Applied Basic Study Based On Bile Acids Metabolism For Macromolecule Drug To Inhibit Lipid Absorption

ObjectiveObesity are rapidly increasing all over the world,which are associated with type2 diabetes,high blood pressure,cardiovascular diseases and even some cancers.Therefore,prevention and treatment of overweight and obesity have become a globally relevant topic.Currently,marketed drugs such as lorcaserin,phentermine/topiramate,bupropion/naltrexone etc.,show promising efficacy for weight loss and are used as treatment options for the management of obesity.The oral drugs are absorbed through the gastrointestinal tracts into the bloodstream and target pathways in the nervous system that influences appetite or energy use.Unfortunately,most of these oral drugs may cause side effects,such as diarrhoea,abdominal pain,cardiovascular disease risk and hypertension.A potential effective and safe approach for the treatment of obesity is an exploration of routes to inhibit the absorption of the calorie dense ingredients of food,such as dietary lipids.This study focus on synthesizing a series of noabsorption polymer based on based on?-CD functionalized branched PEI to increased fecal elimination of dietary lipids for inhibiting lipid absorption.MethodFirstly,OTs-?-CD was synthesized,and PEI-g-CD was further prepared based on OTs-?-CD and PEI.Different molar ratios of alkyl bromides to PEI-g-CD were reacted and the obtained quaternized PEI-g-CD was marked as PEI-g-CD-Cn.Then~1H NMR spectroscopy,FTIR spectra and gel permeation chromatography(GPC)were used to characterize the synthesized PEI-g-CD and PEI-g-CD-Cn.This cationic polymer,as an oral pharmaceutical agent,were tested in bile acid and lipid sequestration study.After oral administration of this polymer,the fecal bile acid,triglyceride and cholesterol levels of mice fed high fat diet were determined.To investigate whether the polymer caused apoptosis of tissue cells after oral administration,the organ samples were stained with Hoechst 33342 and observed via a fluorescence microscopy.ResultIn vitro study,PEI1-g-CD3-C4-3 showed excellent bile acid,triglyceride and cholesterol sequestration capacity among these polymers in the Fed-state-simulated intestinal fluid(FeSSIF).In animal study,we found PEI1-g-CD3-C4-3 significantly increased fecal elimination of bile acids,triglycerides and cholesterol by 6.3,4.8 and5.0-fold compared to the control,respectively.Moreover,no appreciable cytotoxicity and observable histological changes was induced by these polymers.All these results exhibit that these nonabsorbable polymers was effective and safe as an oral pharmaceutical agent for lipid sequestration.ConclusionIn this study,we developed a nonabsorbable and cationic polymer based on?-CD functionalized branched PEI to sequester bile acids and inhibit lipid absorption.These results show that the cationic and nonabsorbable polymer has great property as an oral pharmaceutical agent for lipid sequestration,and this work offers a potential new approach for the prevention and treatment of hypercholesterolemia,type 2diabetes,cardiovascular disease and other common comorbidity in overweight and obese patients.