Exploring the Potential of Sulfonamide-Dihydropyridine Hybrids as Multitargeted Ligands for Alzheimer's Disease Treatment.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease that has a heavy social and economic impact on all societies and for which there is still no cure. Multitarget-directed ligands (MTDLs) seem to be a promising therapeutic strategy for finding an effective treatment for this disease. For this purpose, new MTDLs were designed and synthesized in three steps by simple and cost-efficient procedures targeting calcium channel blockade, cholinesterase inhibition, and antioxidant activity. The biological and physicochemical results collected in this study allowed us the identification two sulfonamide-dihydropyridine hybrids showing simultaneous cholinesterase inhibition, calcium channel blockade, antioxidant capacity and Nrf2-ARE activating effect, that deserve to be further investigated for AD therapy.

Ingestion of titanium dioxide nanoparticles: a definite health risk for consumers and their progeny.

Titanium dioxide (TiO2) is one of the most commonly used nanomaterials in the world. Additive E171, which is used in the food industry, contains a nanometric particle fraction of TiO2. Oral exposure of humans to these nanoparticles (NPs) is intensive, leading to the question of their impact on health. Daily oral intake by rats of amounts of E171 that are relevant to human intake has been associated with an increased risk of chronic intestinal inflammation and carcinogenesis. Due to their food preferences, children are very exposed to this NP. Furthermore, maternal-foetal transfer of TiO2 NPs during pregnancy, as well as exposure of the offspring by breastfeeding, have been recently described. In France, the use of E171 in the production of foodstuffs was suspended in January 2020 as a precautionary measure. To provide some answers to this public health problem and help global regulatory agencies finalize their decisions, we reviewed in vitro and in vivo studies that address the effects of TiO2 NPs through oral exposure, especially their effects on the gastrointestinal tract, one of the most exposed tissues. Our review also highlights the effects of exposure on the offspring during pregnancy and by breastfeeding.

Small silica nanoparticles transiently modulate the intestinal permeability by actin cytoskeleton disruption in both Caco-2 and Caco-2/HT29-MTX models.

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.

Triterpenoid Saponins from the Caryophyllaceae Family Modulate the Efflux Activity of the P-Glycoprotein in an In Vitro Model of Intestinal Barrier.

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.

Liposomes Coloaded with Elacridar and Tariquidar To Modulate the P-Glycoprotein at the Blood-Brain Barrier.

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.

Coadministration of P-glycoprotein modulators on loperamide pharmacokinetics and brain distribution.

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.

Active nanoparticle targeting of MUC5AC ameliorates therapeutic outcome in experimental colitis.

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-1ß). 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.

Comparison of a selective STAT3 inhibitor with a dual STAT3/STAT1 inhibitor using a dextran sulfate sodium murine colitis model: new insight into the debate on selectivity.

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.

Valrubicin-loaded immunoliposomes for specific vesicle-mediated cell death in the treatment of hematological cancers.

We created valrubicin-loaded immunoliposomes (Val-ILs) using the antitumor prodrug valrubicin, a hydrophobic analog of daunorubicin. Being lipophilic, valrubicin readily incorporated Val-lLs that were loaded with specific antibodies. Val-ILs injected intravenously rapidly reached the bone marrow and spleen, indicating their potential to effectively target cancer cells in these areas. Following the transplantation of human pediatric B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T-ALL), or acute myeloid leukemia (AML) in immunodeficient NSG mice, we generated patient-derived xenograft (PDX) models, which were treated with Val-ILs loaded with antibodies to target CD19, CD7 or CD33. Only a small amount of valrubicin incorporated into Val-ILs was needed to induce leukemia cell death in vivo, suggesting that this approach could be used to efficiently treat acute leukemia cells. We also demonstrated that Val-ILs could reduce the risk of contamination of CD34+ hematopoietic stem cells by acute leukemia cells during autologous peripheral blood stem cell transplantation, which is a significant advantage for clinical applications. Using EL4 lymphoma cells on immunocompetent C57BL/6 mice, we also highlighted the potential of Val-ILs to target immunosuppressive cell populations in the spleen, which could be valuable in impairing cancer cell expansion, particularly in lymphoma cases. The most efficient Val-ILs were found to be those loaded with CD11b or CD223 antibodies, which, respectively, target the myeloid-derived suppressor cells (MDSC) or the lymphocyte-activation gene 3 (LAG-3 or CD223) on T4 lymphocytes. This study provides a promising preclinical demonstration of the effectiveness and ease of preparation of Val-ILs as a novel nanoparticle technology. In the context of hematological cancers, Val-ILs have the potential to be used as a precise and effective therapy based on targeted vesicle-mediated cell death.

A "drug cocktail" delivered by microspheres for the local treatment of rat glioblastoma.

For the treatment of glioblastoma multiforme, an "anticancer drug cocktail" delivered by biodegradable poly-lactide-co-glycolide (PLGA)-microspheres is proposed. Celecoxib, etoposide, and elacridar were encapsulated by an oil/water emulsification solvent evaporation method. Drug-loaded microspheres were analyzed for their physicochemical properties and evaluated in a rat glioblastoma model. Microspheres had a mean diameter 10-20 µm, and encapsulation rates varied upon lipophilicity of the drug (celecoxib: 97.4 ± 0.4%; elacridar: 98.1 ± 0.3%; and etoposide: 38.7 ± 8.3%). Drug release of celecoxib and elacridar resulted in a burst (t50: 3.1 h and 1.0 h, respectively) while etoposide release was slower (t50: 45.3 h). The comparison of celecoxib (p = 0.021) and etoposide microspheres (p = 0.002) as well as their combination (p = 0.011) led to a significant increase in the probability of survival compared to blank microspheres. Local delivery of celecoxib and etoposide microspheres was found to be suitable for the treatment of glioblastoma in rats although simultaneous drug administration did not improve the therapeutic outcome.

Lipoproteins as Drug Carriers for Cyclosporine A: Optimization of the Entrapment.

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.

Polymeric Nanoparticles' Accumulation in Atopic Dermatitis: Clinical Comparison between Healthy, Non-Lesional, and Lesional Skin.

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.

Effects of topical docosahexaenoic acid on postoperative fibrosis in an animal model of glaucoma filtration surgery.

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] mm2 vs. 2.3 [2.0-2.8] mm2 , 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.

Interaction and toxicity of ingested nanoparticles on the intestinal barrier.

The gastrointestinal tract represents one of primary routes of entry for many nanomaterials. Their size in the nanometer range and their high surface area confer them very interesting properties as food additives. They are used as texturizing, opacifying or anticaking agents. Food packaging contains nanomaterials with antimicrobial properties. Humans are also orally exposed to nanoparticles (NPs) present in the air or drinking water. Ingested NPs can then reach the intestinal lumen and interact with the gastrointestinal fluids, microbiota, mucus layers and the epithelial barrier, allowing a potential translocation. The toxicological profile of ingested NPs is still unclear due to their variety in terms of composition and physicochemical properties as well as the limited number of investigations. Their unique properties related to their small size could however affect the intestinal ecosystem but also the physical and functional properties of the intestinal barrier. This review focuses on the fate of ingested organic and inorganic NPs in the intestinal lumen and their toxicity on the microbiota and epithelial cells.

Size effect and mucus role on the intestinal toxicity of the E551 food additive and engineered silica nanoparticles.

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.

Adalimumab Decorated Nanoparticles Enhance Antibody Stability and Therapeutic Outcome in Epithelial Colitis Targeting.

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.

Investigation of the spontaneous nanoemulsification process with medium- and long-chain triglycerides.

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.

Amelioration of murine experimental colitis using biocompatible cyclosporine A lipid carriers.

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.

Hyaluronic Acid Increases Anti-Inflammatory Efficacy of Rectal 5-Amino Salicylic Acid Administration in a Murine Colitis Model.

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-1ß 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.

Characterization and biodistribution of Au nanoparticles loaded in PLGA nanocarriers using an original encapsulation process.

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. T1-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.