERIALS AND METHODS: The formulations consisted in oil-in-water (O/W) nanoemulsions, loaded with calixarene molecules. The external phase of the initial liquid nanoemulsion was modified with a combination of thermosensitive gelifying polymers: Poloxamer and HydroxyPropylMethylcellulose (HPMC) or methylcellulose (MC). These new formulations were characterized then tested by ex vivo experiments on Franz cells to prevent uranyl ions diffusion through excoriated pig ear skin explants. RESULTS: Despite strong changes in rheological properties, the physico-chemical characteristics of the new nanoemulsions, such as the size and the zeta potential as well as macroscopic aspect were preserved. In addition, on wounded skin, diffusion of uranyl ions, measured by ICP-MS, was limited to less than 5% for both HPMC and MC nanoemulsions. CONCLUSIONS: These results demonstrated that a hybrid formulation of nanoemulsion in hydrogel is efficient to treat uranium skin contamination.

An injectable, nanostructured implant for the delivery of adenosine triphosphate: towards long-acting formulations of small, hydrophilic drugs.

While long-acting injectable treatments are gaining increasing interest in managing chronic diseases, the available drug delivery systems almost exclusively rely on hydrophobic matrixes, limiting their application to either hydrophobic drugs or large and hydrophilic molecules such as peptides. To address the technological lock for long-acting delivery systems tailored to small, hydrophilic drugs such as anticancer and antiviral nucleoside/nucleotide analogues, we have synthesized and characterized an original approach with a multi-scale structure: (i) a nucleotide (adenosine triphosphate, ATP) is first incorporated in hydrophilic chitosan-Fe(III) nanogels; (ii) these nanogels are then transferred by freeze-drying and resuspension into a water-free, hydrophobic medium containing PLGA and an organic solvent, N-methyl-2-pyrrolidone. We show that this specific association allows an injectable and homogeneous dispersion, able to form in situ implants upon injection in physiological or aqueous environments. This system releases ATP in vitro without any burst effect in a two-step mechanism, first as nanogels acting as an intermediate reservoir over a week, then as free drug over several weeks. In vivo studies confirmed the potential of such nanostructured implants for sustained drug release following subcutaneous injection to mice hock, opening perspectives for sustained and targeted delivery through the lymphatic system.

Calcitermin-Loaded Smart Gels Activity against Candida albicans: A Preliminary In Vitro Study.

Calcitermin is an antimicrobial peptide of 15 amino acids found in human nasal fluid characterized by antifungal and antibacterial properties. Candida albicans is the most common human fungal pathogen affecting many tissues, such as vaginal mucosa. In this study a formulation suitable for calcitermin administration on vaginal mucosa was developed for the treatment of fungal infections. To favor topical application, mucosal adhesion, and permanence, gels based on poloxamer 407 and xanthan gum were designed and compared with regard to their rheological behavior, erosion, and leakage. The selected gel was loaded with calcitermin, whose release kinetic was evaluated in vitro by Franz cells. An antifungal activity assay was conducted to assess the calcitermin anticandidal potential and the effect of its inclusion in the selected gel. The rheological study revealed the elastic and viscous moduli behavior as a function of poloxamer 407 and xanthan gum concentration. Xanthan gum presence decreased the transition temperature of the gel, while prolonging its erosion and leakage. Particularly, poloxamer 407, 18% and xanthan gum 0.4% were chosen. The calcitermin loading in the selected gel resulted in a transparent and homogeneous formulation and in a 4-fold decrease of the release rate with respect to the calcitermin solution, as evidenced by Franz cell study. The anticandidal activity tests demonstrated that calcitermin-loaded gel was more active against Candida albicans with respect to the peptide solution.

Pickering emulsions stabilized with biodegradable nanoparticles for the co-encapsulation of two active pharmaceutical ingredients.

Innovative Pickering emulsions co-encapsulating two active pharmaceutical ingredients (API) were formulated for a topical use. An immunosuppressive agent, either cyclosporine A (CysA) or tacrolimus (TAC), was encapsulated at high drug loading in biodegradable and biocompatible poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NP). These NP stabilized the oil droplets (Miglyol) containing an anti-inflammatory drug, calcitriol (CAL). The influence of the API on the physico-chemical properties of these emulsions were studied. Emulsions formulated with or without API had a similar macroscopic and microscopic structure, as well as interfacial properties, and they exhibited a good stability for at least 55 days. The emulsions did not alter the viability of human keratinocytes (HaCaT cell line) after 2 and 5 days of exposure to NP concentrations equivalent to efficient API dosages. Thus, these new Pickering emulsions appear as a promising multidrug delivery system for the treatment of chronical inflammatory skin diseases.

PLA-PEG forming worm-like nanoparticles despite unfavorable packing parameter: Formation mechanism, thermal stability and potential for cell internalization.

Most nanoparticles produced for drug delivery purposes are spherical. However, the literature suggests that elongated particles are advantageous, notably in terms of cellular uptake. Thus, we synthesized biocompatible polylactide-b-poly(ethylene glycol) (PLA-PEG) polymers bearing carboxylate moieties, and used them to formulate worm-like nanoparticles by a simple emulsion-evaporation process. Worm-like nanoparticles with variable aspect ratio were obtained by simply adjusting the molar mass of the PLA block: the shorter the molar mass of the PLA block, the more elongated the particles. As PLA molar mass decreased from 80,000 g/mol to 13,000 g/mol, the proportion of worm-like nanoparticles increased from 0 to 46%, in contradiction with the usual behavior of block polymers based on their packing parameter. To explain this unusual phenomenon, we hypothesized the shape arises from a combination of steric and electrostatic repulsions between PEG chains bearing a carboxylate moiety present at the dichloromethane-water interface during the evaporation process. Worm-like particles turned out to be unstable when incubated at 37 °C, above polymer glass transition temperature. Indeed, above Tg, a Plateau-Rayleigh instability occurs, leading to the division of the worm-like particles into spheres. However, this instability was slow enough to assess worm-like particles uptake by murine macrophages. A slight but significant increase of internalization was observed for worm-like particles, compared to their spherical counterparts, confirming the interest of developing biocompatible anisotropic nanoparticles for pharmaceutical applications such as drug delivery.

Natural Polyphenol-Containing Gels against HSV-1 Infection: A Comparative Study.

Herpes simplex virus type 1 infection commonly affects many people, causing perioral sores, as well as severe complications including encephalitis in immunocompromised patients. The main pharmacological approach involves synthetic antiviral drugs, among which acyclovir is the golden standard, often leading to resistant virus strains under long-term use. An alternative approach based on antiviral plant-derived compounds, such as quercetin and mangiferin, demonstrated an antiviral potential. In the present study, semisolid forms for cutaneous application of quercetin and mangiferin were designed and evaluated to treat HSV-1 infection. Phosphatidylcholine- and poloxamer-based gels were produced and characterized. Gel physical-chemical aspects were evaluated by rheological measurements and X-ray diffraction, evidencing the different thermoresponsive behaviors and supramolecular organizations of semisolid forms. Quercetin and mangiferin diffusion kinetics were compared in vitro by a Franz cell system, demonstrating the different gel efficacies to restrain the polyphenol diffusion. The capability of gels to control polyphenol antioxidant potential and stability was evaluated, indicating a higher stability and antioxidant activity in the case of quercetin loaded in poloxamer-based gel. Furthermore, a plaque reduction assay, conducted to compare the virucidal effect of quercetin and mangiferin loaded in gels against the HSV-1 KOS strain, demonstrated the suitability of poloxamer-based gel to prolong the polyphenol activity.

Mucoadhesive Poloxamer-Based Hydrogels for the Release of HP-ß-CD-Complexed Dexamethasone in the Treatment of Buccal Diseases.

Oral lichen planus (OLP) is an ongoing and chronic inflammatory disease affecting the mucous membrane of the oral cavity. Currently, the treatment of choice consists in the direct application into the buccal cavity of semisolid formulations containing a corticosteroid molecule to decrease inflammatory signs and symptoms. However, this administration route has shown various disadvantages limiting its clinical use and efficacy. Indeed, the frequency of application and the incorrect use of the preparation may lead to a poor efficacy and limit the treatment compliance. Furthermore, the saliva clearance and the mechanical stress present in the buccal cavity also involve a decrease in the mucosal exposure to the drug. In this context, the design of a new pharmaceutical formulation, containing a steroidal anti-inflammatory, mucoadhesive, sprayable and exhibiting a sustained and controlled release seems to be suitable to overcome the main limitations of the existing pharmaceutical dosage forms. The present work reports the formulation, optimization and evaluation of the mucoadhesive and release properties of a poloxamer 407 thermosensitive hydrogel containing a poorly water-soluble corticosteroid, dexamethasone acetate (DMA), threaded into hydroxypropyl-beta-cyclodextrin (HP-ß-CD) molecules. Firstly, physicochemical properties were assessed to ensure suitable complexation of DMA into HP-ß-CD cavities. Then, rheological properties, in the presence and absence of various mucoadhesive agents, were determined and optimized. The hydration ratio (0.218-0.191), the poloxamer 407 (15-17 wt%) percentage and liquid-cyclodextrin state were optimized as a function of the gelation transition temperature, viscoelastic behavior and dynamic flow viscosity. Deformation and resistance properties were evaluated in the presence of various mucoadhesive compounds, being the sodium alginate and xanthan gum the most suitable to improve adhesion and mucoadhesion properties. Xanthan gum was shown as the best agent prolonging the hydrogel retention time up to 45 min. Furthermore, xanthan gum has been found as a relevant polymer matrix controlling drug release by diffusion and swelling processes in order to achieve therapeutic concentration for prolonged periods of time.

"Plurethosome" as Vesicular System for Cutaneous Administration of Mangiferin: Formulative Study and 3D Skin Tissue Evaluation.

Human skin is dramatically exposed to toxic pollutants such as ozone. To counteract the skin disorders induced by the air pollution, natural antioxidants such as mangiferin could be employed. A formulative study for the development of vesicular systems for mangiferin based on phosphatidylcholine and the block copolymer pluronic is described. Plurethosomes were designed for mangiferin transdermal administration and compared to ethosome and transethosome. Particularly, the effect of vesicle composition was investigated on size distribution, inner and outer morphology by photon correlation spectroscopy, small angle X-ray diffraction, and transmission electron microscopy. The potential of selected formulations as vehicles for mangiferin was studied, evaluating encapsulation efficiency and in vitro diffusion parameters by Franz cells. The mangiferin antioxidant capacity was verified by the 2,2-diphenyl-1-picrylhydrazyl assay. Vesicle size spanned between 200 and 550 nm, being influenced by phosphatidylcholine concentration and by the presence of polysorbate or pluronic. The vesicle supramolecular structure was multilamellar in the case of ethosome or plurethosome and unilamellar in the case of transethosome. A linear diffusion of mangiferin in the case of ethosome and transethosomes and a biphasic profile in the case of plurethosomes indicated the capability of multilamellar vesicles to retain the drug more efficaciously than the unilamellar ones. The antioxidant and anti-inflammatory potential effect of mangiferin against pollutants was evaluated on 3D human skin models exposed to O3. The protective effect exerted by plurethosomes and transethosomes suggests their possible application to enhance the cutaneous antioxidant defense status.

Mangiferin-Loaded Smart Gels for HSV-1 Treatment.

Infections due to HSV-1 affect many people all over the world. To counteract this pathology, usually characterized by perioral sores or by less frequent serious symptoms including keratitis, synthetic antiviral drugs are employed, such as acyclovir, often resulting in resistant viral strains under long-term use. Many plant-derived compounds, such as mangiferin and quercetin, have demonstrated antiviral potentials. In this study, smart semisolid forms based on phosphatidylcholine and Pluronic were investigated as delivery systems to administer mangiferin on skin and mucosae affected by HSV-1 infection. Particularly, lecithin organogels, Pluronic gel, and Pluronic lecithin organogels were formulated and characterized. After the selection of gel compositions, physical aspects, such as rheological behavior, spreadability, leakage, and adhesion were evaluated, suggesting a scarce suitability of the lecithin organogel for topical administration. Mangiferin was efficiently included in all type of gels. An in vitro study based on the Franz cell enabled us to find evidence of the gel capability to control drug diffusion, especially in the case of Pluronic organogel, while an in vivo study conducted on human volunteers demonstrated the safeness of all of the gels after cutaneous administration. Furthermore, a plaque reduction assay demonstrated the virucidal effect of mangiferin loaded in a Pluronic gel and a Pluronic lecithin organogel against the HSV-1 KOS strain.

Tuning morphology of Pickering emulsions stabilised by biodegradable PLGA nanoparticles: How PLGA characteristics influence emulsion properties.

In this study, we proved that the stabilisation of Pickering emulsions by polymer nanoparticles (NPs) heavily depends on polymer characteristics. We prepared NPs with four poly(lactide-co-glycolide) polymers (PLGA), of different molar masses (14,000 and 32,000 g/mol) and end groups (acid or alkylester). NPs were either bare (without stabilising polymer) or covered by polyvinyl alcohol (PVA). Pickering emulsions were prepared by mixing NP aqueous suspensions with various amounts of oil (Miglyol 812 N). First, NP wettability was directly affected by PLGA end group: ester-ending PLGA led to more hydrophobic NPs, compared to acid-ending PLGA. This effect of the end group could be slightly enhanced with smaller molar mass. Thus, bare PLGA NPs stabilised different types of emulsions (W/O/W and W/O), following Finkle's rule. However, the effect of PLGA characteristics was masked when NPs were covered by PVA, as PVA drove the stabilisation of O/W emulsions. Secondly, PLGA molar mass and end group also influenced its glass transition temperature (Tg), with spectacular consequences on emulsion formation. Indeed, the shortest ester-ending PLGA exhibited a Tg close to room temperature, when measured in the emulsion. This Tg, easily exceeded during emulsification process, led to a soft solid emulsion, stabilised by a network of NP debris.

Pitch, Timbre and Intensity Interdependently Modulate Neural Responses to Salient Sounds.

As we listen to everyday sounds, auditory perception is heavily shaped by interactions between acoustic attributes such as pitch, timbre and intensity; though it is not clear how such interactions affect judgments of acoustic salience in dynamic soundscapes. Salience perception is believed to rely on an internal brain model that tracks the evolution of acoustic characteristics of a scene and flags events that do not fit this model as salient. The current study explores how the interdependency between attributes of dynamic scenes affects the neural representation of this internal model and shapes encoding of salient events. Specifically, the study examines how deviations along combinations of acoustic attributes interact to modulate brain responses, and subsequently guide perception of certain sound events as salient given their context. Human volunteers have their attention focused on a visual task and ignore acoustic melodies playing in the background while their brain activity using electroencephalography is recorded. Ambient sounds consist of musical melodies with probabilistically-varying acoustic attributes. Salient notes embedded in these scenes deviate from the melody's statistical distribution along pitch, timbre and/or intensity. Recordings of brain responses to salient notes reveal that neural power in response to the melodic rhythm as well as cross-trial phase alignment in the theta band are modulated by degree of salience of the notes, estimated across all acoustic attributes given their probabilistic context. These neural nonlinear effects across attributes strongly parallel behavioral nonlinear interactions observed in perceptual judgments of auditory salience using similar dynamic melodies; suggesting a neural underpinning of nonlinear interactions that underlie salience perception.

Design and Characterization of Ethosomes for Transdermal Delivery of Caffeic Acid.

The present investigation describes a formulative study aimed at designing ethosomes for caffeic acid transdermal administration. Since caffeic acid is characterized by antioxidant potential but also high instability, its encapsulation appears to be an interesting strategy. Ethosomes were produced by adding water into a phosphatidylcholine ethanol solution under magnetic stirring. Size distribution and morphology of ethosome were investigated by photon correlation spectroscopy, small-angle X-ray spectroscopy, and cryogenic transmission electron microscopy, while the entrapment capacity of caffeic acid was evaluated by high-performance liquid chromatography. Caffeic acid stability in ethosome was compared to the stability of the molecule in water, determined by mass spectrometry. Ethosome dispersion was thickened by poloxamer 407, obtaining an ethosomal gel that was characterized for rheological behavior and deformability. Caffeic acid diffusion kinetics were determined by Franz cells, while its penetration through skin, as well as its antioxidant activity, were evaluated using a porcine skin membrane-covered biosensor based on oxygen electrode. Ethosome mean diameter was ≈200 nm and almost stable within three months. The entrapment of caffeic acid in ethosome dramatically prolonged drug stability with respect to the aqueous solution, being 77% w/w in ethosome after six months, while in water, an almost complete degradation occurred within one month. The addition of poloxamer slightly modified vesicle structure and size, while it decreased the vesicle deformability. Caffeic acid diffusion coefficients from ethosome and ethosome gel were, respectively, 137- and 33-fold lower with respect to the aqueous solution. At last, the caffeic acid permeation and antioxidant power of ethosome were more intense with respect to the simple solution.