Development of a triculture based system for improved benefit/risk assessment in pharmacology and human food

Development of a triculture based system for improved benefit/risk assessment in pharmacology and human food

Targeting of small or biopharmaceutical anti-inflammatory drugs to inflamed bowel disease by nanocarriers

Inflammatory bowel diseases are relapsing and chronic inflammatory disorders of the gut. Although most of the conventional anti-inflammatory agents can be administered orally, non-specific delivery of these drugs is observed, leading to systemic toxicity associated with serious adverse effects. The development of drug delivery systems able to specifically target and to deliver anti-inflammatory drugs to inflamed colonic areas of the colon is of great interest. It should lead to higher local concentrations and maintain therapeutic efficacy while enhancing safety by decreasing non-specific delivery. Use of nanocarriers for this purpose seems promising as they showed a preferential uptake in inflamed areas.   Hence, the aim of this thesis was to encapsulate small drugs (budesonide and curcumin) and biopharmaceutics (ovalbumin as model drug and anti-TNF-α fragment antibody) in various nanocarriers: polymeric nanoparticles, nano-structured lipid carriers and self-nanoemulsifying drug delivery systems. Various delivery strategies were assessed: pH-sensitivity, mucoadhesion, sustained release, active targeting and lipid-based delivery. The potential of these nanoparticulate drug delivery systems for inflamed colon-specific topical targeting and delivery was evaluated in in vitro, ex vivo and in vivo models.   Firstly, we have demonstrated the efficacy of nanostructured lipid carriers for the topical delivery of budesonide in inflamed colon using. Secondly, we compared the topical delivery of curcumin, showing that a nanoscale delivery strategy using pH-sensitive and sustained release nanoparticles gives better in vivo results than the other nanoscale delivery strategy using self-nanoemulsifying drug delivery systems. Thirdly, using ovalbumin as model drug, we have compared several strategies to target the inflamed colon using polymeric nanoparticles as biopharmaceutical drug carrier. Exploiting the ability of design of polymeric nanoparticles, we have demonstrated that active targeting of macrophages and dendritic cells leads to a preferential accumulation in inflamed areas. Finally, we formulated 2 types of polymeric nanoparticles encapsulating an active biopharmaceutical agent possessing features suitable for the inflamed colon delivery.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 201

An oral malaria therapy: Curcumin-loaded lipid-based drug delivery systems combined with β-arteether.

Curcumin (CC), a potential antimalarial drug, has poor water solubility, stability and oral bioavailability. To circumvent these pitfalls, lipid-based drug delivery systems (LBDDSs) with a high CC loading (30mg/g) were formulated. In a biorelevant gastric medium, CC-LBDDSs formed particle sizes in the range of 30-40nm. During in vitro lipolysis, 90-95% of the CC remained solubilized, whereas 5-10% of the CC precipitated as an amorphous solid, with a high rate of re-dissolution in a biorelevant intestinal medium. The transport of the CC-LBDDS across Caco-2 monolayers was enhanced compared with the transport of free drug because of the increased CC solubility. In Plasmodium berghei-infected mice, modest antimalarial efficacy was observed following oral treatment with CC-LBDDSs. However, the combination therapy of CC-LBDDS with a subtherapeutic dose of β-arteether-LBDDS provided an increase in protection and survival rate that was associated with a significant delay in recrudescence. These findings suggest that the combination of oral CC and β-arteether lipid-based formulations may constitute a promising approach for the treatment of malaria

Targeting Inflammatory Bowel Diseases by Nanocarriers Loaded with Small and Biopharmaceutical Anti-Inflammatory Drugs.

Nanotechnology has emerged as a promising strategy toward inflammatory bowel disease (IBD) treatment. Nano-sized drug delivery systems exhibit an increased accumulation in inflamed tissues due to their nanometer size and present the ability to overcome the challenging inflamed colonic barriers (i.e. thick mucus layer, disrupted epithelium, altered colonic transit time). Moreover, nanocarriers are able to increase the amount of drug present at the colonic site decreasing their associated systemic side effects and increasing their efficacy. This review aims to analyze the nanoparticulate systems that have been evaluated for IBD treatment based on (i) the strategy followed towards an increased colonic accumulation and/or permeation, (ii) the small or biopharmaceutical antiinflammatory drug encapsulated within the nanocarriers and (iii) the polymer(s) used for their preparation, highlighting the profits and the drawbacks of each of the candidates based on reported results

pH-sensitive nanoparticles for colonic delivery of curcumin in inflammatory bowel disease.

Nano-scaled particles have been found to preferentially accumulate in inflamed regions. Local delivery of anti-inflammatory drugs loaded in nanoparticles to the inflamed colonic site is of great interest for inflammatory bowel disease (IBD) treatment. Curcumin (CC) is an anti-inflammatory local agent, which presents poor ADME properties. Hence, we evaluated, both in vitro and in vivo, the local delivery of CC using pH-sensitive polymeric nanoparticles (NPs) combining both poly(lactide-co-glycolide) acid (PLGA) and a polymethacrylate polymer (Eudragit(®) S100). CC-NPs significantly enhanced CC permeation across Caco-2 cell monolayers when compared to CC in suspension. CC-NPs significantly reduced TNF-α secretion by LPS-activated macrophages (J774 cells). In vivo, CC-NPs significantly decreased neutrophil infiltration and TNF-α secretion while maintaining the colonic structure similar to the control group in a murine DSS-induced colitis model. Our results support the use of nanoparticles made of PLGA and Eudragit(®) S100 combination for CC delivery in IBD treatment

PLGA-based nanoparticles: an overview of biomedical applications

Poly(lactic-co-glycolic acid) (PLGA) is one of the most successfully developed biodegradable polymers. Among the different polymers developed to formulate polymeric nanoparticles, PLGA has attracted considerable attention due to its attractive properties: (i) biodegradability and biocompatibility, (ii) FDA and European Medicine Agency approval in drug delivery systems for parenteral administration, (iii) well described formulations and methods of production adapted to various types of drugs e.g. hydrophilic or hydrophobic small molecules or macromolecules, (iv) protection of drug from degradation, (v) possibility of sustained release, (vi) possibility to modify surface properties to provide stealthness and/or better interaction with biological materials and (vii) possibility to target nanoparticles to specific organs or cells. This review presents why PLGA has been chosen to design nanoparticles as drug delivery systems in various biomedical applications such as vaccination, cancer, inflammation and other diseases. This review focuses on the understanding of specific characteristics exploited by PLGA-based nanoparticles to target a specific organ or tissue or specific cells

Drug delivery to inflamed colon by nanoparticles: comparison of different strategies

For inflammatory bowel disease (IBD) treatment, local delivery of molecules loaded in nanoparticles to the inflamed colon could be a promising strategy. The aim of this study was to investigate how drug-loaded polymeric nanoparticles target the site of inflammation and to analyse the influence of different colon-specific delivery strategies. Three different polymeric nanoparticles were formulated using ovalbumin (OVA) as a model drug. pH-sensitive nanoparticles were made with Eudragit(®) S100. Mucoadhesive nanoparticles were created with trimethylchitosan (TMC). A mix of polymers, PLGA, PEG-PLGA and PEG-PCL, were used to obtain a sustained drug delivery. Furthermore, ligands targeting immune cells (i.e. mannose) or the inflamed colon (i.e. a specific peptide) were grafted on the PEG chain of PCL. Interaction of nanoparticles with the intestinal epithelium was explored using Caco-2 monolayers designed to mimic an inflamed epithelium and then visualized using confocal laser microscopy. TMC nanoparticles had the highest apparent permeability for OVA in the untreated model. However, in the inflamed model, there were no difference between TMC, PLGA-based and Eudragit(®) nanoparticles. The uptake of nanoparticles in the inflamed mouse colon was assessed in a horizontal diffusion chamber. Mannose-grafted PLGA nanoparticles showed the highest accumulation of OVA in inflamed colon. Based on these results, active targeting of macrophages and dendritic cells may be a promising approach for targeting the colon in IBD

Budesonide-loaded nanostructured lipid carriers reduce inflammation in murine DSS-induced colitis

The challenge for the treatment of inflammatory bowel disease (IBD) is the delivery of the drug to the site of inflammation. Because nanoparticles have the ability to accumulate in inflamed regions, the aim of the present study was to evaluate nanostructured lipid carriers (NLCs) as nanoparticulate drug delivery systems for the treatment of IBD. Budesonide (BDS) was chosen as a candidate anti-inflammatory drug. BDS-loaded NLCs (BDS-NLC) produced by high-pressure homogenization had a size of 200nm and a negative zeta potential. BDS-NLCs reduced the TNF-α secretion by activated macrophages (J774 cells). BDS-NLCs were more active in a murine model of dextran sulfate-induced colitis when compared with Blank-NLCs or a BDS suspension: BDS-NLCs decreased neutrophil infiltration, decreased the levels of the pro-inflammatory cytokines IL-1β and TNF-α in the colon and improved the histological scores of the colons. These data suggest that NLCs could be a promising alternative to polymeric nanoparticles as a targeted drug delivery system for IBD treatment