Studies On The Polymeric Micelles Of Carmofur With Pluronic P123

Carmofur(HCFU) was the third derivative of 5-Fu,which had wide anticancer range,higher lipophil and therapeutic index,nonliver metabolism dependence.It was expected to exhibit tumor-target therapeutic effect by selectively releasing 5-Fu in tumor tissues.However,the clinical application of HCFU might be limited due to its poor aqueous solubility,the low stability and toxic side effects.In the present study,HCFU was taken as the model drug to be wrapped up into Pluronic P123 micelles by modern nano-drug delivery technique.HCFU-loaded micelles were characterized according to their physicochemical characteristics and in vitro release.In vivo pharmacokinetic characteristics and the tissue distribution in mice were investigated,which provided experiment and theoretical basis for utilizing micelles in malignant tumor chemotherapy.The main methods and results were as follows:1.Preparation of HCFU Pluronic P123 micellesThe drug content of HCFU was determined by UV method.The solubility and partition coeffient of HCFU in different pH solvents were also determined.The HCFU-loaded micelles werep repared with Pluronic P123 by thin-film hydration method.The entrapment efficiency was taken as the index to evaluate the effects of the temperature of rotary evaporation,pH of water phase,stirring speed,stirring time,amount of HCFU and amount of water on the characteristics of micelles.The amount of HCFU and amount of water were all chosen as the most influential factors, which were optimized by central composite design-response surface methodology concerning the entrapment efficiency,drug loading and the drug concentration of micelles solution.The final optimized formulation was 3mg of HCFU,100mg Pluronic P123 and 10 mL of water phase.2.The physicochemical characteristics and in vitro drug release of HCFU-loaded micellesThe optimized micelles were sphere and homogeneous in size with average particle size of 29.8nm.The encapsulation efficiency,drug loading and the drug concentration of the optimized nanoparticles were(65.76±1.47)%,(1.48±0.08)%respectively.The stability test indicated that leakage rate of HCFU from micelles reached 26.64%at ambient temperature after 6 months.To improve the stability of micelles,lyophilized HCFU-loaded micelles were prepared by adding sufficient quantum of trehalose into the homogeneous micelles suspension,and the obtained lyophilized micelles showed good redispersibility as well as homogeneity.The mean diameters of lyophilized micelles was 31.1nm.The formation of HCFU-loaded micelles was validated by DSC,which indicated that HCFU successfully encapsuled into micelles.Result of the preliminary stability experiments indicated that the lyophilized HCFU-loaded micelles were almost intact at 4℃for 6 month.Compared with HCFU solution,in vitro release results of HCFU-loaded micelles in 0.05%Tween-80-0.1mol/L HCL,indicated that the drug release slowly from micelles. The in vitro release of HCFU from micelles could be described by double phase kinetics model and expressed by the following equation:100- Q =115.84e^-0.1471t+100.59e^-00059t (R_α=0.9990,R_β=0.9963).In case of solution,the release profiles of HCFU could be described by first order kinetics model and expressed by the following equation: ln(100- Q)= -0.4582t+ 4.2567(r=0.9937)。3.Pharmacokinetics and tissue distribution of HCFU-loaded micelles in mice after intravenousCompared with HCFU suspension of tablets after oral administration,the pharmacokinetics characteristics and tissue distribution of micelles after intravenous administration to mice were investigated.The AUC_0-24h of HCFU-loaded micelles compared with HCFU suspension were 294%.While smaller size micelles reduced the uptake of HCFU in reticuloendothelial system(RES) organs,enhanced drug concentration in plasma,and retention time significantly,thereby exhibited a signification long-circulation property.The tissue distribution showed micelles formulation had lung targeting properties and lower heart and brain accumulations compared with HCFU suspension.These results indicated that Pluronic P123 micelles could offer a promising way to improve the therapeutic efficacy of poorly soluble lipophilic drugs.This study provided new ideas to produce safety,reasonable,effective anticancer drugs and reaserch anti-cancer target therapy.