A comparative study of curcumin-loaded lipid-based nanocarriers in the treatment of inflammatory bowel disease.

Selective drug delivery to inflamed tissues is of widespread interest for the treatment of inflammatory bowel disease (IBD). Because a lack of physiological lipids has been described in patients suffering IBD, and some lipids present immunomodulatory properties, we hypothesize that the combination of lipids and anti-inflammatory drugs together within a nanocarrier may be a valuable strategy for overcoming IBD. In the present study, we investigated and compared the in vitro and in vivo efficacy of three lipid-based nanocarriers containing curcumin (CC) as an anti-inflammatory drug for treating IBD in a murine DSS-induced colitis model. These nanocarriers included self-nanoemulsifying drug delivery systems (SNEDDS), nanostructured lipid carriers (NLC) and lipid core-shell protamine nanocapsules (NC). In vitro, a 30-fold higher CC permeability across Caco-2 cell monolayers was obtained using NC compared to SNEDDS (NC>SNEDDS>NLC and CC suspension). The CC SNEDDS and CC NLC but not the CC NC or CC suspension significantly reduced TNF-α secretion by LPS-activated macrophages (J774 cells). In vivo, only CC NLC were able to significantly decrease neutrophil infiltration and TNF-α secretion and, thus, colonic inflammation. Our results show that a higher CC permeability does not correlate with a higher efficacy in IBD treatment, which suggests that lipidic nanocarriers exhibiting increased CC retention at the intestinal site, rather than increased CC permeability are efficient treatments of IBD.

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.

An oral malaria therapy: curcumin-loaded lipid-based drug delivery systems combined with ß-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 (30 mg/g) were formulated. In a biorelevant gastric medium, CC-LBDDSs formed particle sizes in the range of 30-40 nm. 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 ß-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 ß-arteether lipid-based formulations may constitute a promising approach for the treatment of malaria.

Combined effect of PLGA and curcumin on wound healing activity.

Wound healing is a complex process involving many interdependent and overlapping sequences of physiological actions. The application of exogenous lactate released from poly (lactic-co-glycolic acid) (PLGA) polymer accelerated angiogenesis and wound healing processes. Curcumin is a well-known topical wound healing agent for both normal and diabetic-impaired wounds. Hence, we hypothesized that the PLGA nanoparticles encapsulating curcumin could much potentially accelerate the wound healing. In a full thickness excisional wound healing mouse model, PLGA-curcumin nanoparticles showed a twofold higher wound healing activity compared to that of PLGA or curcumin. Histology and RT-PCR studies confirmed that PLGA-curcumin nanoparticles exhibited higher re-epithelialization, granulation tissue formation and anti-inflammatory potential. PLGA nanoparticles offered various benefits for the encapsulated curcumin like protection from light degradation, enhanced water solubility and showed a sustained release of curcumin over a period of 8 days. In conclusion, we demonstrated the additive effect of lactic acid from PLGA and encapsulated curcumin for the active healing of wounds.

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 200 nm 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-1ß 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.

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.

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.