The Study Of Amphiphilic PEGylated Curcumin Micells As A Durg Carrier: Synthesis, Characteristic And Pharmacokinetics

Curcumin is a polyphenol extracted from the herb Curcuma longa L.Pharmacological researches have demonstrated several kinds of biological andpharmacological activities of it, including anti-inflammatory, antioxidantantiproliferative and anticancer properties. We can conclude from toxicologicresearches that curcumin is a safety drug for animals and human even at aconsiderably high dose. So it absorbs much more attention as a potentialchemotherapeutics without any serious toxic effects. The characteristics ofcurcumin such as Water-insoluble, poor bioavailability, fast metabolism andsensitive to heat or light have limit the clinical application remarkably.Currently studys are focus on modifying the molecule of curcumin oremploying new formulations specially nano technology to improvepharmacological activities, water-solubility and bioavailability. Nanoparticle,liposome, inclusion compound, polymeric compound of curcumin havemanifested a tremendous application prospect.This study is aim to modify curcumin with polyethylene glycol to produceamphiphilic PEGylated curcumin which can self-assembly in aqueous phase toform micelles act as vehicles for the delivery of drugs. Characteristic andpharmacokinetics parameters of micelles will be investigated.Part one Synthesis of PEGylated curcuminObjective: The terminal hydroxyl of methoxypolyethylene glycols waschanged into carboxy group firstly, and then carboxylic methoxypolyethyleneglycols esterify with curcumin to produce PEGylated Curcumin. Confirm thechemical constitution of the product by1H-NMR.Methods: The reaction of methoxypolyethylene glycols and succinicanhydride was catalyzed by DMAP at room temperature, and triethylaminewas added as acid-binding agent. Esterification of carboxylic methoxypolyethylene glycols and curcumin was dehydrate by DCC, DMAPwas added as catalyst. The product was recrystal in ethyl ether to obtain thepurified PEGylated Curcumin.Results: The chemical structure of PEGylated Curcumin was confirmedby1H-NMR.Conclusion: The method with two steps to produce product is verysimple and easy to do.Part two Preparation and properties of amphiphilic PEGylatedcurcumin micellsObjective: The4durgs loaded by amphiphilic carrier micells wereevaluated. We determine the diameter and Zeta potential of the micelles withdifferent amount of durg loaded. A HPLC method was established todetermine the drug load of the micelles.Methods: The micelles were prepared using the thin-film hydrationmethod, and their stability was evaluated. An dynamic light scattering wasused to menstruate the diameter of the micelles and their Zeta potential werealso determined. The drug concentration was determined by HPLC.Results: The amphiphilic carrier was suitable for loading curcumin toimprove its solubility and applied to intravenous administration. The micellesmean diameter was about13nm with-20Mv Zeta potential. The concentrationof curcumin is about5%in micelles.Conclusion: The PEGylated curcumin micelle is suitable for curcuminwith a good stability and a considerable drug loaded.Part three The study of pharmacokinetics about PEGylated curcuminmicelleObjective: A HPLC method was established to determine both curcuminand PEG-curcumin in plasma. PEG-curcumin micelle was injectedintravenous to male KM mice, and pharmacokinetics characterization wasevaluated.Methods: The lyopilization micelle was dissolved and injectedintravenous to male KM mice. The plasma samples were collected at0,5, 10,15,30,40,60,120,180,240min after dosing and curcumine andPEG-curcumin was determined.Results: The HPLC method was feasible to determine the drugconcentration. The concentration-time curves and pharmacokineticsparameters were acquired.Conclusion: The micelle was fast eliminated in plasma. The probablereason is that the micelles has a considerable small size and is easy to filter byglomerulus without reabsorption or fast metabolize by enzyme system.