Nanocarriers overcoming biological barriers induced by multidrug resistance of chemotherapeutics in 2D and 3D cancer models.

Multidrug resistance (MDR) is currently a big challenge in cancer therapy and limits its success in several patients. Tumors use the MDR mechanisms to colonize the host and reduce the efficacy of chemotherapeutics that are injected as single agents or combinations. MDR mechanisms are responsible for inactivation of drugs and formbiological barriers in cancer like the drug efflux pumps, aberrant extracellular matrix, hypoxic areas, altered cell death mechanisms, etc. Nanocarriers have some potential to overcome these barriers and improve the efficacy of chemotherapeutics. In fact, they are versatile and can deliver natural and synthetic biomolecules, as well as RNAi/DNAi, thus providing a controlled release of drugs and a synergistic effect in tumor tissues. Biocompatible and safe multifunctional biopolymers, with or without specific targeting molecules, modify the surface and interface properties of nanocarriers. These modifications affect the interaction of nanocarriers with cellular models as well as the selection of suitable models for in vitro experiments. MDR cancer cells, and particularly their 2D and 3D models, in combination with anatomical and physiological structures of tumor tissues, can boost the design and preparation of nanomedicines for anticancer therapy. 2D and 3D cancer cell cultures are suitable models to study the interaction, internalization, and efficacy of nanocarriers, the mechanisms of MDR in cancer cells and tissues, and they are used to tailor a personalized medicine and improve the efficacy of anticancer treatment in patients. The description of molecular mechanisms and physio-pathological pathways of these models further allow the design of nanomedicine that can efficiently overcome biological barriers involved in MDR and test the activity of nanocarriers in 2D and 3D models of MDR cancer cells.

In Situ Swelling Formulation of Glycerol-Monooleate-Derived Lyotropic Liquid Crystals Proposed for Local Vaginal Application.

Hydrogels have been extensively investigated to identify innovative formulations that can fulfill all the necessary purposes to improve local vaginal therapy through the mucosa. Herein, we propose in situ-forming lyotropic liquid crystals (LLCs) derived from a cheap and GRAS (generally recognized as safe) ingredient as an intravaginal delivery system. The system consists of a precursor solution loaded with sertaconazole nitrate as a model drug, which is able to easily swell in a stable three-dimensional structure by absorbing simulated vaginal fluid. Under polarized light microscopy the precursor solution and the formed phase of LLCs showed the typical textures belonging to anisotropic and an isotropic mesophases, respectively. A deep rheological investigation by Kinexus® Pro proved the stability and strength of the cubic phase, as well as its potential in mucoadhesion. In vitro degradation studies showed a slow matrix erosion, consistent with data obtained from lipophilic drug release studies in simulated vaginal fluid. Therefore, the suggested cubic phase based on lyotropic liquid crystals could represent a valid proposal as a vaginal drug delivery system due to its characteristics of resistance, adhesion and the possibility of providing a slow and controlled release of drugs directly at the administration site.

A comparison between silicone-free and silicone-based emulsions: Technological features and in vivo evaluation.

OBJECTIVE: Nowadays, the use of silicones in cosmetic formulation is still controversial, given that "natural" or "biodegradable" components are preferred. Often, the exclusion and/or the discrimination of these excipients from cosmetic field are unmotivated because all things cannot be painted with the same brush. Hence, we want to bring to light and underline the advantages of including silicones in cosmetic emulsions, refuting and debunking some myths related to their use. METHODS: Silicone-free and silicone-based emulsions were obtained within an easy homogenization process. Droplet size distribution was assessed by laser diffraction particle size analyser Mastersizer 2000™, and by optical microscopy. The long-time stability profiles were investigated thanks to the optical analyser Turbiscan® Lab Expert. Diffusing wave spectroscopy (DWS) by Rheolaser Master™ and frequency sweep measurements by Kinexus® Pro Rotational Rheometer were carried out to assess a full rheological characterization. In vivo studies were carried out by the evaluation of Trans Epidermal Water Loss (TEWL) over time on healthy human volunteers. A skin feeling rating was collected from the same volunteers by questionnaire. RESULTS: From size distribution analysis, a better coherence of data appeared for silicone-based emulsion, as the size of the droplets was kept unchanged after 1 month, as well as the uniformity parameter. Morphological investigation confirmed a homogenous droplet distribution for both samples. Silicones enhanced the viscosity, compactness and strength of the cream, providing a suitable stability profile both at room temperature and when heated at 40°C. The solid-like viscoelastic behaviour was assessed in the presence of dynamic oscillatory stresses. The monitoring of TEWL over time demonstrated non-occlusive properties of emulsions containing silicones, the values of which were comparable to the negative control. Silicone-based emulsions gained higher scores from the volunteers in silkiness, freshness and softness features, while lower scores were obtained in greasiness compared to silicone-free emulsions. No cases of irritation were recorded by the candidates. CONCLUSION: The presence of specific silicones inside a cosmetic product improved its technological characteristics. The rheological identity and the stability feature showed the real suitability of prepared emulsion as a cosmetic product. Moreover, this study demonstrated that silicone-based emulsions are safe for the skin and did not cause skin occlusion. Improved skin sensations are registered by potential consumers when silicones are included in the formulation.

OBJECTIF: De nos jours, l'utilisation de silicones dans la formulation cosmétique reste controversée, étant donné que les ingrédients «naturels¼ ou «biodégradables¼ sont privilégiés. Souvent, l'exclusion et/ou la discrimination de ces excipients du domaine cosmétique ne sont pas motivées, parce que tous les éléments ne peuvent pas être logés à la même enseigne. Par conséquent, nous souhaitons mettre en évidence et souligner les avantages de l'inclusion des silicones dans les émulsions cosmétiques, tout en réfutant et en démystifiant certains mythes liés à leur utilisation. MÉTHODES: Des émulsions sans silicone et des émulsions à base de silicone ont été obtenues dans le cadre d'un processus d'homogénéisation facile. La distribution des tailles de gouttelettes a été évaluée par diffraction laser avec le granulomètre Mastersizer 2000™ et par microscopie optique. Les profils de stabilité à long terme ont été étudiés grâce à l'analyseur optique Turbiscan® Lab Expert. La spectroscopie par diffusion d'ondes (Diffusing Wave Spectroscopy, DWS) par le Rheolaser Master™ et les mesures de balayage de fréquence par le rhéomètre rotatif Kinexus® Pro ont été réalisées pour évaluer une caractérisation rhéologique complète. Des études in vivo ont été menées par le biais de l'évaluation de la perte d'eau transépidermique (PETE) au fil du temps sur des volontaires humains en bonne santé. Une évaluation de la sensation cutanée a été recueillie auprès des mêmes volontaires par le biais d'un questionnaire. RÉSULTATS: L'analyse de la distribution des tailles a révélé une meilleure cohérence des données pour l'émulsion à base de silicone, car la taille des gouttelettes a été maintenue inchangée après 1 mois, ainsi que le paramètre d'uniformité. L'investigation morphologique a confirmé une distribution homogène des gouttelettes pour les deux échantillons. Les silicones ont amélioré la viscosité, la densité et la résistance de la crème, offrant ainsi un profil de stabilité approprié aussi bien à température ambiante qu'après chauffage à 40°C. Le comportement viscoélastique analogue à celui d'un solide a été évalué en présence de contraintes oscillatoires dynamiques. Le suivi de la perte d'eau transépidermique (PETE) au fil du temps a établi des propriétés non occlusives des émulsions contenant des silicones, dont les valeurs étaient comparables à celles du contrôle négatif. Les émulsions à base de silicone ont obtenu des scores plus élevés chez les volontaires en termes de caractéristiques de douceur, de fraîcheur et de souplesse, tandis que des scores plus faibles ont été obtenus en termes d'onctuosité par rapport aux émulsions sans silicone. Aucun cas d'irritation n'a été enregistré chez les candidats. CONCLUSION: La présence de silicones spécifiques dans un produit cosmétique a amélioré ses caractéristiques technologiques. L'identité rhéologique et la caractéristique de stabilité ont montré la pertinence réelle d'une émulsion préparée en tant que produit cosmétique. De plus, cette étude a démontré que les émulsions à base de silicone sont sans danger pour la peau et n'ont provoqué aucune occlusion cutanée. Les consommateurs potentiels enregistrent une amélioration des sensations cutanées lorsque des silicones sont inclus dans la formulation.

Conventional Nanosized Drug Delivery Systems for Cancer Applications.

Clinical responses and tolerability of conventional nanocarriers (NCs) are sometimes different from those expected in anticancer therapy. Thus, new smart drug delivery systems (DDSs) with stimuli-responsive properties and novel materials have been developed. Several clinical trials demonstrated that these DDSs have better clinical therapeutic efficacy in the treatment of many cancers than free drugs. Composition of DDSs and their surface properties increase the specific targeting of therapeutics versus cancer cells, without affecting healthy tissues, and thus limiting their toxicity versus unspecific tissues. Herein, an extensive revision of literature on NCs used as DDSs for cancer applications has been performed using the available bibliographic databases.

Influence of Materials Properties on Bio-Physical Features and Effectiveness of 3D-Scaffolds for Periodontal Regeneration.

Periodontal diseases are multifactorial disorders, mainly due to severe infections and inflammation which affect the tissues (i.e., gum and dental bone) that support and surround the teeth. These pathologies are characterized by bleeding gums, pain, bad breath and, in more severe forms, can lead to the detachment of gum from teeth, causing their loss. To date it is estimated that severe periodontal diseases affect around 10% of the population worldwide thus making necessary the development of effective treatments able to both reduce the infections and inflammation in injured sites and improve the regeneration of damaged tissues. In this scenario, the use of 3D scaffolds can play a pivotal role by providing an effective platform for drugs, nanosystems, growth factors, stem cells, etc., improving the effectiveness of therapies and reducing their systemic side effects. The aim of this review is to describe the recent progress in periodontal regeneration, highlighting the influence of materials' properties used to realize three-dimensional (3D)-scaffolds, their bio-physical characteristics and their ability to provide a biocompatible platform able to embed nanosystems.

Cardiac Stem Cell-Loaded Delivery Systems: A New Challenge for Myocardial Tissue Regeneration.

Cardiovascular disease (CVD) remains the leading cause of death in Western countries. Post-myocardial infarction heart failure can be considered a degenerative disease where myocyte loss outweighs any regenerative potential. In this scenario, regenerative biology and tissue engineering can provide effective solutions to repair the infarcted failing heart. The main strategies involve the use of stem and progenitor cells to regenerate/repair lost and dysfunctional tissue, administrated as a suspension or encapsulated in specific delivery systems. Several studies demonstrated that effectiveness of direct injection of cardiac stem cells (CSCs) is limited in humans by the hostile cardiac microenvironment and poor cell engraftment; therefore, the use of injectable hydrogel or pre-formed patches have been strongly advocated to obtain a better integration between delivered stem cells and host myocardial tissue. Several approaches were used to refine these types of constructs, trying to obtain an optimized functional scaffold. Despite the promising features of these stem cells' delivery systems, few have reached the clinical practice. In this review, we summarize the advantages, and the novelty but also the current limitations of engineered patches and injectable hydrogels for tissue regenerative purposes, offering a perspective of how we believe tissue engineering should evolve to obtain the optimal delivery system applicable to the everyday clinical scenario.

Influence of Various Model Compounds on the Rheological Properties of Zein-Based Gels.

The controlled release of a compound entrapped in a biocompatible formulation is a sought-after goal in modern pharmaceutical technology. Zein is a hydrophobic protein which has several advantageous properties that make it suitable for use as a biocompatible and degradable material under physiological conditions. It is, therefore, proposed for different biomedical and pharmaceutical applications. In particular, due to its gelling properties, it can be used to form a polymeric network able to preserve biomolecules from harsh environments. The current study was designed to investigate the influence of different probes on the rheological properties of gels made up of zein, in order to characterize the systems as a function of the polymer concentration. Four model compounds characterized by different physico-chemical properties were entrapped in zein gels, and different behaviors (viscoelastic or pronounced solid-like characteristics) of the systems were observed. Zein-based gels showed various release profiles of the encapsulated compounds, suggesting that there are different interaction rates between the probes and the polymeric matrix.

The Rheolaser Master™ and Kinexus Rotational Rheometer® to Evaluate the Influence of Topical Drug Delivery Systems on Rheological Features of Topical Poloxamer Gel.

Poloxamer 407 copolymer is a versatile and widely used thermo-reversible material. Its use has many advantages, such as bio-adhesion, enhanced solubilization of poorly water-soluble drugs and many applications fields like oral, rectal, topical, nasal drug administration. Hydrogels made up of Poloxamer 407 are characterized by specific rheological features, which are affected by temperature, concentration and presence of other compounds. A strategic approach in topical therapeutic treatments may be the inclusion of drug delivery systems, such as ethosomes, transfersomes and niosomes, into hydrogel poloxamer formulation. The evaluation of the interaction between colloidal carriers and the Poloxamer 407 hydrogel network is essential for a suitable design of an innovative topical dosage form. For this reason, the Rheolaser Master™, based on diffusing wave spectroscopy, and a Kinexus Rotational Rheometer were used to evaluate the influence of nanocarriers on the microrheological features of hydrogels. The advantages of the Rheolaser Master™ analyzer are: (i) its ability to determine viscoelastic parameter, without altering or destroying the sample and at rest (zero shear); (ii) possibility of aging analysis on the same sample. This study provide evidence that vesicular systems do not influence the rheological features of the gel, supporting the possibility to encapsulate an innovative system into a three-dimensional network.

Liquid crystal delivery of ciprofloxacin to treat infections of the female reproductive tract.

Infections of the female reproductive tract are a major cause of morbidity and mortality in humans, requiring significant investment to sustain treatment and representing a major challenge to health. The increasing prevalence of bacterial resistance, and an almost complete absence of new antibiotic therapies for the past five decades, mean there is a desperate need for novel approaches to the treatment of bacterial infections. Within the present study, we demonstrate the effective ex vivo treatment of bacterial infection of the female reproductive tract using a controlled-release, liquid crystal-based platform. Liquid crystal encapsulation of ciprofloxacin significantly enhanced its bactericidal efficacy and reduced cell toxicity. Liquid crystal structures are low-cost, simple to manufacture and provide a sustained-release profile of encapsulated ciprofloxacin. Treatment of Escherichia coli infected reproductive tract epithelial cells and whole organ cultures with liquid crystal encapsulated ciprofloxacin proved to be an effective strategy for reducing bacterial load and reproductive tract inflammatory responses to infection. These data suggest that such an approach could provide an efficacious treatment modality for enhancing the effectiveness of current antibiotic therapies.

Niosomes as Drug Nanovectors: Multiscale pH-Dependent Structural Response.

The use of nanocarriers, which respond to different stimuli controlling their physicochemical properties and biological responsivness, shows a growing interest in pharmaceutical science. The stimuli are activated by targeting tissues and biological compartments, e.g., pH modification, temperature, redox condition, enzymatic activity, or can be physically applied, e.g., a magnetic field and ultrasound. pH modification represents the easiest method of passive targeting, which is actually used to accumulate nanocarriers in cells and tissues. The aim of this paper was to physicochemically characterize pH-sensitive niosomes using different experimental conditions and demonstrate the effect of surfactant composition on the supramolecular structure of niosomes. In this attempt, niosomes, made from commercial (Tween21) and synthetic surfactants (Tween20 derivatives), were physicochemically characterized by using different techniques, e.g., transmission electron microscopy, Raman spectroscopy, and small-angle X-ray scattering. The changes of niosome structure at different pHs depend on surfactants, which can affect the supramolecular structure of colloidal nanocarriers and their potential use both in vitro and in vivo. At pH 7.4, the shape and structure of niosomes have been maintained; however, niosomes show some differences in terms of bilayer thicknesses, water penetration, membrane coupling, and cholesterol dispersion. The acid pH (5.5) can increase the bilayer fluidity, and affect the cholesterol depletion. In fact, Tween21 niosomes form large vesicles with lower curvature radius at acid pH; while Tween20-derivative niosomes increase the intrachain mobility within a more interchain correlated membrane. These results demonstrate that the use of multiple physicochemical procedures provides more information about supramolecular structures of niosomes and improves the opportunity to deeply investigate the effect of stimuli responsiveness on the niosome structure.

Polyaspartamide-doxorubicin conjugate as potential prodrug for anticancer therapy.

PURPOSE: To synthesize a new polymeric prodrug based on α,ß-poly(N-2-hydroxyethyl)(2-aminoethylcarbamate)-d,l-aspartamide copolymer bearing amine groups in the side chain (PHEA-EDA), covalently linked to the anticancer drug doxorubicin and to test its potential application in anticancer therapy. METHODS: The drug was previously derivatized with a biocompatible and hydrophilic linker, leading to a doxorubicin derivative highly reactive with amino groups of PHEA-EDA. The PHEA-EDA-DOXO prodrug was characterized in terms of chemical stability. The pharmacokinetics, biodistribution and cytotoxicity of the product was investigated in vitro and in vivo on human breast cancer MCF-7 and T47D cell lines and NOD-SCID mice bearing a MCF-7 human breast carcinoma xenograft. Data collected were compared to those obtained using free doxorubicin. RESULTS: The final polymeric product is water soluble and easily hydrolysable in vivo, due to the presence of ester and amide bonds along the spacer between the drug and the polymeric backbone. In vitro tests showed a retarded cytotoxic effect on tumor cells, whereas a significant improvement of the in vivo antitumor activity of PHEA-EDA-DOXO and a survival advantage of the treated NOD-SCID mice was evidenced, compared to that of free doxorubicin. CONCLUSIONS: The features of the PHEA-EDA-DOXO provide a potential protection of the drug from the plasmatic enzymatic degradation and clearance, an improvement of the blood pharmacokinetic parameters and a suitable body biodistribution. The data collected support the promising rationale of the proposed macromolecular prodrug PHEA-EDA-DOXO for further potential development and application in the treatment of solid cancer diseases.

Evaluation of anticancer activity of celastrol liposomes in prostate cancer cells.

CONTEXT: Celastrol, a natural compound derived from the herb Tripterygium wilfordii, is known to have anticancer activity, but is not soluble in water. OBJECTIVE: Formation of celastrol liposomes, to avoid the use of toxic solubilising agents. MATERIALS AND METHODS: Two different formulations of PEGylated celastrol liposomes were fabricated. Liposomal characteristics and serum stability were determined using dynamic light scattering. Drug entrapment efficacy and drug release were measured spectrophotometrically. Cellular internalisation and anticancer activity was measured in prostate cancer cells. RESULTS: Liposomal celastrol displayed efficient serum stability, cellular internalisation and anticancer activity, comparable to that of the free drug reconstituted in dimethyl sulfoxide. DISCUSSION AND CONCLUSION: Liposomal celastrol can decrease the viability of prostate cancer cells, while eliminating the need for toxic solubilising agents.

Unraveling the impact of different liposomal formulations on the plasma protein corona composition might give hints on the targeting capability of nanoparticles.

Nanoparticles (NPs) interact with biological fluids after being injected into the bloodstream. The interactions between NPs and plasma proteins at the nano-bio interface affect their biopharmaceutical properties and distribution in the organ and tissues due to protein corona (PrC) composition, and in turn, modification of the resulting targeting capability. Moreover, lipid and polymer NPs, at their interface, affect the composition of PrC and the relative adsorption and abundance of specific proteins. To investigate this latter aspect, we synthesized and characterized different liposomal formulations (LFs) with lipids and polymer-conjugated lipids at different molar ratios, having different sizes, size distributions and surface charges. The PrC composition of various designed LFs was evaluated ex vivo in human plasma by label-free quantitative proteomics. We also correlated the relative abundance of identified specific proteins in the coronas of the different LFs with their physicochemical properties (size, PDI, zeta potential). The evaluation of outputs from different bioinformatic tools discovered protein clusters allowing to highlight: (i) common as well as the unique species for the various formulations; (ii) correlation between each identified PrC and the physicochemical properties of LFs; (iii) some preferential binding determined by physicochemical properties of LFs; (iv) occurrence of formulation-specific protein patterns in PrC. Investigating specific clusters in PrC will help decode the multivalent roles of the protein pattern components in the drug delivery process, taking advantage of the bio-nanoscale recognition and identification for significant advances in nanomedicine.

Improved anti-breast cancer activity by doxorubicin-loaded super stealth liposomes.

PEGylation is currently used for the synthesis of stealth liposomes and to enhance the pharmacokinetic and biopharmaceutical properties of payloads. PEGylated dendron phospholipids can decrease the detachment of polyethylene glycol (PEG) from the liposomal surface owing to an increased hydrophobic anchoring effect on the phospholipid bilayer of liposomes and thus generating super stealth liposomes that are suitable for the systemic delivery of anticancer drugs. Herein, doxorubicin hydrochloride-loaded super stealth liposomes were studied for the treatment of breast cancer lung metastasis in an animal model. The results demonstrated that the super stealth liposomes had suitable physicochemical properties for in vivo administration and could significantly increase the efficacy of doxorubicin in breast cancer lung metastasis tumor-bearing mice compared to the free drug. The super stealth liposomes also increased doxorubicin accumulation inside the tumor tissue. The permanence of PEG on the surface of the super stealth liposomes favored the formation of a depot of therapeutic nanocarriers inside the tumor tissue by improving their permanence after stopping treatment. The doxorubicin-loaded super stealth liposomes increased the survival of the mouse tumor model. These promising results demonstrate that the doxorubicin-loaded super stealth liposomes could be an effective nanomedicine to treat metastatic breast cancer.

OX26-cojugated gangliosilated liposomes to improve the post-ischemic therapeutic effect of CDP-choline.

Cerebrovascular impairment represents one of the main causes of death worldwide with a mortality rate of 5.5 million per year. The disability of 50% of surviving patients has high social impacts and costs in long period treatment for national healthcare systems. For these reasons, the efficacious clinical treatment of patients, with brain ischemic stroke, remains a medical need. To this aim, a liposome nanomedicine, with monosialic ganglioside type 1 (GM1), OX26 (an anti-transferrin receptor antibody), and CDP-choline (a neurotrophic drug) (CDP-choline/OX26Lip) was prepared. CDP-choline/OX26Lip were prepared by a freeze and thaw method and then extruded through polycarbonate filters, to have narrow size distributed liposomes of ~80 nm. CDP-choline/OX26Lip were stable in human serum, they had suitable pharmacokinetic properties, and 30.0 ± 4.2% of the injected drug was still present in the blood stream 12 h after its systemic injection. The post-ischemic therapeutic effect of CDP-choline/OX26Lip is higher than CDP-choline/Lip, thus showing a significantly high survival rate of the re-perfused post-ischemic rats, i.e. 96% and 78% after 8 days. The treatment with CDP-choline/OX26Lip significantly decreased the peroxidation rate of ~5-times compared to CDP-choline/Lip; and the resulting conjugated dienes, that was 13.9 ± 1.1 mmol/mg proteins for CDP-choline/Lip and 3.1 ± 0.8 for CDP-choline/OX26Lip. OX26 increased the accumulation of GM1-liposomes in the brain tissues and thus the efficacious of CDP-choline. Therefore, this nanomedicine may represent a strategy for the reassessment of CDP-choline to treat post-ischemic events caused by brain stroke, and respond to a significant clinical need.

Skin Tolerability of Oleic Acid Based Nanovesicles Designed for the Improvement of Icariin and Naproxen Percutaneous Permeation.

Deformable nanovesicles have a crucial role in topical drug delivery through the skin, due to their capability to pass intact the stratum corneum and epidermis (SCE) and significantly increase the efficacy and accumulation of payloads in the deeper layers of the skin. Namely, lipid-based ultradeformable nanovesicles are versatile and load bioactive molecules with different physicochemical properties. For this reason, this study aims to make oleic acid based nanovesicles (oleosomes) for the codelivery of icariin and sodium naproxen and increase their permeation through the skin. Oleosomes have suitable physicochemical properties and long-term stability for a potential dermal or transdermal application. The inclusion of oleic acid in the lipid bilayer increases 3-fold the deformable properties of oleosomes compared to conventional liposomes and significantly improves the percutaneous permeation of icariin and sodium naproxen through the human SCE membranes compared to hydroalcoholic solutions of both drugs. The tolerability studies on human volunteers demonstrate that oleosomes are safer and speed up the recovery of transepidermal water loss (TEWL) baselines compared to saline solution. These results highlight promising properties of icariin/sodium naproxen coloaded oleosomes for the treatment of skin disorders and suggest the potential future applications of these nanovesicles for further in vivo experiments.

Rutin-loaded zein gel as a green biocompatible formulation for wound healing application.

Wound healing is a challenging clinical problem and efficient wound management is essential to prevent infection. This is best done by utilizing biocompatible materials in order to complete the healing in a rapid manner, with functional and esthetic outcomes. In this context, the zein protein fulfills the criteria of the ideal wound dressing which include non-toxicity and non-inflammatory stimulation. Zein gels containing rutin were prepared without any chemical refinement or addition of gelling agents in order to obtain a natural formulation characterized by antioxidant and anti-inflammatory properties to be proposed for the treatment of burns and sores. In vitro scratch assay showed that the proposed gel formulations promoted cell migration and a rapid gap closure within 24 h (~90 %). In addition, the in vivo activities of rutin-loaded zein gel showed a greater therapeutic efficacy in Wistar rats, with a decrease of the wound area of about 90 % at day 10 with respect to the free form of the bioactive and to DuoDERM®. The evaluation of various markers (TNF-α, IL-1ß, IL-6, IL-10) confirmed the anti-inflammatory effect of the proposed formulation. The results illustrate the feasibility of exploiting the peculiar features of rutin-loaded zein gels for wound-healing purposes.

Characterization and Preliminary In Vitro Antioxidant Activity of a New Multidrug Formulation Based on the Co-Encapsulation of Rutin and the α-Acylamino-ß-Lactone NAAA Inhibitor URB894 within PLGA Nanoparticles.

A biodegradable and biocompatible polymeric matrix made up of poly(d,l-lactide-co-glycolide) (PLGA) was used for the simultaneous delivery of rutin and the (S)-N-(2-oxo-3-oxetanyl)biphenyl-4-carboxamide derivative (URB894). The goal was to exploit the well-known radical scavenging properties of rutin and the antioxidant features recently reported for the molecules belonging to the class of N-acylethanolamine-hydrolyzing acid amidase (NAAA) inhibitors, such as URB894. The use of the compounds, both as single agents or in association promoted the development of negatively-charged nanosystems characterized by a narrow size distribution and an average diameter of ~200 nm when 0.2-0.6 mg/mL of rutin or URB894 were used. The obtained multidrug carriers evidenced an entrapment efficiency of ~50% and 40% when 0.4 and 0.6 mg/mL of rutin and URB894 were associated during the sample preparation, respectively. The multidrug formulation evidenced an improved in vitro dose-dependent protective effect against H2O2-related oxidative stress with respect to that of the nanosystems containing the active compounds as a single agent, confirming the rationale of using the co-encapsulation approach to obtain a novel antioxidant nanomedicine.

Perspective use of bio-adhesive liquid crystals as ophthalmic drug delivery systems.

The success of many drugs in ophthalmic treatments is hindered by their physico-chemical properties and the limited precorneal retention time. Here, lyotropic liquid crystals are proposed as a new ophthalmic drug delivery system. Acyclovir was chosen as model drug for its solubility and its controlled release from cubic phase was achieved. We demonstrated the effortless application of lamellar phase on corneal surface and its ability to convert itself in cubic phase in situ. While the complex viscosity of lamellar phase was affected by temperature (5.1 ± 1.4 kPa·s at 25 °C and 0.12 ± 0.001 Pa·s at 35 °C, respectively), the cubic phase shown no changes in viscosity values and shear thinning behaviour at both temperatures and even in presence of the drug The degradation kinetic of drug-loaded cubic phase was slightly slower than the empty formulation, recording 27.92 ± 1.43% and 33.30 ± 3.11% of weight loss after 8 h. Ex vivo studies conducted on porcine eyeballs and isolated cornea confirmed the instantaneous transition to cubic phase, its ability to resist to gravity force, and forced dripping of simulated tear fluid. Histopathological investigation showed how treated cornea did not report changes in epithelial and stroma structures. In summary, lyotropic liquid crystals could represent an advantageous ophthalmic drug delivery system.

Gelled Liquid Crystal Nanocarriers for Improved Antioxidant Activity of Resveratrol.

As many natural origin antioxidants, resveratrol is characterized by non-suitable physicochemical properties for its topical application. To allow its benefits to manifest on human skin, resveratrol has been entrapped within liquid crystal nanocarriers (LCNs) made up of glyceryl monooleate, a penetration enhancer, and DSPE-PEG 750. The nanosystems have been more deeply characterized by using dynamic light scattering and Turbiscan Lab® Expert optical analyzer, and they have been tested in vitro on NCTC 2544. The improved antioxidant activity of entrapped resveratrol was evaluated on keratinocyte cells as a function of its concentration. Finally, to really propose the resveratrol-loaded LCNs for topical use, the systems were gelled by using two different gelling agents, poloxamer P407 and carboxymethyl cellulose, to improve the contact time between skin and formulation. The rheological features of obtained gels were evaluated using two important methods (microrheology at rest and dynamic rheology), before testing their safety profile on human healthy volunteers. The obtained results showed the ability of LCNs to improve antioxidant activity of RSV and the gelled LCNs showed good rheological profiles. In conclusion, the results confirmed the potentiality of gelled resveratrol-loaded nanosystems for skin disease, mainly related to their antioxidant effects.