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

摘要

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).Melhods: 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 phy sicochemical 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 T.LR4.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-vivopotential of Ora-Curcumin-S in preventing IBD was investigated on dextran sulfate sodium(DSS)induced acute colitis model.