Site-Directed Polymer-Drug Complexes for Modulating Gut Innate Immune System to Prevent/Treat Inflammatory Bowel Diseases (IBD)

Purpose:Continuous inflammation in the colon often leads to chronic diseases such as IBD and colorectal cancer. Conventional treatment of IBD involves the use of anti-inflammatory drugs, immunosuppressants, and biological agents. However, these treatments often do not prevent or delay the progression of IBD and pose several side effects. Curcumin is a natural dietary component with demonstrated anti-inflammatory and safety profile. Its clinical use is limited by its low oral bioavailability and short biological half-life. In addition, curcumin is water insoluble and inhibits metabolic enzymes (CYP3A4) and efflux transporters (P-glycoprotein). The goal of the study is to deliver a water soluble and bioactive curcumin formulation to the luminal side of the colon without exposing the systemic circulation (Local therapy) to prevent or treat IBD by engineering non-covalent complexes of Eudragit® S100 with curcumin (Ora-Curcumin-S).

Methods: Ora-Curcumin-S was prepared using the nanoprecipitation method. The formulation was optimized to enhance the curcumin loading and its aqueous solubility. The apparent solubility of curcumin in phosphate buffer, pH 7.0 (PB) was determined in 4 h. The physicochemical characterization of the complexes was performed by using FTIR spectroscopy, NMR spectroscopy, DSC, powder XRD, and SEM analysis. The anti-inflammatory properties of Ora-Curcumin-S were assessed for the inhibition of the activation (cytokine release) of mouse dendritic cells in response to dead E.Coli. The ability of Ora-curcumin-S as a novel Toll-like receptor-4 (TLR4) antagonist was established using a known TLR4 agonist, Monophosphoryl Lipid-A (MPLA) and genetically modified human kidney epithelial cells expressing functionally active TLR4. The cytotoxicity of Ora-Curcumin-S on colon cancer cells (HCT116 and HT29) was investigated using MTT based cell viability assay. A single dose (15 mg/kg) pharmacokinetics parameters were investigated in healthy Balb/c mice. The in-vivo potential of Ora-Curcumin-S in preventing IBD was investigated on dextran sulfate sodium (DSS) induced acute colitis model.

Results: By complexing with a Eudragit® S100, the aqueous solubility of curcumin was increased from ~1 µg/mL to ~1000 µg/ml (~1000 times), and importantly, the solubility is pH dependent; only at pHs above 6.8. In addition, around 90 % of Ora-Curcumin-S was stable in PB and simulated intestinal fluid after 24 h of incubation, in contrast to 10-20 % unformulated curcumin. In-vitro studies indicated that Ora-Curcumin-S is more potent than soluble curcumin in inhibiting Tumor necrosis factor-a (TNF-a) release from dendritic cells in response to inflammatory stimulus (MPLA or E.coli). Ora-Curcumin-S was ~2.5 times more potent than soluble curcumin in antagonizing TLR4 stimulation. Mouse studies showed differential pharmacokinetics kinetic patterns of curcumin (systemic) and Ora-Curcumin-S (colon-targeted). Oral delivery of Ora-Curcumin-S significantly prevented DSS-induced acute colitis in mice as estimated using multiple paramters colonoscopy, changes in body weight, colon length, colon edema, spleen weight and independent pathological scoring.

Conclusions: The present study provides a unique polymer-drug complex based dietary technology as a local therapy for the prevention/treatment of IBD or colon cancer. Ora-Curcumin-S has several competitive advantages over existing technologies: targeted local therapy, high aqueous solubility and stability, cost-effective and the use of FDA approved ingredients etc.