Search

Polyethylene (PE) is one of the most widely used plastics in the world. Its degradation leads to the production of small particles including microplastics and nanoplastics (NPs). Plastic particles' presence poses a health risk. The aim of this work was to investigate the toxicity of two model surfactant-free PE NPs prepared by polymerization of ethylene from cationic and anionic water-soluble initiators on human cell lines Caco-2 and HT29-MTX. After physicochemical characterization, their acute and subacute toxicity profile, including cytotoxicity, oxidative stress, and genotoxicity, was evaluated on both cell lines. Results showed a size increase of PE NPs in culture medium. Zeta potential values close to -10 mV were no longer dependent on the initiator charge after adsorption of serum components in culture medium. However, the cellular toxicity of the cationic and anionic PE NPs was very different. A time-and-concentration dependent cytotoxic, oxidative, and genotoxic effects on Caco-2 cells were only observed for PE NPs prepared with cationic initiators. No toxicity was observed on HT29-MTX, likely due to the protective mucus layer. Genotoxicity correlated with oxidative stress of some PE NPs on Caco-2 cells was observed from a concentration of 0.1 mg.mL -1 after 48-h exposure.

Background: Recent advances in the treatment of inflammatory bowel disease include antitumor necrosis factor antibodies and the Janus kinase inhibitor tofacitinib, approved for ulcerative colitis. Janus kinase recruits signal transducers and activators of transcriptions (STAT), which are promising targets in inflammatory bowel diseases. However few inhibitors have been evaluated, and their selectivity with respect to STAT1 and STAT3 remains controversial. Here, we investigated the therapeutic potential of a selective inhibitor vs. a non-selective, closely related compound, in a dextran sulfate sodium (DSS) murine colitis model., Methods: Thirty Swiss/CD-1 male mice were used in this study. They were divided into a healthy control group, a colitis-DSS control group, a compound (cpd) 23-treated group, a cpd 46-treated group and an icariin-treated group. For the coadministration experiment with rutin, the cpd 46-treated group and the icariin-treated group were replaced by the oral rutin-treated group and the coadministration rutin/cpd 23-treated group. The effect of the tested inhibitors was also assessed by quantification of proinflammatory markers., Results: The selective inhibitor had a significantly greater effect than the dual inhibitor on the disease activity index. We also noticed in curative treatment a significant decrease in the most abundant proinflammatory biomarker present in neutrophilic granulocytes, myeloperoxidase and on proinflammatory cytokines, including tumor necrosis factor-α, interferon-γ, interleukins -6 and -23, with a mild synergy with rutin, the glycoside of quercetin., Conclusion: The current study shows how STAT3 selective inhibitors can exert a significant therapeutic effect in the treatment of experimental DSS-colitis., Competing Interests: Conflict of Interest: None, (Copyright: © Hellenic Society of Gastroenterology.)

Inflammatory bowel diseases (IBDs), which include Crohn's disease (CD) and ulcerative colitis (UC), are chronic inflammatory diseases of the gastrointestinal tract and are characterized by chronic recurrent ulceration of the bowels. Colon-targeted drug delivery systems (DDS) have received significant attention for their potential to treat IBD by improving the inflamed tissue selectivity. Herein, antiMUC5AC-decorated drug loaded nanoparticles (NP) are suggested for active epithelial targeting and selective adhesion to the inflamed tissue in experimental colitis. NPs conjugated with antiMUC5AC (anti-MUC5) were tested for their degree of bioadhesion with HT29-MTX cells by comparison with non-targeted BSA-NP conjugates . In vivo , the selectivity of bioadhesion and the influence of ligand density in bioadhesion efficiency as well as the therapeutic benefit for glucocorticoid loaded anti-MUC5-NP were studied in a murine colitis model. Quantitative adhesion analyses showed that anti-MUC5-conjugated NP exhibited a much higher binding and selectivity to inflamed tissue compared to PNA-, IgG1- and BSA-NP conjugates used as controls. This bioadhesion efficiency was found to be dependent on the ligand density, present at the NP surface. The binding specificity between anti-MUC5 ligand and inflamed tissues was confirmed by fluorescence imaging. Both anti-MUC5-NP and all other glucocorticoid containing formulations led to a significant mitigation of the experimental colitis, as became evident from the substantial reduction of myeloperoxidase activity and pro-inflammatory cytokine concentrations (TNF-α, IL-1β). Targeted NP by using anti-MUC5 appears to be a very promising tool in future treatment of various types of local disorders affecting the gastro-intestinal tract but not limited to colitis.

A major limitation in the current topical treatment strategies for inflammatory skin disorders is the inability to selectively target the inflamed site with minimal exposure of healthy skin. Atopic dermatitis is one of the most prevalent types of dermatitis. The use of polymeric nanoparticles for targeting inflamed skin has been recently proposed, and therefore the aim of this proof-of-concept clinical study was to investigate the skin penetration and deposition of polymeric biodegradable nanoparticles in the atopic dermatitis lesions and compare the data obtained to the deposition of the particles into the healthy skin or lesion-free skin of the atopic dermatitis patients. For that, fluorescent PLGA nanoparticles in sizes of approximately 100 nm were prepared and applied to the skin of healthy volunteers and the lesional and non-lesional skin of atopic dermatitis patients. Skin biopsies were examined using confocal laser scanning microscopy to track the skin deposition and depth of penetration of the particles. Immunohistochemistry was performed to investigate the alteration in tight-junction protein distribution in the different types of skin. Results have shown that nanoparticles were found to have higher deposition into the atopic dermatitis lesions with minimal accumulation in healthy or non-lesional skin. This has been primarily correlated with the impaired barrier properties of atopic dermatitis lesions with the reduced production of Claudin-1. It was concluded that polymeric nanoparticles offer a potential tool for selective drug delivery to inflamed skin with minimal exposure risk to healthy skin.

Skin is a major administration route for drugs, and all transdermal formulations must be tested for their capability to overcome the cutaneous barrier. Therefore, developing highly reliable skin models is crucial for preclinical studies. The current in vitro models are unable to replicate the living skin in all its complexity; thus, to date, excised human skin is considered the gold standard for in vitro permeation studies. However, skin explants have a limited life span. In an attempt to overcome this problem, we used an innovative bioreactor that allowed us to achieve good structural and functional preservation in vitro of explanted human skin for up to 72 h. This device was then used to set up an in vitro inflammatory model by applying two distinct agents mimicking either exogenous or endogenous stimuli: i.e., dithranol, inducing the contact dermatitis phenotype, and the substance P, mimicking neurogenic inflammation. Our in vitro system proved to reproduce inflammatory events observed in vivo, such as vasodilation, increased number of macrophages and mast cells, and increased cytokine secretion. This bioreactor-based system may therefore be suitably and reliably used to simulate in vitro human skin inflammation and may be foreseen as a promising tool to test the efficacy of drugs and cosmetics.

Purpose: The aim of this study was to evaluate docosahexaenoic acid (DHA) as a potential antifibrotic agent after glaucoma filtration surgery (GFS) in rats., Methods: A total of 36 10-week-old Brown Norway rats underwent GFS. Animals were equally divided into three groups: a control group, a DHA group and a mitomycin C (MMC) group. Intraocular pressure (IOP) was measured using a dynamic rebound tonometer, and a photograph of the surgical site was taken on days 1, 3, 7, 10, 14 and 17. The incorporation of DHA into fibroblasts was evaluated by gas chromatography. The expression of alfa-smooth muscle actin (α-SMA) and Smad proteins was assessed by Western blotting., Results: IOP decreased after surgery in animals from the three groups on day 1 after surgery. Over time, IOP remained lower in the DHA and MMC groups than in the control group (median [interquartile range] 8.0 [7.0-8.0] and 8.0 [7.3-8.0] mmHg vs. 9.0 [8.0-9.0] mmHg, respectively; p < 0.001). Bleb area in the DHA and MMC groups remained larger than that of the control group from day 7 to day 14 (3.9 [2.9-5.2] and 3.5 [2.3-4.4] mm 2 vs. 2.3 [2.0-2.8] mm 2 , respectively; p = 0.0021). We did not observe any change in DHA concentrations in the fibroblasts of the DHA group compared with the other groups., Conclusion: The impact of DHA on IOP and bleb area was similar to that of MMC. The mechanisms of action of DHA in rat eye fibroblasts deserve further investigation., (© 2022 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Lipoproteins are natural nanostructures responsible for the transport of cholesterol and other lipids in the blood. They are characterized by having a lipophilic core surrounded by an amphiphilic shell composed of phospholipids, cholesterol and one or more apolipoproteins. Being endogenous carriers makes them suitable for drug delivery purposes. Here, we investigate the effect of lipoproteins' intricate composition on the entrapment efficiency of a model drug "Cyclosporine A" into the different types of lipoproteins, namely, HDL, LDL and VLDL. It was observed that the protein content of the lipoproteins had the highest effect on the entrapment of the drug with a correlation coefficient of 0.80, 0.81 and 0.96 for HDL, LDL and VLDL respectively. This was even confirmed by the effect of plasma on the association rate of lipoproteins and the drug. The second effective factor is the cholesterol concentration, while triglycerides and phospholipids had a negligible effect.

Spray-freeze-drying (SFD) processes are usually using aqueous solvent systems, which however, exclude the use of SFD for poorly water-soluble drugs/excipients. Here, we evaluated dimethyl sulfoxide for its suitability in formulating SFD particles (lyospheres®). Rivaroxaban was spray-freeze-dried from DMSO solutions containing polyvinyl pyrrolidone (PVP; Kollidon® 25), vinylpyrrolidone-vinyl acetate copolymer (PVP-VA; Kollidon® VA64) or polyvinyl alcohol 4-88 (PVA) forming porous lyospheres® (median particle size 250 to 350 µm). Rivaroxaban was amorphous with all three polymers, which in combination with the high porosity resulted in rapid dissolution in vitro within 10 min. Consequently, this translated in lower T max (0.5-1.0 h) after oral administration of lyospheres® to rats (compared with T max of 4 h with coarse rivaroxaban). Lyosphere formulations achieved a distinct bioavailability increase (AUC (0-inf)  = 1487 ± 657 ng*h/ml with PVP; 4426 ± 1553 ng*h/ml with PVP-VA; 9569 ± 3868 ng*h/ml with PVA lyospheres®; whereas 385 ± 145 ng*h/ml with coarse rivaroxaban). These in vitro and in vivo results underlined the benefit of using DMSO in SFD that can broaden the applicability of the SFD process to a much larger repertoire of poorly water-soluble drugs/excipients., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jan Kozak reports financial support was provided by German Academic Exchange Service. Alf Lamprecht reports financial support was provided by French National Research Agency. Jan Kozak reports a relationship with German Academic Exchange Service that includes: funding grants. Alf Lamprecht has patent #WO2021110732 (A1) pending to University of Bonn., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Poorly water-soluble drugs are still a major challenge to overcome in order to achieve sufficiently high oral bioavailability. Spray freeze drying (SFD) is proposed here as an alternative for the preparation of amorphous, free-flowing porous celecoxib spheres for enhanced drug dissolution. Tertiary butyl alcohol solutions of celecoxib + excipient (povidone, hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and Soluplus®) at variable ratios were sprayed into a cooled spray tower, followed by vacuum freeze drying. Final porous particles were free-flowing, highly spherical (circularity ≥ 0.96) and mean diameters ranging from 210 to 800 µm, depending on excipient and drug content. XRPD measurements showed that Celecoxib was amorphous in all formulations and remained stable during 6 months storage. Kollidon 25 and HPMC-AS combinations resulted in the highest dissolution rates as well as dissolved drug amounts (30.4 ± 1.5 µg/ml and 41.8 ± 1.7 µg/ml) which in turn was 2-fold and 1.3-fold increase compared to film casted amorphous reference formulations, respectively. This phenomenon also translated into a faster onset of the drug absorption in-vivo, with significantly lower tmax values, while AUC values were non-significantly lowered compared to amorphous references. The high porosity of SFDs led to the advantageous accelerated dissolution which also translated into faster onset of absorption in-vivo., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The E551 food additive is composed of synthetic amorphous silica particles. The current regulation does not mention any specifications regarding their size and granulometric distribution, thus allowing the presence of silica nanoparticles despite their potential toxicity. The digestion process could modify their physicochemical properties and then influence their toxicological profile. After physicochemical characterization, subacute toxicity of engineered silica nanoparticles from 20 to 200 nm, native and digested E551 additives were evaluated from in vitro models of the intestinal barrier. Single cultures and a co-culture of enterocytes and mucus-secreting cells were established to investigate the mucus role. Toxicological endpoints including cytotoxicity, ROS production, intestinal permeability increase, and actin filament disruption were addressed after a 7-day exposure. The results showed a size-dependent effect of silica nanoparticles on cytotoxicity and intestinal permeability. A time-dependent disruption of actin filaments was observed in Caco-2 cells. The mucus layer spread on the HT29-MTX single culture acted as an efficient protective barrier while in the co-culture, small nanoparticles were able to cross it to reach the cells. From a hydrodynamic diameter of 70 nm, nanoparticles were not internalized in the intestinal cells, even in mucus-free models. Digestion did not affect the physicochemical properties of the additive. Due to a mean hydrodynamic diameter close to 200 nm, both native and digested E551 additives did not induce any toxic effect in intestinal barrier models. This study emphasized a cutoff size of 70 nm from which the interactions of the E551 additive with intestinal cells would be limited.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract with increasing incidence worldwide. Although a deeper understanding of the underlying mechanisms of IBD has led to new therapeutic approaches, treatment options are still limited. Severe adverse events in conventional drug therapy and poor drug targeting are the main cause of early therapy failure. Nanoparticle-based targeting approaches can selectively deliver drugs to the site of inflammation and reduce the risk of side effects by decreasing systemic availability. Here, we developed a nanoparticulate platform for the delivery of the anti-TNF-α antibody adalimumab (ADA) by covalent crosslinking to the particle surface. ADA binding to nanoparticles improved the stability of ADA against proteolytic degradation in vitro and led to a significantly better therapeutic outcome in a murine colitis model. Moreover, immobilization of ADA reduced systemic exposure, which can lead to enhanced therapeutic safety. Thus, nanoparticle protein decoration constitutes a platform through which epithelial delivery of any biological of interest to the inflamed gut and hence a local treatment can be achieved.

5-amino salicylic acid (5-ASA) is a standard therapy for the treatment of mild to moderate forms of inflammatory bowel diseases (IBD) whereas more severe forms involve the use of steroids and immunosuppressive drugs. Hyaluronic acid (HA) is a naturally occurring non-sulfated glycosaminoglycan that has shown epithelium protective effects in experimental colitis recently. In this study, both 5-ASA (30 mg/kg) and HA (15 mg/kg or 30 mg/kg) were administered rectally and investigated for their potential complementary therapeutic effects in moderate or severe murine colitis models. Intrarectal treatment of moderate and severe colitis with 5-ASA alone or HA alone at a dose of 30 mg/kg led to a significant decrease in clinical activity and histology scores, myeloperoxidase activity (MPO), TNF-α, IL-6 and IL-1β in colitis mice compared to untreated animals. The combination of HA (30 mg/kg) and 5-ASA in severe colitis led to a significant improvement of colitis compared to 5-ASA alone. Combined rectal therapy with HA and 5-ASA could be a treatment alternative for severe cases of IBD as it was the only treatment tested that was not significantly different from the healthy control group. This study further underlines the benefit of searching for yet unexplored drug combinations that show therapeutic potential in IBD without the need of designing completely new drug entities.

Due to their imaging and radiosensitizing properties, ultrasmall gadolinium chelate-coated gold nanoparticles (AuNP) represent a promising approach in the diagnosis and the treatment of tumors. However, their poor pharmacokinetic profile, especially their rapid renal clearance prevents from an efficient exploitation of their potential for medical applications. The present study focuses on a strategy which resides in the encapsulation of AuNP in large polymeric NP to avoid the glomerular filtration and then to prolong the vascular residence time. An original encapsulation procedure using the polyethyleneimine (PEI) was set up to electrostatically entrap AuNP in biodegradable poly(lactic-co-glycolic acid) (PLGA) and polyethylene glycol -PLGA (PLGA-PEG) NP. Hydrodynamic diameters of NP were dependent of the PEI/Au ratio and comprised between 115 and 196 nm for ratios equal or superior to 4. Encapsulation yield was close to 90 % whereas no loading was observed without PEI. No toxicity was observed after 24 h exposure in hepatocyte cell-lines. Entrapement of AuNP in polymeric nanocarriers facilitated the passive uptake in cancer cells after only 2 h incubation. In healthy rat, the encapsulation allowed increasing the gold concentration in the blood within the first hour after intravenous administration. Polymeric nanoparticles were sequestered in the liver and the spleen rather than the kidneys. T 1 -weighted magnetic resonance demonstrated that encapsulation process did not alter the contrast agent properties of gadolinium. The encapsulation of the gold nanoparticles in PLGA particles paves the way to innovative imaging-guided anticancer therapies in personalized medicine., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Essential oils (EOs) or their components are widely used by inhalation or nebulization to fight mild respiratory bacterial infections. However, their interaction with antibiotics is poorly known. In this study we evaluated the effects of citral, the main component of lemongrass oil, on in vitro susceptibility of Pseudomonas aeruginosa to antibiotics. Exposure of strain PA14 to subinhibitory concentrations of citral increased expression of operons encoding the multidrug efflux systems MexEF-OprN and MexXY/OprM, and bacterial resistance to anti-pseudomonal antibiotics including imipenem (twofold), gentamicin (eightfold), tobramycin (eightfold), ciprofloxacin (twofold), and colistin (≥128-fold). Use of pump deletion mutants showed that in addition to efflux other mechanisms were involved in this citral-induced phenotype. Determination of Zeta potential suggested that citral impairs the cell surface binding of aminoglycosides and colistin used at low concentrations (≤10 μg/mL). Moreover, experiments based on Raman spectroscopy and high-resolution mass spectrometry demonstrated formation of a Schiff base between the aldehyde group of citral and amino-groups of tobramycin and colistin. Chemical synthesis of tobracitryl, the imine compound resulting from condensation of citral and tobramycin, confirmed the loss of antibiotic activity due to adduct formation. Altogether these data point to the potential risk concern of self-medication with EOs containing citral in patients suffering from P. aeruginosa chronic lung infections and being treated with aerosols of aminoglycoside or colistin., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tetard, Foley, Mislin, Brunel, Oliva, Torrealba Anzola, Zedet, Cardey, Pellequer, Ramseyer, Plésiat and Llanes.)

The influence of supersaturation and solubilization on oral absorption was assessed independently from the dissolution process for the non-formulated model drugs celecoxib and telmisartan. In vitro, physicochemical characterization and biphasic dissolution were used to characterize the supersaturation and solubilization effects of three water soluble polymers (copovidone, methylcellulose and Soluplus®) on the drugs. While celecoxib precipitated in a crystalline form resulting in pronounced stabilization of supersaturation, telmisartan precipitated as a highly energetic amorphous form and the potential of the polymers to enhance its solubility was subsequently, limited. In vivo, for the crystalline precipitating celecoxib, supersaturation and solubilization increased its oral bioavailability up to 10-fold. On the contrary, the amorphous precipitating telmisartan did not benefit from the limited stabilization in terms of oral exposure. Amongst all investigated in vitro tests the biphasic dissolution test was the most predictive in relation to supersaturation. However, for the potential micellar solubilization and the respective impact in the aqueous/organic interface, prediction accuracy of the biphasic dissolution test was limited in combination with Soluplus®. Despite the hetergeneous micellar distribution in vitro and permeation in vivo, the biphasic approach could clearly show the supersaturation potential on bioavailability (BA) for celecoxib on the one hand and the inferiority of supersaturation on BA for telmisartan., (Copyright © 2021. Published by Elsevier B.V.)

Pharmacologically active macromolecules, such as peptides, are still a major challenge in terms of designing a delivery system for their transport across absorption barriers and at the same time provide sufficiently high long-term stability. Spray freeze dried (SFD) lyospheres ® are proposed here as an alternative for the preparation of fast dissolving porous particles for nasal administration of insulin. Insulin solutions containing mannitol and polyvinylpyrrolidone complemented with permeation enhancing excipients (sodium taurocholate or cyclodextrins) were sprayed into a cooled spray tower, followed by vacuum freeze drying. Final porous particles were highly spherical and mean diameters ranged from 190 to 250 µm, depending on the excipient composition. Based on the low density, lyospheres resulted in a nasal deposition rates of 90% or higher. When tested in vivo for their glycemic potential in rats, an insulin-taurocholate combination revealed a nasal bioavailability of insulin of 7.0 ± 2.8%. A complementary study with fluorescently labeled-dextrans of various molecular weights confirmed these observations, leading to nasal absorption ranging from 0.7 ± 0.3% (70 kDa) to 10.0 ± 3.1% (4 kDa). The low density facilitated nasal administration in general, while the high porosity ensured immediate dissolution of the particles. Additionally, due to their stability, lyospheres provide an extremely promising platform for nasal peptide delivery.

Lipoproteins are biodegradable and biocompatible natural carriers that can be utilized for the transport of hydrophobic drugs, such as cyclosporin A (CycloA), a calcineurin inhibitor utilized for the inflammatory bowel disease, such as ulcerative colitis. A major limitation in the drug treatment of inflammatory bowel disease is the inability to deliver the drug selectively toward the inflamed tissues. Nanotechnology-based drug delivery systems have led to an amelioration of the therapeutic selectivity, but still the majority of the entrapped drug is eliminated without exercising a therapeutic effect. The present study aimed to prepare three lipoprotein formulations (HDL-, LDL-, and VLDL-based) loaded with cyclosporin A for the treatment of colitis in a murine model. After an intravenous injection of a drug dose of 2 mg/kg, clinical activity (colon weight/length ratio) and therapeutic effects (evaluated by the inflammatory markers MPO and TNF-α) were compared with those of the untreated colitis control group. All CycloA-containing lipoproteins reduced clinical activity, with a significant decrease in the case of LDL-CycloA formulation, which also led to the higher therapeutic effect.

Anxio-depressive symptoms as well as severe cognitive dysfunction including aberrant decision-making (DM) are documented in neuropsychiatric patients with hypercortisolaemia. Yet, the influence of the hypothalamo-pituitary-adrenal (HPA) axis on DM processes remains poorly understood. As a tractable mean to approach this human condition, adult male C57BL/6JRj mice were chronically treated with corticosterone (CORT) prior to behavioural, physiological and neurobiological evaluation. The behavioural data indicate that chronic CORT delays the acquisition of contingencies required to orient responding towards optimal DM performance in a mouse Gambling Task (mGT). Specifically, CORT-treated animals show a longer exploration and a delayed onset of the optimal DM performance. Remarkably, the proportion of individuals performing suboptimally in the mGT is increased in the CORT condition. This variability seems to be better accounted for by variations in sensitivity to negative rather than to positive outcome. Besides, CORT-treated animals perform worse than control animals in a spatial working memory (WM) paradigm and in a motor learning task. Finally, Western blotting neurobiological analyses show that chronic CORT downregulates glucocorticoid receptor expression in the medial Prefrontal Cortex (mPFC). Besides, corticotropin-releasing factor signalling in the mPFC of CORT individuals negatively correlates with their DM performance. Collectively, this study describes how chronic exposure to glucocorticoids induces suboptimal DM under uncertainty in a mGT, hampers WM and motor learning processes, thus affecting specific emotional, motor, cognitive and neurobiological endophenotypic dimensions relevant for precision medicine in biological psychiatry., Competing Interests: Conflicts of Interest All authors declare no conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

Findings from recent studies revealed a significant anti-inflammatory effect of polysaccharide-based excipients when formulated with classical drugs in experimental inflammatory bowel disease models. In this study, acacia and guar gum were investigated beyond their typical functionality for a possible additive anti-inflammatory effect when administered with 5-amino salicylic acid (5ASA) in murine experimental colitis. Anti-inflammatory effects of acacia and guar gum-based aqueous suspensions of 5ASA were evaluated in a murine experimental colitis. Acacia or guar gum (30 or 300 mg/kg) were administered via rectal administration alone or in combination with 5ASA (30 mg/kg). Disease activity, myeloperoxidase activity (MPO) and intratissue concentrations of various cytokines were assessed. Both acacia and guar gum separately showed significant effects in reducing the inflammatory markers in murine colitis model in vivo . When combined with the anti-inflammatory drug 5ASA, acacia showed a stronger therapeutic effect than guar gum, especially at the higher dose of acacia (300 mg/kg) which significantly reduced the inflammation in vivo compared to 5ASA alone (MPO, 5ASA: 5743 ± 1334, 5ASA + 30 mg/kg acacia: 3762 ± 2342; 5ASA + 30 mg/kg guar gum: 7373 ± 2115, 5ASA + 300 mg/kg acacia: 3131 ± 1012, 5ASA + 300 mg/kg guar gum: 6358 ± 2379; all U/g tissue). Acacia and guar gum separately showed significant anti-inflammatory effects in murine colitis, and furthermore, high dose acacia led to an additional therapeutic benefit when co-administered with 5ASA. These results indicate that further investigations are surely warranted in the search of better colitis therapy., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (© 2021 The Author(s).)

Using polymers as additives to formulate ternary amorphous solid dispersions (ASDs) has successfully been established to increase the bioavailability of poorly soluble drugs, when one polymer is not able to provide both, stabilizing the drug in the matrix and the supersaturated solution. Therefore, we investigated the influence of low-viscosity hydroxypropyl cellulose (HPC) polymers as an additive in HPMC based ternary ASD formulations made by hot-melt extrusion (HME) on the bioavailability of itraconazole (ITZ). The partitioning potential of the different HPC grades was screened in biphasic supersaturation assays. Solid-state analytics were performed using differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD). The addition of HPCs, especially HPC-UL, resulted in a superior partitioned amount of ITZ in biphasic supersaturation assays. Moreover, the approach in using HPCs as an additive in HPMC based ASDs led to an increase in partitioned ITZ compared to Sporanox® in biorelevant biphasic dissolution studies. The results from the biphasic dissolution experiments correlated well with the in vivo studies, which revealed the highest oral bioavailability for the ternary ASD comprising HPC-UL and HPMC., Competing Interests: This work was funded by Nisso Chemical Europe GmbH. University of Bonn and Nisso Chemical Europe GmbH participated in study design, research, interpretation of data, writing, data collection, analysis, reviewing, and approving the publication. Edmont Stoyanov is an employee of Nisso Chemical Europe GmbH and does not own stocks on Nippon Soda Ltd. Rafael Bachmaier, Marius Monschke, Anna K. Krome and Thilo Faber are PhD students and Karl G. Wagner and Alf Lamprecht are professors at the University of Bonn. Yann Pellequer is an employee of the University of Franche-Comté in Besancon. They have no additional conflicts of interest to report., (© 2021 The Authors. Published by Elsevier B.V.)

Oil-in-water nanoemulsions are used in numerous biomedical applications as delivery systems. The droplet size in the nanometer range and their composition were extensively developed for carrying and enhancing the absorption of lipophilic drugs and lipids of interest. In the present study, critical parameters involved in the spontaneous nanoemulsification process such as the temperature, the oil type, the surfactant-to-oil and water-to-oil ratios were investigated. The aim was to design a solvent-free procedure for the spontaneous nanoemulsification at a low temperature of a large variety of triglycerides including vegetable oils. Nanoemulsification of medium-chain triglyceride (MCT) was not dependent on the temperature while nanodroplets of long-chain triglycerides (LCT) were only obtained by reaching the cloud point of ethoxylated surfactant Kolliphor® HS15. The molar volume of triglycerides was considered as a predictive parameter governing both, the spontaneous nanoemulsification at low temperature and the Ostwald ripening rate. The physical mixture of MCT and LCT was a promising strategy to prepare stable and fine nanoemulsions at 37 °C. They were characterized by a hydrodynamic diameter comprised between 20 and 30 nm and a narrow size distribution. These findings pave the way to new applications for the parenteral nutrition and the delivery of thermosensitive drugs and lipophilic molecules such as antioxidants., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Chitosan is used in various drug delivery approaches as a pharmaceutical excipient. Although its potential as an immunomodulatory agent has been reported, its use in this capacity has not been fully explored. The efficacy of chitosan as an active pharmacological agent, particularly in anti-inflammatory therapy in inflammatory bowel diseases (IBD), was investigated in this study. The potential impact of the molecular weight (MW) and degree of deacetylation (DD) of chitosan was investigated together with 5-amino salicylic acid (5-ASA) for its efficacy in a combination anti-inflammatory therapy in murine experimental colitis. Such a combination would potentially be developed into novel dual strategies whereby chitosan acts as a mucoadhesive excipient as well as provide an additional anti-inflammatory benefit. Chitosan grades with different MW and DD were administered intrarectally alone or in combination with 5-ASA to colitis mice for 3 days. Myeloperoxidase (MPO) and alkaline phosphatase (ALP) activity and tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β) and nuclear factor kappa-B (NF-κB) levels were assessed from the colon. Intrarectal treatment of colitis with 30 mg/kg chitosan alone and with 30 mg/kg 5-ASA for 3 days led to a significant decrease in MPO, ALP, TNF-α, IL-6, IL-1β and NF-κB in colitis mice compared to untreated mice. Surprisingly, the efficacy of chitosan as an anti-inflammatory polymer was relatively independent from its structural properties, namely DD and MW. However, combinations of chitosan with 5-ASA showed a significant pharmacological improvement, whereby the additive anti-inflammatory efficacy observed shows the possibility of finetuning chitosan by combining it with anti-inflammatory agents to optimize its anti-inflammatory potential.

Inflammatory bowel disease (IBD) refers to progressive inflammatory disorders that impair the gastrointestinal tract's structure and function. Given their selective accumulation in inflamed tissues, nanoparticles are promising drug delivery systems for IBD treatment. The hypothesis here was that drug-free nanoscaled cationic ammonio methacrylate copolymers (AMCNP) may have a beneficial therapeutic effect in murine TNBS-induced colitis. Type A and B AMCNP (RLNP and RSNP, respectively) were prepared and characterized in vitro, and were rectally administered in two concentrations (5 and 25 mg ml -1 ) for the treatment of two grades of murine experimental colitis. The impact of the nanoparticles upon the inflammatory markers, circulating LPS, intestinal permeability and colonic leukocyte populations was examined. Both RLNP and RSNP led to a significant mitigation of mild to moderate experimental colitis, as evident from the substantial reduction of myeloperoxidase (MPO) and alkaline phosphatase (AP) activities (more than two-fold, P < 0.05) and various pro-inflammatory cytokine concentrations (TNF-α, IL-1β, IL-6, IL-12). The best therapeutic efficiency was observed when the particles were used at 5 mg ml -1 , while the more cationic RLNP performed superior. When used against a severe grade of colitis, RLNP (5 mg ml -1 ) resulted in a significant decrease of tissue MPO and TNF-α. It was found that treatment with AMCNP resulted in significant intestinal immune cell depletion, intestinal barrier function improvement, and 1.5-2.5 times reduction of the systemic endotoxin concentration. These findings highlighted the fact that nanoscaling endows the cationic amphiphilic AMCs unique therapeutic properties, which help mitigate murine experimental colitis in the absence of any drug load. The results also provided a glimpse of possible underlying mechanisms through which nanoscaled AMCs might have exerted their therapeutic effect within this context.

Amorphous silica nanoparticles are widely used as pharmaceutical excipients and food additive (E551). Despite the potential human health risks of mineral nanoparticles, very few data regarding their oral toxicity are currently available. This study aims to evaluate and to understand the interactions of silica particles at 1 and 10 mg mL -1 with the intestinal barrier using a Caco-2 monolayer and a Caco-2/HT29-MTX co-culture. A size- and concentration-dependent reversible increase of the paracellular permeability is identified after a short-term exposure to silica nanoparticles. Nanoparticles of 30 nm induce the highest transepithelial electrical resistance drop whereas no effect is observed with 200 nm particles. Additive E551 affect the Caco-2 monolayer permeability. Mucus layer reduces the permeability modulation by limiting the cellular uptake of silica. After nanoparticle exposure, tight junction expression including Zonula occludens 1 (ZO-1) and Claudin 2 is not affected, whereas the actin cytoskeleton disruption of enterocytes and the widening of ZO-1 staining bands are observed. A complete permeability recovery is concomitant with the de novo filament actin assembly and the reduction of ZO-1 bands. These findings suggest the paracellular modulation by small silica particles is directly correlated to the alteration of the ZO-actin binding strongly involved in the stability of the tight junction network.

Commercial development of nanosuspensions for oral drug delivery generally involves a drying step which aims to generate a stable product that rapidly releases the nanocrystals once rehydrated and can be easily processed into a final dosage form (e.g., filled into hard capsule). Cryopelletisation is a freeze drying technique allowing the production of lyophilised micrometric spheres with good flowability. In the current work, the possibility to formulate redispersible ketoconazole nanocrystal-based cryopellets able to withstand intensive handling was investigated. Cryopellets were generated by first freezing regular droplets of nanosuspension using liquid nitrogen followed by water removal by sublimation in a standard freeze dryer. Low-friable cryopellets (< 1%) were produced by embedding the nanocrystals in a stabilizing hydroxypropyl cellulose SSL grade matrix, thus proving that these structures can withstand intensive handling. A threshold quantity of hydroxypropyl cellulose SSL grade (5/20 hydroxypropyl cellulose SSL grade-to-drug mass ratio) was required in combination with D-α-tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS) to successfully recover the nanocrystals over storage. A further addition of micronised crospovidone has shown a positive effect on the dissolution performance of cryopellets. Altogether, this study demonstrated that the design of cryopellets combining the strengths of freeze-dried powders (porous internal structure, low residual humidity) and pellets (free-flowing units, mechanical resistance during handling) can potentially improve the nanocrystal's redispersibility compared with other drying techniques while facilitating the downstream processing.

This study sought to develop a simple nanoparticle-based approach to enhance the efficiency and tolerability of lipopolysaccharide (LPS), a potent ligand of Toll-like Receptor 4 (TLR4), for immunotherapy in cancer. Despite holding promise within this context, the strong pro-inflammatory properties of LPS also account for its low tolerability given localized and systemic side effects, which restrict the administrable dosage. Herein, we investigated the effect of LPS decoration as a surface-active molecule on a polymeric matrix upon its efficiency and tolerability. The LPS-decorated nanoparticles (LPS-NP) were about 150 nm in size, with slightly negative zeta potential (about -15 mV) and acceptable LPS incorporation (about 70%). In vitro, the particles accounted for a higher induction of apoptosis in tumor cells cultured with murine splenocytes compared to LPS solution. When used for the treatment of a murine syngeneic colorectal tumor model, higher intratumoral deposition of the particle-bound LPS was observed. Furthermore, unlike LPS solution, which accounted for localized necrosis at high concentrations, treatment of tumor-bearing animals with equivalent doses of LPS-NP was well tolerated. We propose that the observed localized necrosis can be Shwartzman phenomenon, which, due to modulated 24-h post-injection systemic TNF-α and LPS concentrations, have been avoided in case of LPS-NP. This has in turn enhanced the therapeutic efficiency and enabled complete tumor regression at concentrations at which LPS solution was intolerable. The findings indicate that nanoparticles can serve as beyond carriers for the delivery of superficially decorated LPS molecules, but impact their overall efficiency and tolerability in cancer therapy.

Nanomedicines represent a promising approach in the treatment and diagnosis of numerous disorders. The majority of the injected dose of nanoparticles (NPs) is sequestrated in the liver. Despite this hepatic tropism, the interaction of NPs with the detoxification function of the liver remains unclear. The present study consists of evaluating the impact of biodegradable poly(lactide-co-glycolide) (PLGA) and silica NPs on cytochrome P450 (CYP) activities. The effects of NPs were evaluated in vitro on human and rat hepatocytes in primary cultures and in vivo by intravenous injections in healthy rats. More than the physicochemical properties, the composition of NPs (organic, inorganic) dramatically influenced the detoxification function of the liver. Silica NPs modulated the CYP activity both in rat and human hepatocytes, in contrast to PLGA NPs. A CYP isoform-dependent effect was reported and the modulation of the metabolic hepatic activity was species-dependent. Human hepatocytes were sensitive to an exposure to PLGA NPs, whereas no marked effect was detected in rat hepatocytes. The in vitro data obtained in rat hepatocytes were correlated with the in vivo data. This study emphasizes the interest to set up relevant in vitro models using human hepatic cells to evaluate the hepatotoxicity of nanomedicines.

Active Freeze Drying allows for producing lyophilised powders by progressive agitation of frozen blocks undergoing sublimation. One potential application of this process is the formulation design of unstable nanosuspensions for oral drug delivery, as here shown for nanocrystal-based ketoconazole powder. With this technique, a critical vapour flow needs to be achieved in order to obtain reasonable process yields (>78%). The size distribution of powder particles (median size between 21 and 44 μm) was affected by the nanocrystal concentration and the drug-to-stabilizer ratio. This was assumed to be related to the mechanical strength of the solid network from which the powder particles break off. The adjustments of the drug-to-stabilizer ratio and the freezing procedure proved to play a major role in improving powder redispersibility. However, differences in powder redispersibility did not translate into significant changes in in-vitro dissolution rates. Active Freeze Drying has confirmed to be a promising tool to efficiently produce redispersible nanocrystal powders., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Epithelial administration of low molecular weight heparin (LMWH) has proven its therapeutic efficiency in ulcerative colitis (UC) but still lacks of a sufficiently selective drug delivery system. Polymeric nanoparticles were used here not only to protect LMWH from intestinal degradation but also to provide targeted delivery to inflamed tissue in experimental colitis mice. LMWH was associated with polymethacrylate nanoparticles (NP) type A (PEMT-A) or type B (PEMT-B) of a size: 150 nm resulting in a maximum drug loading: 0.1 mg/mg. In a lipopolysaccharide-stimulated macrophages both, free LMWH and LMWH-NP have significantly reduced the cytokines secretion independently from cellular uptake. The in-vivo therapeutic efficiency was dose dependent as at low doses (100 IU/kg) only minor differences between free LMWH and LMWH-NP were found and the superiority of LMWH-NP became prominent with dose increase (500 IU/kg). Administration of LMWH-NP at 500 IU/kg has markedly improved the clinical activity as compared to LMWH while similarly pathophysiological indicators revealed increased therapeutic outcome in presence of NP compared to LMWH alone: Myeloperoxidase (Colitis control: 10 480 ± 5335, LMWH-PEMT-A NP: 1507 ± 2165, LMWH-PEMT-B NP: 382 ± 143, LMWH: 8549 ± 5021 units/g) and tumor necrosis factor: (Colitis control: 1636 ± 544, LMWH-PEMT-A NP: 511 ± 506, LMWH-PEMT-B NP: 435 ± 473, LMWH: 1110 ± 309 pg/g). Associating LMWH with NP is improving the anti-inflammatory efficiency of LMWH in-vivo by its protection against degradation in luminal environment and selective drug delivery. Such a combination holds promise for a highly specific therapy by its double selectivity towards the inflamed intestinal tissue. LMWH-PEMT NP have significantly improved the clinical activity in-vivo in comparison to free LMWH.

In this present study, the secretory transport of P-gp substrates, rhodamine 123 and digoxin, was evaluated using a Caco-2/HT29-MTX co-culture characterized by an efflux mechanism and a paracellular permeability closer to the human intestinal barrier compared to the Caco-2 monolayer gold standard. The influence of simulated intestinal fluids termed FeSSIF and FaSSIF on the intestinal absorption was also assessed in comparison with a conventional saline buffer. Labrasol ® ALF and Gelucire ® 44/14 in saline buffer significantly decreased to 83% and 62%, the P-gp-mediated transport of rhodamine 123 across the co-culture, respectively. The effects of Gelucire ® 44/14 were much more exacerbated with the Caco-2 monolayer model with a reduced permeability to 34% but they were partially reversed in the co-culture with FeSSIF. The modulation by the lipid excipients of digoxin secretory transport across the Caco-2 monolayer and the co-culture was reduced compared with the rhodamine 123. This work also emphasizes the numerous parameters that have to be considered for predicting accurately the effects of potential P-gp inhibitors including the in-vitro model, the incubation media and the intrinsic properties of P-gp substrates., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The oral bioavailability of drugs is often limited due to the presence of the P-glycoprotein, an efflux pump strongly expressed on the luminal side of the intestinal barrier. In an attempt to circumvent drug efflux, strategies consisting in the coadministration of drugs with surface-active agents have been found to be promising. In this context, the role of saponins on the intestinal permeability of a P-glycoprotein substrate was investigated. The P-glycoprotein inhibition activity of three triterpenoid saponins extracted from several plants of the Caryophyllaceae family was evaluated using an intestinal barrier model comprised of Caco-2 cell lines. The results showed a strong effect of two saponins on P-glycoprotein-mediated transport. At a concentration of 15 µM, the efflux ratio was close to 1 for both saponins, thus suggesting a total inhibition of the efflux pump in contrast to verapamil HCl, a conventional P-glycoprotein inhibitor. In addition, measurements of the transepithelial electrical resistance revealed that the integrity of the monolayers was not altered at such concentrations, thereby reducing potential adverse effects. The presence of acetylated sugars in the saponin structure could possibly facilitate interactions with the efflux pump by an ATP-dependent mechanism or by fluidization of cell membranes., (Georg Thieme Verlag KG Stuttgart · New York.)

A major limitation in the current topical treatment of inflammatory skin diseases is the inability to selectively deliver the drug to the inflammation site. Recently, smart drug delivery systems such as nanocarriers are being investigated to enhance the selective deposition of anti-inflammatory drugs in inflamed areas of the skin to achieve higher therapeutic efficacy with minimal side effects. Of such systems, polymeric nanoparticles are considered very efficient carriers for the topical drug delivery. In the current work, poly(l-lactide-co-glycolide) nanoparticles of nominal sizes of 70nm (NP70) and 300nm (NP300) were studied for their intra-epidermal distribution in murine and pig atopic dermatitis models over time against the respective healthy controls. Confocal laser scanning microscopical examination of skin biopsies was utilized for the qualitative and semi-quantitative analyses of nanoparticles skin deposition and penetration depth. While no skin penetration was found for any of the particles in healthy skin, the accumulation of NP70 was significantly higher than NP300 in inflamed skin (15-fold in mice, 5-fold in pigs). Penetration depth of NP70 decreased over time in mice from 55±3μm to 20±2μm and similar tendencies were observed for the other formulations. In inflamed pig skin, a similar trend was found for the penetration depth (NP70: 46±12μm versus NP300: 23±3μm); however, the NP amount remained constant for the whole analyzed period. Their ability to penetrate specifically into inflamed skin combined with minimal effects on healthy skin underlines small polymeric nanoparticles' potential as selective drug carriers in future treatment of chronic inflammatory skin diseases such as atopic dermatitis., (Copyright © 2016 Elsevier B.V. All rights reserved.)

This study prepared three liposomal formulations coloaded with elacridar and tariquidar to overcome the P-glycoprotein-mediated efflux at the blood-brain barrier. Their pharmacokinetics, brain distribution, and impact on the model P-glycoprotein substrate, loperamide, were compared to those for the coadministration of free elacridar plus free tariquidar. After intravenous administration in rats, elacridar and tariquidar in conventional liposomes were rapidly cleared from the bloodstream. Their low levels in the brain did not improve the loperamide brain distribution. Although elacridar and tariquidar in PEGylated liposomes exhibited 2.6 and 1.9 longer half-lives than free elacridar and free tariquidar, respectively, neither their Kp for the brain nor the loperamide brain distribution was improved. However, the conjugation of OX26 F(ab')2 fragments to PEGylated liposomes increased the Kps for the brain of elacridar and tariquidar by 1.4- and 2.1-fold, respectively, in comparison to both free P-gp modulators. Consequently, the Kp for the brain of loperamide increased by 2.7-fold. Moreover, the plasma pharmacokinetic parameters and liver distribution of loperamide were not modified by the PEGylated OX26 F(ab')2 immunoliposomes. Thus, this formulation represents a promising tool for modulating the P-glycoprotein-mediated efflux at the blood-brain barrier and could improve the brain uptake of any P-glycoprotein substrate that is intended to treat central nervous system diseases.

Polymeric nanoparticles (NPs) are currently being investigated for various therapeutic, diagnostic and drug delivery applications. The study of their interactions and fate in biological systems is frequently performed via their fluorescent labeling and following them using fluorescent microscopy. Quantum dots are proposed as stable fluorescent label and compared to other organic dyes (Nile red and DiI) in terms of their entrapment, diffusion in different aqueous or lipophilic media and photostability. In vitro transfer to hydrophilic PBS solution showed that after 8h, 4.2±2.2, 15.5±2.0 and 0.9±0.02% was released from the QDs, NR and DiI nanoparticles, respectively. However, higher diffusion rates were observed in the lipophilic medium chain triglyceride and artificial sebum for all the dyes used. Fluorescent intensity of the three different markers was found to be stable over a period of 24h. Continuous illumination with laser beam using a confocal laser scanning microscopy indicated the superior stability of quantum dots compared to the other organic dyes. Skin permeation experiments have shown that QDs were the most representative marker for the polymeric nanoparticles skin penetration., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Cell culture models are currently used to predict absorption pattern of new compounds and formulations in the human gastro-intestinal tract (GIT). One major drawback is the lack of relevant apical incubation fluids allowing mimicking luminal conditions in the GIT. Here, we suggest a culture model compatible with biorelevant media, namely Fasted State Simulated Intestinal Fluid (FaSSIF) and Fed State Simulated Intestinal Fluid (FeSSIF). Co-culture was set up from Caco-2 and mucus-secreting HT29-MTX cells using an original seeding procedure. Viability and cytotoxicity assays were performed following incubation of FeSSIF and FaSSIF with co-culture. Influence of biorelevant fluids on paracellular permeability or transporter proteins were also evaluated. Results were compared with Caco-2 and HT29-MTX monocultures. While Caco-2 viability was strongly affected with FeSSIF, no toxic effect was detected for the co-cultures in terms of viability and lactate dehydrogenase release. The addition of FeSSIF to the basolateral compartment of the co-culture induced cytotoxic effects which suggested the apical mucus barrier being cell protective. In contrast to FeSSIF, FaSSIF induced a slight increase of the paracellular transport and both tested media inhibited partially the P-gp-mediated efflux in the co-culture. Additionally, the absorptive transport of propranolol hydrochloride, a lipophilic β-blocker, was strongly affected by biorelevant fluids. This study demonstrated the compatibility of the Caco-2/HT29-MTX model with some of the current biorelevant media. Combining biorelevant intestinal fluids with features such as mucus secretion, adjustable paracellular and P-gp mediated transports, is a step forward to more realistic in-vitro models of the human intestine., (Copyright © 2015. Published by Elsevier B.V.)

Nanoparticles (NPs) are currently used as drug delivery systems for numerous therapeutic macromolecules, e.g. proteins or DNA. Based on the preparation by double emulsion solvent evaporation a sponge-like structure was postulated entrapping hydrophilic drugs inside an internal aqueous phase. However, a direct proof of this hypothesized structure is still missing today. NPs were prepared from different polymers using a double-emulsion method and characterized for their physicochemical properties. Combining ion milling with field emission scanning electron microscopy allowed to cross section single NP and to visualize their internal morphology. The imaging procedure permitted cross-sectioning of NPs and visualization of the internal structure as well as localizing drugs associated with NPs. It was observed that none of the model actives was encapsulated inside the polymeric matrix when particle diameters were below around 470 nm but predominantly adsorbed to the particle surface. Even at larger diameters only a minority of particles of a diameter below 1 μm contained an internal phase. The properties of such drug loaded NPs, i.e. drug release or the observations in cellular uptake or even drug targeting needs to be interpreted carefully since in most cases NP surface properties are potentially dominated by the 'encapsulated' drug characteristics., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A major limitation in the drug treatment of inflammatory bowel disease is the inability to deliver the drug selectively towards the inflamed tissues. Nanotechnology-based drug delivery systems have led to an amelioration of the therapeutic selectivity but still the majority of the entrapped drug is eliminated without exercising a therapeutic effect. Here, lectin-decorated drug loaded nanoparticles (NP) are suggested for active targeting and selective adhesion to the inflamed tissue in experimental colitis. Peanut (PNA) and wheat germ (WGA) lectins were covalently bound to the surface of NP and were tested for their stability and degree of bioadhesion in cell culture. In-vivo, the selectivity of bioadhesion and distribution of NP throughout the intestinal tract as well as the therapeutic benefit for glucocorticoid loaded lectin-NP was studied in murine colitis models. Quantitative adhesion analyses showed that lectin-conjugated NP exhibited a much higher binding and selectivity to inflamed tissue compared to plain NP (PNA conjugates: 52.2±5.6%; WGA conjugates: 22.0±0.8%; plain NP: 18.6±9.8%). Lectin-associated NP revealed a further increase in the selectivity of bioadhesion towards inflamed tissues which partially translates into increased therapeutic efficiency. In terms of therapeutic efficiency, all glucocorticoid containing formulations revealed an enhanced therapeutic effect with lectin conjugates especially PNA-NP (myeloperoxidase: 55±37U/g; TNF-alpha: 3880±380U/g) compared to plain NP (myeloperoxidase: 145±98U/g; TNF-alpha: 6971±1157U/g). Targeted NP by using lectins, especially with PNA, as stable targeting moiety in the gastrointestinal tract appears to be a very promising tool in future treatment of inflammatory bowel disease., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Topical treatment of skin diseases is an attractive strategy as it receives high acceptance from patients, resulting in higher compliance and therapeutic outcomes. Recently, the use of variable nanocarriers for dermal application has been widely explored, as they offer several advantages compared with conventional topical preparations, including higher skin penetration, controlled and targeted drug delivery and the achievement of higher therapeutic effects. This article will focus on skin inflammation or dermatitis as it is one of the most common skin problems, describing the different types and causes of dermatitis, as well as the typical treatment regimens. The potential use of nanocarriers for targeting skin inflammation and the achievement of higher therapeutic effects using nanotechnology will be explored.

Standard monoculture models utilizing Caco-2 monolayers were extensively used to mimic the permeability of the human intestinal barrier. However, they exhibit numerous limitations such as the lack of mucus layer, an overestimation of the P-gp-mediated efflux and a low paracellular permeability. Here, we suggest a new procedure to set up an in vitro model of intestinal barrier to adjust gradually the properties of the absorption barrier. Mucin-secreting HT29-MTX cells were added to Caco-2 absorptive cells in a Transwell® at different time intervals. Effects of seeding day of HT29-MTX on the paracellular permeability of lucifer yellow (LY) and on the P-gp-mediated efflux of rhodamine 123 were investigated. Apparent permeability of the rhodamine 123 in the secretory direction was highly dependent on the seeding day of goblet cells. Transepithelial electrical resistance values and LY transport across the co-cultures in the apical-to-basolateral direction were intermediary between single Caco-2 and HT29-MTX models. Early seeding days of HT29-MTX allowed increasing the fraction of goblet cells in the co-culture. Co-culture permeability was unchanged between 21 and 30 days after Caco-2 seeding, corresponding to the period of use for Caco-2-based cell models. Thus, the HT29-MTX seeding day was a key factor to set up an in vitro intestinal model with tailor-made barrier properties in terms of P-gp expression and paracellular permeability., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The efflux transporter P-glycoprotein, expressed at high levels at the blood-brain barrier, exerts a profound effect on the disposition of various therapeutic compounds in the brain. A rapid and efficient modulation of this efflux transporter could enhance the distribution of its substrates and thereby improve central nervous system pharmacotherapies. This study explored the impact of the intravenous coadministration of two P-glycoprotein modulators, tariquidar and elacridar, on the pharmacokinetics and brain distribution of loperamide, a P-glycoprotein substrate probe, in rats. After 1 hour postdosing, tariquidar and elacridar, both at a dose of 1.0 mg/kg, increased loperamide levels in the brain by 2.3- and 3.5-fold, respectively. However, the concurrent administration of both P-glycoprotein modulators, each at a dose of 0.5 mg/kg, increased loperamide levels in the brain by 5.8-fold and resulted in the most pronounced opioid-induced clinical signs. This phenomenon may be the result of a combined noncompetitive modulation by tariquidar and elacridar. Besides, the simultaneous administration of elacridar and tariquidar did not significantly modify the pharmacokinetic parameters of loperamide. This observation potentially allows the concurrent use of low but therapeutic doses of P-gp modulators to achieve full inhibitory effects.

Inflammatory bowel disease is a chronic relapsing inflammation of the gut with the two main forms being ulcerative colitis and Crohn's disease. Nanoparticulate drug carrier systems have been proven to enhance the therapeutic efficiency and to diminish adverse effects of the anti-inflammatory treatment due to their size dependent accumulation in the inflamed regions of the gut. The influence of surface properties on the accumulation selectivity and intensity of such nanoparticles is mainly unclear. Accordingly sized particles (~200 nm) were prepared by the emulsification solvent evaporation technique using different surfactants (polysorbate 20, sodium dodecyl sulphate, sodium cholate, cetyltrimethylammonium bromide, polyvinyl alcohol). In a murine colitis model the particles prepared with polysorbate 20 as surfactant led to a 34.8-fold higher particle content in the inflamed areas of the colon compared to the healthy gut and to a 4.5-fold increase of the particle content in the inflamed segments compared to particles prepared with sodium dodecyl sulphate. This effect translates also into a significantly higher mitigating effect when entrapping betamethasone into such nanoparticles. This study shows the importance of surface properties for the passive targeting approach in experimental colitis. The influence seems to be as important as the influence of the particle size., (© 2013.)

Nanoparticles (NPs) have shown a certain potential to overcome the drawbacks of oral peptide delivery in the gastrointestinal tract such as low peptide stability and permeability. The preparation of insulin loaded NPs was carried out with Eudragit RL or RS dissolved in different non-toxic polyethylene glycol (PEG) derivatives. The use of these non-toxic solvents allowed the design of an one step NP preparation method where insulin retained its full biological activity as it was proven in vitro and in vivo. The insulin trapping NPs were in a size range of around 150-250 nm and exhibited a pH-dependent release. The type of solvent did not distinctly influence the particle properties or insulin stability but modified significantly the performance in vivo in rats, NPs prepared with glycofurol led to a bioavailability of F=1.4 ± 1.0% after oral administration while NPs prepared with PEG 300 were hardly efficient (F=0.3 ± 0.5%). In all cases t(max) was shifted to 2h compared to 1h after subcutaneous insulin solution. In general, we believe that the method presented here is a promising way to encapsulate sensitive drugs, especially for the production of peptide loaded NPs., (Copyright © 2013 Elsevier B.V. All rights reserved.)