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

机译:用于调节肠道先天免疫系统的部位定向聚合物 - 药物复合物,以预防/治疗炎症性肠病(IBD)

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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.
机译:目的:结肠中的连续炎症经常导致IBD和结肠直肠癌等慢性疾病。IBD的维持治疗涉及使用抗炎药,免疫抑制剂和生物制剂。但是,这些治疗通常不会预防或延迟进展IBD和姿势若干副作用。滤蛋白是一种天然饮食成分,具有证明的抗炎和安全性剖面。临床使用受其低口服生物利用度和短生物半衰期的限制。此外,姜黄素是水不溶性并抑制代谢酶(CYP3A4)和流出转运蛋白(P-糖蛋白)。该研究的目标是将水溶性和生物活性姜黄素配方递送到结肠的腔侧,而不暴露全身循环(局部疗法)以防止或治疗IBD Eudragit的工程非共价复合物?用姜黄素(ORA-姜黄素-S).melhods:使用纳米沉淀法制备甲纤维蛋白-s。优化制剂以增强姜黄素负载及其水溶性。姜黄素在磷酸盐缓冲液中的表观溶解度,pH7.0 (Pb)在4小时内测定。通过使用FTIR光谱,NMR光谱,DSC,粉末XRD和SEM分析来进行复合物的PHY Sicochemical表征。评估ORA-姜黄素-S的抗炎性能抑制死鼠树突细胞的激活(细胞因子释放)响应于死去的大肠杆菌。使用已知的TLR4激动剂,单磷酸酯(单磷虾)建立了ORA-姜黄素-S作为新型收费受体-4(TLR4)拮抗剂的能力脂质-A(MPLA)和遗传修饰的人肾上皮细胞表达功能源性活性的T.LR4.使用MTT基细胞活力测定研究了对结肠癌细胞(HCT116和HT29)进行的ora-姜黄素-S的细胞毒性。单剂量( 15毫克/千克)Pharmacok在健康的BALB / C小鼠中研究了INETICS参数。在硫酸葡聚糖钠(DSS)诱导的急性结肠炎模型上研究了预防IBD中的ORA-姜黄素-S的体内vivotencential。

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