Superior Drug Delivery Performance of Multifunctional Bilosomes: Innovative Strategy to Kill Skin Cancer Cells for Nanomedicine Application.

Purpose: Numerous failures in melanoma treatment as a highly aggressive form of skin cancer with an unfavorable prognosis and excessive resistance to conventional therapies are prompting an urgent search for more effective therapeutic tools. Consequently, to increase the treatment efficiency and to reduce the side effects of traditional administration ways, herein, it has become crucial to combine photodynamic therapy as a promising therapeutic approach with the selectivity and biocompatibility of a novel colloidal transdermal nanoplatform for effective delivery of hybrid cargo with synergistic effects on melanoma cells. Methods: The self-assembled bilosomes, co-stabilized with L-α-phosphatidylcholine, sodium cholate, Pluronic® P123, and cholesterol, were designated, and the stability of colloidal vesicles was studied using dynamic and electrophoretic light scattering, also provided in cell culture medium (Dulbecco's Modified Eagle's Medium). The hybrid compounds - a classical photosensitizer (Methylene Blue) along with a complementary natural polyphenolic agent (curcumin), were successfully co-loaded, as confirmed by UV-Vis, ATR-FTIR, and fluorescent spectroscopies. The biocompatibility and usefulness of the polymer functionalized bilosome with loaded double cargo were demonstrated in vitro cyto- and phototoxicity experiments using normal keratinocytes and melanoma cancer cells. Results: The in vitro bioimaging and immunofluorescence study upon human skin epithelial (A375) and malignant (Me45) melanoma cell lines established the protective effect of the PEGylated bilosome surface. This effect was confirmed in cytotoxicity experiments, also determined on human cutaneous (HaCaT) keratinocytes. The flow cytometry experiments indicated the enhanced uptake of the encapsulated hybrid cargo compared to the non-loaded MB and CUR molecules, as well as a selectivity of the obtained nanocarriers upon tumor cell lines. The phyto-photodynamic action provided 24h-post irradiation revealed a more significant influence of the nanoplatform on Me45 cells in contrast to the A375 cell line, causing the cell viability rate below 20% of the control. Conclusion: As a result, we established an innovative and effective strategy for potential metastatic melanoma treatment through the synergism of phyto-photodynamic therapy and novel bilosomal-origin nanophotosensitizers.

Sodium cholate ameliorates nonalcoholic steatohepatitis by activation of FXR signaling.

Non-alcoholic steatohepatitis (NASH) has become a major cause of liver transplantation and liver-associated death. The gut-liver axis is a potential therapy for NASH. Sodium cholate (SC) is a choleretic drug whose main component is bile acids and has anti-inflammatory, antifibrotic, and hepatoprotective effects. This study aimed to investigate whether SC exerts anti-NASH effects by the gut-liver axis. Mice were fed with an high-fat and high-cholesterol (HFHC) diet for 20 weeks to induce NASH. Mice were daily intragastric administrated with SC since the 11th week after initiation of HFHC feeding. The toxic effects of SC on normal hepatocytes were determined by CCK8 assay. The lipid accumulation in hepatocytes was virtualized by Oil Red O staining. The mRNA levels of genes were determined by real-time quantitative PCR assay. SC alleviated hepatic injury, abnormal cholesterol synthesis, and hepatic steatosis and improved serum lipid profile in NASH mice. In addition, SC decreased HFHC-induced hepatic inflammatory cell infiltration and collagen deposition. The target protein-protein interaction network was established through Cytoscape software, and NR1H4 [farnesoid x receptor (FXR)] was identified as a potential target gene for SC treatment in NASH mice. SC-activated hepatic FXR and inhibited CYP7A1 expression to reduce the levels of bile acid. In addition, high-dose SC attenuated the abnormal expression of cancer markers in NASH mouse liver. Finally, SC significantly increased the expression of FXR and FGF15 in NASH mouse intestine. Taken together, SC ameliorates steatosis, inflammation, and fibrosis in NASH mice by activating hepatic and intestinal FXR signaling so as to suppress the levels of bile acid in NASH mouse liver and intestine.

Regulating the Size of Simvastatin-loaded Discoidal Reconstituted Highdensity Lipoprotein: Preparation, Characterization, and Investigation of Cellular Cholesterol Efflux.

BACKGROUND: Reverse cholesterol transportation is essential for high-density lipoprotein (HDL) particles to reduce the cholesterol burden of peripheral cells. Studies have shown that particle size plays a crucial role in the cholesterol efflux capacity of HDLs, and the reconstituted HDLs (rHDLs) possess a similar function to natural ones. OBJECTIVE: The study aimed to investigate the effect of particle size on the cholesterol efflux capacity of discoidal rHDLs and whether drug loadings may have an influence on this effect. METHODS: Different-sized simvastatin-loaded discoidal rHDLs (ST-d-rHDLs) resembling nascent HDL were prepared by optimizing key factors related to the sodium cholate of film dispersion-sodium cholate dialysis method with a single controlling factor. Their physicochemical properties, such as particle size, zeta potential, and morphology in vitro, were characterized, and their capacity of cellular cholesterol efflux in foam cells was evaluated. RESULTS: We successfully constructed discoidal ST-d-rHDLs with different sizes (13.4 ± 1.4 nm, 36.6 ± 2.6 nm, and 68.6 ± 3.8 nm) with over 80% of encapsulation efficiency and sustained drug release. Among them, the small-sized ST-d-rHDL showed the strongest cholesterol efflux capacity and inhibitory effect on intracellular lipid deposition in foam cells. In addition, the results showed that the loaded drug did not compromise the cellular cholesterol efflux capacity of different-sized ST-d-rHDL. CONCLUSION: Compared to the larger-sized ST-d-rHDLs, the small-sized ST-d-rHDL possessed enhanced cellular cholesterol efflux capacity similar to drug-free one, and the effect of particle size on cholesterol efflux was not influenced by the drug loading.

The effect of surfactant type on characteristics, skin penetration and anti-aging effectiveness of transfersomes containing amniotic mesenchymal stem cells metabolite products in UV-aging induced mice.

Transfersome has been developed to enhance dermal delivery of amniotic mesenchymal stem cell metabolite products (AMSC-MP). AMSC-MP contains many growth factors for managing skin aging, thus improving the quality of an adjusted life year. This study aims to determine the effect of surfactant types acting as the edge activator on transfersome-loading AMSC-MP. Transfersome was prepared by thin-layer hydration method and composed of l-α-phosphatidylcholine as a phospholipid and three types of surfactants, namely; cationic (stearylamine), anionic (sodium cholate), and nonionic surfactant (Tween 80) at a weight ratio of 85:15, respectively. Transfersomes were evaluated for physical characteristics, penetration, effectiveness, and safety. The results showed that sodium cholate, an anionic surfactant, produced the smallest transfersome particle size, i.e., 144.2 ± 3.2 nm, among all formulas. Trans-SA containing stearylamine had a positive charge of 41.53 ± 6.03 mV compared to Trans-SC and Trans-TW, whose respective charges were -56.9 ± 0.55 mV and -41.73 ± 0.86 mV. The small particle size and low negative value of zeta potential enabled high dermal penetration by transfersomes containing AMSC-MP, while the positive charge of stearylamine hindered its penetration of deeper skin layers. Trans-SC and Trans-TW produced higher collagen density values at 77.11 ± of 4.15% and 70.05 ± of 6.95%, than that of Trans-SA. All the AMSC-MP transfersomes were relatively safe with 0.5-1.0 macrophage cell numbers invaded the dermis per field of view. In conclusion, sodium cholate, an anionic surfactant, demonstrated considerable capacity as the edge activator of transfersome-loading AMSC-MP for skin anti-aging therapy.

An electronic nose based on 2D group VI transition metal dichalcogenides/organic compounds sensor array.

Rapid volatile organic compounds (VOCs) detection is a hot topic today; in this framework nanomaterials and their tailorable chemistry offer a plethora of compelling opportunities. In this work, Group VI transition metal dichalcogenides (TMDs, i.e., MoS2, WSe2, MoSe2, and WSe2) were functionalized with organic compounds (ellagic acid, tannic acid, catechin, and sodium cholate) able to assist their sonochemical exfoliation in water. The 16 resulting water-dispersed 2D hybrid inorganic/organic TMDs resulted in a few-layer nanoflakes conformation and were used to modify quartz crystal microbalances (QCMs) to equip an e-nose for VOCs determination. The ability of the sensors for the detection of VOCs was assessed on alcohols, terpenes, esters, and aldehydes; the responses were significatively different, confirming the synergic effect of TMD and the organic compound in the interaction with VOCs. The 16 sensors exhibited quantitative responses for VOCs (R2≥0.978) with fast signals recovery (<100 s) and repeatable (RSD ≤9.3%, n = 5), reproducible (RSD ≤12.8%, n = 3) and stable (RSD ≤14.6%, 3 months) signals. As proof of applicability, in an e-nose format, banana aroma evolution during post-harvest ripening was successfully monitored using the 2D TMDs-based sensors array. These data demonstrate that TMDs exfoliated in water with different organic compounds are sustainable functional nanomaterials, able to offer new opportunities in nano-bioelectronic applications.

Antioxidation Function of EGCG by Activating Nrf2/HO-1 Pathway in Mice with Coronary Heart Disease.

Objective: To explore the effect and mechanism of epigallocatechin gallate (EGCG) in mice with coronary heart disease (CHD). Methods: Firstly, a CHD model of mouse was established by feeding mice high-fat diet and randomly divided into four groups, including Model group (0.5% sodium cholate) and 10 mg/kg EGCG, 20 mg/kg EGCG, and 40 mg/kg EGCG groups. After oral administration of sodium cholate or EGCG, HE staining was conducted to assess the pathological changes of mouse cardiac tissues in each group of mice, biochemical kits to measure the levels of blood lipid and oxidative stress substance activity, and western blot to detect matrix metalloproteinase 2 (MMP-2), vascular endothelial growth factor (VEGFA), as well as expression levels of protein related to Nrf2/HO-1/NQO1 pathway in cardiac tissues. Results: The mice in the CHD model appeared to have myocardial pathological damage with elevated serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and decreased high-density lipoprotein cholesterol (HDL-C). Of note, administration of EGCG significantly attenuated myocardial injuries and improved blood lipid levels in mice in a concentration-dependent manner. The advent of EGCG significantly decreased the expression of VEGFA and MMP-2 and increased the activity of superoxide dismutase (SOD), when reducing the content of reactive oxygen species (ROS) in the myocardial tissue and upregulating the expression of HO-1, NQO1, and Nrf2. Conclusion: EGCG may reduce atherosclerotic plaque and alleviate pathological damage in the cardiac tissue of CHD mice as well as improve blood lipid levels with antioxidative effect. The mechanism of its effect may be related to the activation of the Nrf2/HO-1/NQO1 antioxidant pathway in vivo of the CHD mice.

Simultaneous separation and determination of four active ingredients in Picria fel-terrae Lour. and its preparations by micellar electrokinetic chromatography.

INTRODUCTION: Picfeltarraenins IA, IB and IV and acteoside are the four bioactive ingredients of Picria fel-terrae Lour. Their pharmacological effects include central inhibitory, cardiovascular, anti-inflammatory, anti-pyretic, analgesic, anti-bacterial, antioxidative and anti-tumor effects. OBJECTIVE: We aimed to develop an efficient micellar electrokinetic chromatography (MEKC) method modified with mixed organic solvents for the simultaneous separation and determination of the four components in Picriae Herba and its formulations. METHODS: Method optimization was carried out by investigating influences of significant factors on the separation, and this method was successfully applied for the determination of the four components in Picriae Herba and its formulations. RESULTS: The optimal running buffer was composed of 20 mM sodium tetraborate, 40 mM sodium cholate, 10% (v/v) methanol and 10% (v/v) isopropanol (pH 9.76). The separation voltage was 18 kV, the temperature was 25°C and the detection wavelength was 266 nm. Under the optimal separation conditions, the baseline separation of four components was achieved in less than 14 min. The correlation coefficients of the calibration curves were 0.9984-0.9995 for the analytes. The intraday and interday precision ranged from 1.5% to 2.5% and from 1.4% to 5.0%, respectively. Recoveries of analytes varied from 96.6% to 104.1%. CONCLUSION: The method was proved suitable for the determination of four components in Picriae Herba and its formulations. Good performance was obtained under optimal conditions, and the method provides an effective tool for the quality control of Picriae Herba and its formulations.

A novel nasal co-loaded loratadine and sulpiride nanoemulsion with improved downregulation of TNF-α, TGF-ß and IL-1 in rabbit models of ovalbumin-induced allergic rhinitis.

PURPOSE: The work aimed to develop a co-loaded loratadine and sulpiride nasal nanoemulsion for allergic rhinitis management. METHODS: Compatibility studies were conducted adopting differential scanning calorimetry and Fourier transform infrared spectroscopy. Nanoemulsion formulations were prepared using soybean lecithin, olive oil and tween 80. Sodium cholate and glycerol were employed as co-surfactants. Nanoemulsions were assessed for viscosity, pH, droplet size, polydispersity index, zeta potential, electrical conductivity, entrapment, In vitro drug release and corresponding kinetics. Stability of the selected formulation was investigated. The biological effectiveness was evaluated in rabbit models of ovalbumin-induced allergic rhinitis by measuring TNF-α, TGF-ß and IL-1. RESULTS: Compatibility studies revealed absence of drug/drug interactions. Nanoemulsions exhibited > 90% entrapment efficiency. The selected nanoemulsion demonstrated small droplet size (85.2 ± 0.2 nm), low PDI (0.35 ± 0.0) and appropriate Zeta Potential (-23.3 ± 0.2) and stability. It also displayed enhanced in vitro drug release following the Higuashi Diffusion and Baker-Lonsdale models. The mean relative mRNA expression of TNF-α, IL-1 and TGF-ß significantly decreased from 9.59 ± 1.06, 4.15 ± 0.02 and 4.15 ± 0.02 to 1.28 ± 0.02, 1.93 ± 0.06 and 1.56 ± 0.02 respectively after treatment with the selected nanoemulsion formulation. CONCLUSION: The results reflected a promising potent effect of the combined loratadine and sulpiride nasal nanoemulsion in managing the symptoms of allergic rhinitis.

Sodium Cholate Bile Acid-Stabilized Ferumoxytol-Doxorubicin-Lipiodol Emulsion for Transcatheter Arterial Chemoembolization of Hepatocellular Carcinoma.

PURPOSE: To develop bile acid-stabilized multimodal magnetic resonance (MR) imaging and computed tomography (CT)-visible doxorubicin eluting lipiodol emulsion for transarterial chemoembolization of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Ferumoxytol, a US Food and Drug Administration-approved iron oxide nanoparticle visible under MR imaging was electrostatically complexed with doxorubicin (DOX). An amphiphilic bile acid, sodium cholate (SC), was used to form a stable dispersion of ferumoxytol-DOX complex in lipiodol emulsion. Properties of the fabricated emulsion were characterized in various component ratios. Release kinetics of DOX were evaluated for the chemoembolization applications. Finally, in vivo multimodal MR imaging/CT imaging properties and potential therapeutic effects upon intra-arterial (IA) infusion bile acid-stabilized ferumoxytol-DOX-lipiodol emulsion were evaluated in orthotopic McA-Rh7777 HCC rat models. RESULTS: DOX complexed with ferumoxytol through electrostatic interaction. Amphiphilic SC bile acid at the interface between the aqueous ferumoxytol-DOX complexes and lipiodol enabled a sustained DOX release (17.2 ± 1.6% at 24 hours) at an optimized component ratio. In McA Rh7777 rat HCC model, IA-infused emulsion showed a significant contrast around tumor in both T2-weighted MR imaging and CT images (P = .044). Hematoxylin and eosin and Prussian blue staining confirmed the local deposition of IA-infused SC bile acid-stabilized emulsion in the tumor. The deposited emulsion induced significant increases in TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) stain-positive cancer cell apoptosis compared to those in a group treated with the nonstabilized emulsion. CONCLUSIONS: SC bile acid-stabilized ferumoxytol-DOX-lipiodol emulsion demonstrated sustained drug release and multimodal MR imaging/CT imaging capabilities. The new lipiodol-based formulation may enhance the therapeutic efficacy of chemoembolization in HCC.

Poloxamer/sodium cholate co-formulation for micellar encapsulation of doxorubicin with high efficiency for intracellular delivery: An in-vitro bioavailability study.

HYPOTHESIS: Doxorubicin hydrochloride (DX) is widely used as a chemotherapeutic agent, though its severe side-effects limit its clinical use. A way to overcome these limitations is to increase DX latency through encapsulation in suitable carriers. However, DX has a high solubility in water, hindering encapsulation. The formulation of DX with sodium cholate (NaC) will reduce aqueous solubility through charge neutralization and hydrophobic interactions thus facilitating DX encapsulation into poloxamer (F127) micelles, increasing drug latency. EXPERIMENTS: DX/NaC/PEO-PPO-PEO triblock copolymer (F127) formulations with high DX content (DX-PMs) have been prepared and characterized by scattering techniques, transmission electron microscopy and fluorescence spectroscopy. Cell proliferation has been evaluated after DX-PMs uptake in three cell lines (A549, Hela, 4T1). Cell uptake of DX has been studied by means of confocal laser scanning microscopy and flow cytometry. FINDINGS: DX-PMs formulations result in small and stable pluronic micelles, with the drug located in the apolar core of the polymeric micelles. Cell proliferation assays show a delayed cell toxicity for the encapsulated DX compared with the free drug. Data show a good correlation between cytotoxic response and slow DX delivery to nuclei. DX-PMs offer the means to restrict DX delivery to the cell interior in a highly stable and biocompatible formulation, suitable for cancer therapy.

Provesicular elastic carriers of Simvastatin for enhanced wound healing activity: An in-vitro/in-vivo study.

The aim of this study was to prepare and evaluate simvastatin (SIM) loaded elastic provesicular systems for effective topical wound management. SIM provesicles were prepared using the non-ionic surfactant Span 40, cholesterol and three edge activators i.e. Span 80, Tween 80 and sodium cholate. The vesicles revealed high SIM encapsulation efficiency ranging from 87.25 to 98.15%, whereas vesicle sizes ranged from 462.3 to 801.5 nm. Vesicle sizes decreased with increasing the concentration of the edge activator. High negative zeta potential values were observed, revealing good stability of the vesicular formulations. The release of SIM from hydrated provesicular carriers was biphasic in nature. The selected SIM provesicular elastic carrier exerted approximately two-fold increase in the amount of SIM permeated through rat skin, compared to the free drug. Evaluation of wound healing activity of the selected provesicular formulation revealed significant reduction in wound size in rats, fourteen days post-wounding. These results were further confirmed by a significant increase in expression of vascular endothelial growth factor and collagen type I compared to the free drug. These results indicate that provesicular carriers could be a promising drug delivery system for encapsulating SIM and enhancing its wound healing efficacy.

Concentration-dependent effects of sodium cholate and deoxycholate bile salts on breast cancer cells proliferation and survival.

Bile acids (BAs) are bioactive molecules that have potential therapeutic interest and their derived salts are used in several pharmaceutical systems. BAs have been associated with tumorigenesis of several tissues including the mammary tissue. Therefore, it is crucial to characterize their effects on cancer cells. The objective of this work was to analyse the molecular and cellular effects of the bile salts sodium cholate and sodium deoxycholate on epithelial breast cancer cell lines. Bile salts (BSs) effects over breast cancer cells viability and proliferation were assessed by MTS and BrdU assays, respectively. Activation of cell signaling mediators was determined by immunobloting. Microscopy was used to analyze cell migration, and cellular and nuclear morphology. Interference of membrane fluidity was studied by generalized polarization and fluorescence anisotropy. BSs preparations were characterized by transmission electron microscopy and dynamic light scattering. Sodium cholate and sodium deoxycholate had dual effects on cell viability, increasing it at the lower concentrations assessed and decreasing it at the highest ones. The increase of cell viability was associated with the promotion of AKT phosphorylation and cyclin D1 expression. High concentrations of bile salts induced apoptosis as well as sustained activation of p38 and AKT. In addition, they affected cell membrane fluidity but not significant effects on cell migration were observed. In conclusion, bile salts have concentration-dependent effects on breast cancer cells, promoting cell proliferation at physiological levels and being cytotoxic at supraphysiological ones. Their effects were associated with the activation of kinases involved in cell signalling.

Preparation and evaluation of self-assembly Soluplus®-sodium cholate-phospholipid ternary mixed micelles of docetaxel.

Ternary mixed micelles constituted of Soluplus®, sodium cholate, and phospholipid were prepared as nano-delivery system of the anticancer drug, docetaxel. The formulation of docetaxel-loaded ternary mixed micelles (DTX-TMMs) with an optimized composition (Soluplus®/sodium cholate/phospholipid= 3:2:1 by weight) were obtained. The main particle size of DTX-TMMs was 76.36 ± 2.45 nm, polydispersity index (PDI) was 0.138 ± 0.039, and the zeta potential was -8.46 ± 0.55 mv. The encapsulation efficiency was 94.24 ± 4.30% and the drug loading was 1.25%. The critical micelle concentration value was used to assess the ability of carrier materials to form micelles. The results indicated that the addition of Soluplus® to sodium cholate-phospholipid mixed micelles could reduce the critical micelle concentration and improve the stability. In vitro release studies demonstrated that compared with DTX-Injection group, the DTX-TMMs presented a controlled release property of drugs. In vivo pharmacodynamics results suggested that DTX-TMMs had the most effective inhibitory effect on tumor proliferation and had good biosafety. In addition, the relative bioavailability of mixed micelles was increased by 1.36 times compared with the DTX-Injection in vivo pharmacokinetic study indicated that a better therapeutic effect could be achieved. In summary, the ternary mixed micelles prepared in this study are considered to be promising anticancer drug delivery systems.

Fiber and phenolic compounds contribution to the hepatoprotective effects of mango diets in rats fed high cholesterol/sodium cholate.

The present study evaluated the contribution of mango fiber (MF) and mango phenolic compounds (MP) to the hepatoprotective effect of freeze-dried mango pulp (FDM) cultivar (cv.) "Ataulfo" diets in high cholesterol/sodium cholate (HCC)-fed rats. Male Wistar rats were fed with a HCC diet for 12 weeks, either untreated, or supplemented with MF, MP, FDM, or a control diet (no HCC; n = 6/group). All mango treatments significantly decreased hepatic cholesterol deposition and altered its fatty acid profile, whereas MF and MP mitigated adipose tissue hypertrophy. MF caused a lower level of proinflammatory cytokines (IL-1α/ß, IFN-γ, TNF-α) whereas FDM increased the anti-inflammatory ones (IL-4, 6, 10). Mango treatments increased catalase (CAT) activity and its mRNA expression; superoxide dismutase (SOD) activity was normalized by MF and FDM, but its activity was unrelated to its hepatic mRNA expression. Changes in CAT and SOD mRNA expression were unrelated to altered Nrf2 mRNA expression. Higher hepatic PPARα and LXRα mRNA levels were found in MP and MF. We concluded that MF and MP are highly bioactive, according to the documented hepatoprotection in HCC-fed rats; their mechanism of action appears to be related to modulating cholesterol and fatty acid metabolism as well as to stimulating the endogenous antioxidant system.

Polyethylenimine and sodium cholate-modified ethosomes complex as multidrug carriers for the treatment of melanoma through transdermal delivery.

Aim: Multidrug resistance is the main reason for the failure of chemotherapy during the treatment of the tumor. To overcome multidrug resistance, this study attempts to develop a novel transdermal drug-delivery system (TDDS) loading cytotoxic drug and chemosensitizer. Materials & methods: The polyethylenimine-modified ethosomes (Eth-PEI) and sodium cholate-modified ethosomes (Eth-SC) were firstly fabricated, and then a novel TDDS based on the carriers complex of Eth-PEI/Eth-SC was prepared by electrostatic interaction and evaluated both in vitro and in vivo. Results: The Eth-PEI/Eth-SC showed the excellent antitumor effect on treating melanoma, using doxorubicin and curcumin as the cytotoxic drug and chemosensitizer, respectively. Conclusion: The as-prepared TDDS composed of Eth-PEI/Eth-SC loading multidrug is an effective means for treating melanoma.

Superoxide dismutase in nanoarchaeosomes for targeted delivery to inflammatory macrophages.

Oxidative stress plays an essential role in the pathogenesis and progression of inflammatory bowel disease. Co-administration of antioxidants and anti-inflammatory drugs has shown clinical benefits. Due to its significant reactive oxygen species (ROS) scavenging ability, great interest has been focused on superoxide dismutase (SOD) for therapeutic use. However, oral SOD is exposed to biochemical degradation along gastrointestinal transit. Furthermore, the antioxidant activity of SOD must be achieved intracellularly, therefore its cell entry requires endocytic mediating mechanisms. In this work, SOD was loaded into nanoarchaeosomes (ARC-SOD), nanovesicles fully made of sn 2,3 ether linked phytanyl saturated archaeolipids to protect and target SOD to inflammatory macrophages upon oral administration. Antioxidant and anti-inflammatory activities of ARC-SOD, non-digested and digested in simulated gastrointestinal fluids, on macrophages stimulated with H2O2 and lipopolysaccharide were determined and compared with those of free SOD and SOD encapsulated into highly stable liposomes (LIPO-SOD). Compared to SOD and LIPO-SOD, ARC-SOD (170 ± 14 nm, -30 ± 4 mV zeta potential, 122 mg protein/g phospholipids) showed the highest antioxidant and anti-inflammatory activity: it reversed the cytotoxic effect of H2O2, decreased intracellular ROS and completely suppressed the production of IL-6 and TNF-α on stimulated J774 A.1 cells. Moreover, while the activity of LIPO-SOD was lost upon preparation, gastrointestinal digestion and storage, ARC-SOD was easy to prepare and retained its antioxidant capacity upon digestion in simulated gastrointestinal fluids and after 5 months of storage. Because of their structural and pharmacodynamic features, ARC-SOD may be suitable for oral targeted delivery of SOD to inflamed mucosa.

Spectral-fluorescent study of the interaction of polymethine dye probes with biological surfactants - bile salts.

Spectral-fluorescent properties of polymethine dye probes anionic 3,3'-di(sulfopropyl)-4,5,4',5'-dibenzo-9-ethylthiacarbocyanine-betaine (DEC) and cationic 3,3',9-trimethylthiacarbocyanine iodide (Cyan 2) in the presence of biological surfactants, bile salts sodium cholate (NaC), sodium deoxycholate (NaDC) and sodium taurocholate (NaTC), as well as sodium dodecyl sulfate (SDS), have been studied in a wide range of surfactant concentrations. When a surfactant is introduced into a solution of DEC, changes of the spectral-fluorescent properties are observed due to decomposition of dye dimers into cis-monomers and cis-trans conversion of the resulting monomers. In the presence of SDS, both processes occur in parallel, caused by noncovalent interaction of dye monomers with micelles, and mainly occur near the critical micelle concentration (CMC). In contrast, upon the introduction of increasing concentrations of bile salts, decomposition of dye dimers into the monomers begins at lower concentrations than cis-trans conversion. The former process is almost completed at concentrations close to CMC of secondary micelles (CMC2), while the latter process occurs even at concentrations of bile salts much higher than CMC2. Hence, DEC can serve as a probe that permits estimating the value of CMC2 and is indicative of reorganization of secondary micelles upon an increase in bile salt concentration. Aggregation of DEC and Cyan 2 on bile salts is also observed. Since it is observed at relatively low concentrations of bile salts (

Overcoming Poor Tabletability of Bulky Absorption Enhancers by Spray Drying Technology.

Absorption enhancers are often a major component of solid oral peptide formulations as compared to the active pharmaceutical ingredient and excipients. This commonly results in poor tabletability that is hard to mitigate in direct compaction by addition of small amounts of excipients. To improve the tabletability of bulky absorption enhancers, the model absorption enhancers, sodium cholate and deoxycholic acid, were co-spray-dried with hydroxypropyl methylcellulose E5, where the percentage of absorption enhancers was not lower than 90% (w/w). The physicochemical properties of the resulting powders were assessed by laser diffraction, scanning electron microscopy, X-ray powder diffraction, thermogravimetric analysis, and differential scanning calorimetry. The powders were compressed into tablets, and the tabletability was evaluated. Co-spray drying with 10% of hydroxypropyl methylcellulose significantly improved the tabletability of the both absorption enhancers. Moreover, it was demonstrated that small particle size and amorphous state rather than high moisture content contributed to the improved tabletability of the spray-dried powders. The study suggests that spray drying technology can be promising to overcome the poor tabletability of oral peptide formulation consisting of large amounts of absorption enhancers.

Structural, antioxidant and adsorption properties of dietary fiber from foxtail millet (Setaria italica) bran.

BACKGROUND: Foxtail millet (Setaria italica) bran is a by-product of millet processing, rich in dietary fiber (DF) and has great application value. A comparative study was conducted to explore the differences in structural and functional properties among millet bran DF, soluble dietary fiber (SDF) and insoluble dietary fiber (IDF). RESULTS: There was a significant difference in the content of monosaccharides between SDF and IDF, in which xylose, arabinose and glucose were the main compositions. The results of scanning electron microscopy showed that DF and IDF had different forms of network structure, and SDF presented a sign of mutual adhesion. The total phenolic and flavonoid contents were 0.54 and 0.08 g kg-1 in SDF. Antioxidant activity of SDF was higher than that of IDF based on the evaluation of free radical scavenging and iron reducing capacity in vitro. Meanwhile, the glucose dialysis retardation index of IDF and SDF was 12.59% and 9.26% at 30 min, respectively. And, there was no significant difference in the adsorption capacity of glucose among different samples (P > 0.05). Furthermore, SDF had strong α-amylase inhibition (17.92% inhibition rate) and sodium cholate adsorption capacities; the adsorption amount was 16.76 g kg-1 in 2.00 g L-1 sodium cholate solution. CONCLUSION: Foxtail millet bran DF, especially SDF, has good functional properties and would be a suitable ingredient for health-beneficial food production. However, the relevant verification trials in vivo need to be carried out in the next steps. © 2019 Society of Chemical Industry.

A fluorescence study of the loading and time stability of doxorubicin in sodium cholate/PEO-PPO-PEO triblock copolymer mixed micelles.

HYPOTHESIS: Doxorubicin hydrochloride (DX) is one of the most powerful anticancer agents though its clinical use is impaired by severe undesired side effects. DX encapsulation in nanocarrier systems has been introduced as a mean to reduce its toxicity. Micelles of the nonionic triblock copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) (PEO-PPO-PEO), are very promising carrier systems. The positive charge of DX confines the drug to the hydrophilic corona region of the micelles. The use of mixed micelles of PEO-PPO-PEO copolymers and a negatively charged bile salt should favour the solubilization of DX in the apolar core region of the micelles. EXPERIMENTS: We studied the DX uptake in the micellar systems formed by sodium cholate (NaC) and the PEO100PPO65PEO100 (F127) copolymer, prepared with different mole ratios (MR = nNaC/nF127) in the range 0 ÷ 1. The systems were characterized by small angle X-ray scattering (SAXS) and dynamic light scattering (DLS); DX encapsulation was followed by steady-state and time-resolved fluorescence spectroscopy. FINDINGS: The successful solubilization of DX in the host micellar systems did not affect their structure, as evidenced by both SAXS and DLS data. In the presence of NaC, DX experiences a more apolar environment as indicated by its characteristic fluorescent behaviour. The almost complete uptake of the drug occurred shortly after the sample preparation; however, time resolved fluorescence revealed a slow partition of DX between corona and core regions of the micelles. DX degradation in the mixed micellar systems was markedly reduced relative to aqueous DX solutions.