Lipid- and polymer-based formulations containing TNF-α inhibitors for the treatment of inflammatory bowel diseases.

Monoclonal antibodies inhibiting tumor necrosis factor-alpha (iTNF-α) have revolutionized the therapeutic regimen of inflammatory bowel disease, but their main drawback is the parenteral route of administration they require. An alternative approach lies in the delivery of these molecules to the area involved in the inflammatory process by means of innovative formulations able to promote their localization in affected tissues while also decreasing the number of administrations required. This review describes the advantages deriving from the use of lipid- and polymer-based systems containing iTNF-α, focusing on their physicochemical and technological properties and discussing the preclinical results obtained in vivo using rodent models of colitis.

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.

DIFUCOSIN: DIclofenac sodium salt loaded FUCOidan-SericIN nanoparticles for the management of chronic inflammatory diseases.

The current investigation emphasizes the use of fucoidan and sericin as dual-role biomaterials for obtaining novel nanohybrid systems for the delivery of diclofenac sodium (DS) and the potential treatment of chronic inflammatory diseases. The innovative formulations containing 4 mg/ml of fucoidan and 3 mg/ml of sericin showed an average diameter of about 200 nm, a low polydispersity index (0.17) and a negative surface charge. The hybrid nanosystems demonstrated high stability at various pHs and temperatures, as well as in both saline and glucose solutions. The Rose Bengal assay evidenced that fucoidan is the primary modulator of relative surface hydrophobicity with a two-fold increase of this parameter when compared to sericin nanoparticles. The interaction between the drug and the nanohybrids was confirmed through FT-IR analysis. Moreover, the release profile of DS from the colloidal systems showed a prolonged and constant drug leakage over time both at pH 5 and 7. The DS-loaded nanohybrids (DIFUCOSIN) induced a significant decrease of IL-6 and IL-1ß with respect to the active compound in human chondrocytes evidencing a synergistic action of the individual components of nanosystems and the drug and demonstrating the potential application of the proposed nanomedicine for the treatment of inflammation.

Strategies of stabilization of zein nanoparticles containing doxorubicin hydrochloride.

Hybrid nanoparticles made up of zein and various stabilizers were developed and characterized. In detail, a zein concentration of 2 mg/ml was blended with various amounts of different phospholipids or PEG-derivatives in order to obtain formulations with suitable physico-chemical properties for drug delivery purposes. Doxorubicin hydrochloride (DOX) was used as a model of a hydrophilic compound and its entrapment efficiency, release profile and cytotoxic activity were investigated. Photon correlation spectroscopy showed that the best formulations were obtained using DMPG, DOTAP and DSPE-mPEG2000 as stabilizers of zein nanoparticles, which were characterized by an average diameter of ~100 nm, a narrow size distribution and a significant time- and temperature-dependent stability. The interaction between protein and stabilizers was confirmed through FT-IR analysis, while TEM analysis showed the presence of a shell-like structure around the zein core. The release profiles of the drug from the zein/DSPE-mPEG2000 nanosystems, evaluated at two pHs (5.5 and 7.4), showed a prolonged and constant leakage of the drug. The encapsulation of DOX within zein/DSPE-mPEG2000 nanosystems did not compromise its biological efficacy, demonstrating the potential application of these hybrid nanoparticles as drug carriers.

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.

Gliadin Nanoparticles Containing Doxorubicin Hydrochloride: Characterization and Cytotoxicity.

Doxorubicin hydrochloride (DOX) is a well-known antitumor drug used as first line treatment for many types of malignancies. Despite its clinical relevance, the administration of the compound is negatively affected by dose-dependent off-target toxicity phenomena. Nanotechnology has helped to overcome these important limitations by improving the therapeutic index of the bioactive and promoting the translation of novel nanomedicines into clinical practice. Herein, nanoparticles made up of wheat gliadin and stabilized by polyoxyethylene (2) oleyl ether were investigated for the first time as carriers of DOX. The encapsulation of the compound did not significantly affect the physico-chemical features of the gliadin nanoparticles (GNPs), which evidenced a mean diameter of ~180 nm, a polydispersity index < 0.2 and a negative surface charge. The nanosystems demonstrated great stability regarding temperature (25−50 °C) and were able to retain high amounts of drug, allowing its prolonged and sustained release for up to a week. In vitro viability assay performed against breast cancer cells demonstrated that the nanoencapsulation of DOX modulated the cytotoxicity of the bioactive as a function of the incubation time with respect to the free form of the drug. The results demonstrate the potential use of GNPs as carriers of hydrophilic antitumor compounds.

Co-Encapsulation of Paclitaxel and JQ1 in Zein Nanoparticles as Potential Innovative Nanomedicine.

The manuscript describes the development of zein nanoparticles containing paclitaxel (PTX) and the bromo-and extra-terminal domain inhibitor (S)-tertbutyl2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno(3,2-f)(1,2,4)triazolo(4,3-a)(1,4)diazepin-6-yl)acetate (JQ1) together with their cytotoxicity on triple-negative breast cancer cells. The rationale of this association is that of exploiting different types of cancer cells as targets in order to obtain increased pharmacological activity with respect to that exerted by the single agents. Zein, a protein found in the endosperm of corn, was used as a biomaterial to obtain multidrug carriers characterized by mean sizes of ˂200 nm, a low polydispersity index (0.1-0.2) and a negative surface charge. An entrapment efficiency of ~35% of both the drugs was obtained when 0.3 mg/mL of the active compounds were used during the nanoprecipitation procedure. No adverse phenomena such as sedimentation, macro-aggregation or flocculation occurred when the nanosystems were heated to 37 °C. The multidrug nanoformulation demonstrated significant in vitro cytototoxic activity against MDA-MB-157 and MDA-MB-231 cancer cells by MTT-test and adhesion assay which was stronger than that of the compounds encapsulated as single agents. The results evidence the potential application of zein nanoparticles containing PTX and JQ1 as a novel nanomedicine.

Application of Biocompatible Drug Delivery Nanosystems for the Treatment of Naturally Occurring Cancer in Dogs.

BACKGROUND: Cancer is a common disease in dogs, with a growing incidence related to the age of the animal. Nanotechnology is being employed in the veterinary field in the same manner as in human therapy. AIM: This review focuses on the application of biocompatible nanocarriers for the treatment of canine cancer, paying attention to the experimental studies performed on dogs with spontaneously occurring cancer. METHODS: The most important experimental investigations based on the use of lipid and non-lipid nanosystems proposed for the treatment of canine cancer, such as liposomes and polymeric nanoparticles containing doxorubicin, paclitaxel and cisplatin, are described and their in vivo fate and antitumor features discussed. CONCLUSIONS: Dogs affected by spontaneous cancers are useful models for evaluating the efficacy of drug delivery systems containing antitumor compounds.

First muography of Stromboli volcano.

Muography consists in observing the differential absorption of muons - elementary particles produced through cosmic-ray interactions in the Earth atmosphere - going through the volcano and can attain a spatial resolution of tens of meters. We present here the first experiment of nuclear emulsion muography at the Stromboli volcano. Muons have been recorded during a period of five months by a detector of 0.96 m2 area. The emulsion films were prepared at the Gran Sasso underground laboratory and were analyzed at Napoli, Salerno and Tokyo scanning laboratories. Our results highlight a significant low-density zone at the summit of the volcano with density contrast of 30-40% with respect to bedrock. The structural setting of this part of the volcanic edifice controls the eruptive dynamics and the stability of the "Sciara del Fuoco" slope, which is affected by recurrent tsunamigenic landslides. Periodical imaging of the summit of the Stromboli volcano such as that provided by muography can become a useful method for studying the evolution of the internal structure of the volcanic edifice.

The Continuous Motion Technique for a New Generation of Scanning Systems.

In the present paper we report the development of the Continuous Motion scanning technique and its implementation for a new generation of scanning systems. The same hardware setup has demonstrated a significant boost in the scanning speed, reaching 190 cm2/h. The implementation of the Continuous Motion technique in the LASSO framework, as well as a number of new corrections introduced are described in details. The performance of the system, the results of an efficiency measurement and potential applications of the technique are discussed.

Kinetic characterization of the photosynthetic reaction centres in microalgae by means of fluorescence methodology.

The kinetic characterization of the photosynthetic activity in autotrophic microalgae plays a key role in the design of optimized photobioreactors. This paper presents a procedure to assess kinetic parameters of a three-state photosynthetic reaction centres model. Four kinetic parameters of the model were assessed by processing the time-series measurements of pulse-amplitude modulation fluorimetry. The kinetic parameters were assessed for several microalgal strains (Stichococcus bacillaris, Scenedesmus vacuolatus, Chlamydomonas reinhardtii, Chlorella vulgaris) growth in vertical and inclined bubble columns and irradiated by white-light or red/blue light. The procedure was successfully applied to the investigated strains. The assessed parameters allow identifying the irradiance range under which: the photochemical process is controlled by the photons capture; the photoinhibition competes with the photochemical quenching. The analysis of the time-scale of the photosynthetic reaction centres as a function of the irradiance allows interpreting the performances of photobioreactors characterized by non-homogeneous irradiance.

NMR (¹H) analysis of crude extracts detects light stress in Beta vulgaris and Spinacia oleracea leaves.

In highlight stress conditions, the mechanism of non-photochemical quenching (NPQ) of chlorophyll fluorescence is triggered at the chloroplast level. This process allows thermal quenching of the excessive excitation energy and it is strictly related to the efficiency of the xanthophyll cycle. Nowadays, the utilization of the nuclear magnetic resonance (NMR) spectroscopy provides a powerful complementary way for the identification and quantitative analysis of plant metabolites either in vivo or in tissue extracts. Seeing that the oxidative damage caused by light stress in plants and the consequent involvement of pigments are widely studied, NMR spectroscopy can be utilized to compare crude leaf extract at different levels of light stress, allowing an analysis of these compounds. In this paper, the identification of possible relationships between light stress and ¹H NMR signal variations is discussed. The analysis of the ¹H NMR (1D) spectra of two agronomic species (Spinacia oleracea and Beta vulgaris) exposed to different light intensities is presented. In particular, change in carotenoids and xanthophylls signals are analyzed.

Total body water in health and disease: Have anthropometric equations any meaning?

BACKGROUND: The accurate measurement of total body water (TBW) requires isotopic dilution techniques that are not easily applicable to the clinical setting. Therefore, indirect methods of estimating TBW are commonly employed, such as bioelectrical impedance analysis (BIA) and anthropometry. In the human body, >90% of the measured impedance is composed of resistance (R). METHODS: The aim of the present study was to compare TBW estimated by means of two anthropometric equations (by Watson and Hume) with TBW obtained by BIA (equations proposed by Sun et al.) in a group of white disease-free individuals (n = 3625, 1860 men and 1765 women) and white haemodialysis (HD) patients (n = 688, 443 men and 245 women). They underwent one single-frequency BIA measurement, on the nondominant side of the body, injecting an 800-muA and 50-kHz alternating sinusoidal current with a standard tetrapolar technique. The BIA variable measured was R. RESULTS: Among them, a selection of disease-free individuals (n = 481) and HD patients (n = 270), pair-matched by age, body weight and height, after stratification by gender, was made. When comparing the four pair-matched groups, it was found that (1) TBW was not different (disease-free men versus HD men; disease-free women versus HD women) when using anthropometric equations, which utilize quite identical parameters (age, body weight and height); (2) R was statistically significantly different in the four groups (511 +/- 58 SD Omega in disease-free men versus 558 +/- 80 in HD men, P < 0.0001; 593 +/- 70 Omega in disease-free women versus 615 +/- 100 in HD women, P < 0.02) and (3) therefore, TBW was statistically significantly different only when applying BIA equations (P < 0.0001 and 0.05, respectively). CONCLUSIONS: The present study demonstrates that anthropometric equations for the estimation of TBW can be used only within a specific population in order to assess individual differences; they cannot be used in order to compare two different populations.

Development and validation of bioimpedance analysis prediction equations for dry weight in hemodialysis patients.

BACKGROUND: Accurate assessment of hydration status and specification of dry weight (DW) are major problems in the clinical treatment of hemodialysis (HD) patients. Bioelectrical impedance analysis (BIA) has been recognized as a noninvasive and simple technique for the determination of DW in HD patients. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: This study was designed to develop and validate BIA prediction equations for DW in HD patients. It included white adults (1540 disease-free adults with normal body mass index [BMI] and 456 prevalent and 27 incident HD patients). All participants underwent at least one single-frequency BIA measurement (800 muA and 50 kHz alternating sinusoidal current with a standard tetrapolar technique). The BIA variable measured was resistance (R). Data of 1463 (95% of the cohort) disease-free individuals with normal BMI (prediction sample) were used to establish best-fitting BIA prediction equations of body weight. The latter were cross-validated in the residual 5% subset (77 individuals) of the same cohort (validation sample). RESULTS: Multiple regression analysis showed a significant relationship among body weight, R, age, and height in 739 men (R(2) = 0.82, P < 0.0001) and among body weight, R, and height in 724 women (R(2) = 0.68, P < 0.0001) in the prediction sample. The Bland Altman analysis showed a mean difference between predicted and measured body weight of 0.3 +/- 1.0 kg (95% confidence interval +/- 2.0 kg) in the validation sample. The BIA prediction equations that were obtained in disease-free individuals with normal BMI were applied to a cohort of 456 prevalent HD patients: The mean difference between achieved and estimated DW was 0.1 +/- 1.0 kg (P = 0.53) in men and -0.3 +/- 1.0 (P = 0.76) in women. Finally, BIA prediction equations were tested in a cohort of 27 incident HD patients. The mean difference between predicted and achieved DW was -0.6 +/- 1.0 kg (P = 0.76) in men and 0.6 +/- 1.0 (P = 0.50) in women. CONCLUSIONS: This study was able to develop and validate BIA prediction equations for DW in HD patients. They seem to be a promising tool; however, they still need external validation.