Preparation,in Vitro And In Vivo Study Of Curcumin Nanosuspensions

Curcumin(CUR)is very rare natural polyphenolic compounds in plant community.Domestic and international research shows that it has a variety of pharmacological actions,such as antioxidation,anti-inflalmation,antitumor,inhibition of liver and lung fibrosis and kidney protection,thus has good prospect in clinic application with safety and less toxicity.However,poor stability,poor solubility and fast metabolism greatly limit curcumin's use in clinic[1].Nanosuspensions are nanoscale pure drug particles stabilized by small amount of surfactants or amphiphilic polymers,with enomous surface area helpful to provide the drug with improved bioavailability and enhanced stability.This study used simple micro precipitation method to prepare curcumin nanosuspensions.The main research contents include the preparation and characterization of curcumin nanosuspensions,pharmacokinetics,biodistribution study,pharmacodynamics and so on.The micro precipitation method was employed to prepare curcumin nanosuspensions(CUR-NSPs).mPEG2000-PCL2000,DSPE-mPEG2000,mPEG-PLGA75/25(6000),mPEG2000-PLA2000,SPC,TPGS,BSA,HP-?-CD and chitosan were used respectively for stabilizer screening and formulation study according to the particle size and polydispersity index of the resultant nanoparticles,.The results showed that the DSPE-mPEG2000 and SPC(1:0.5,weight ratio)was optimal combinatorial stabilizer and the resultant CUR-NSPswere(186.33±2.73)nm in mean size with a PDI of(0.222±0.042).The encapsulation efficiency and drug loading of CUR nanosuspensions prepared usingthe formulation composed of CUR,DSPE-mPEG2000 and SPC(5:1:0.5,weight ratio)was(96.08±1.05)%and(67.07±1.03)%,respectively.The obtained CUR-NSPs stored under 4?was quite stable for a long time.They were also stable in plasma and not hemolytic and thus suitable for intravenous administration.Transmission electron microscope(TEM)showed CUR-NSPs were almost spherical in morphology.X-ray diffraction(XRD)and Differential Scanning Calorimeter(DSC)revealed that curcumin was in crystalline form in the nanosuspensions.MTT showed that CUR-NSPs had stronger cytotoxicity than free curcumin(dissolved in DMSO)against A549(2.10?g/mL vs 7.02?g/mL,IC50),Hela(2.884?g/mL vs 930?g/mL,IC50)and HepG2(4.451 ?g/mL vs 950?g/mL,IC50)cell.The pharmacokinetics of CUR-NSPs was stidied on SD rats through intravenous adminstration.The results showed that AUC0-24,half-life and mean residence time of CUR-NSPs was respectively5.15-fold,61-fold and 19.9-fold greater than CUR solution.The bioavailability of CUR-NSPs in rats was increased remarkably.This may be because the PEG moiety of amphiphilic DSPE-mPEG2000 formed a hydrophilic layer around the the surface of CUR-NSPs,maintaining the stability of NSPs in blood,reducing the opsonization and clearance by the reticuloendothelial system.The sustained drug release also played an important role.The biodistribution on tumor-bearing mice showed that,the AUC0-24,MRT and Cmax of CUR-NSPs was 1.14?2.01,1.04?1.2 and 1.20?1.50 fold as those of curcuin solution in the brain,liver,kidney and tumor,respectively.The higher drug accumulation in brain and spleen displayed CUR-NSPs may have a better therapeutic efficacy on the treatment of brain tumor.The pharmacodynamics study showed that antitumor effect of CUR-NSPs was dose-dependent.The antitumor effect of CUR-NSps group(2.5mg/kg)was better than curcumin solution(10mg/kg).The antitumor effect of nanosuspensions in vivo has a very significant advantage over CUR solution.