Preparation,in vivo pharmacokinetics and anti-tumor activity of artesunate nanomicelles
AIM To prepare artesunate nanomicelles,and to evaluate their in vivo pharmacokinetics and anti-tumor activity.METHODS The nanomicelles were prepared with poly(ethylene glycol)-poly(D,L-lactide)-poly(L-histidine)(mPEG-PLA-PHis)as a carrier,after which the formulation was optimized by single factor test combined with Box-Behnken response surface method,and encapsulation efficiency,drug loading,settling rate,particle size,Zeta potential,in vitro drug release were determined.Twelve H22 tumor-bearing mice were randomly assigned into two groups and given tail vein injection of Artesunate Injection and artesunate nanomicelles(1 mg/kg),respectively,after which blood collection was made at different time points,HPLC was adopted in the plasma concentration determination of artesunate,and main pharmacokinetic parameters were calculated.Thirty-six H22 tumor-bearing mice were randomly assigned into six groups,containing model group(normal saline),positive group(20 mg/kg cyclophosphamide),Artesunate Injection group(30 mg/kg)and artesunate nanomicelles low-dose,medium-dose,high-dose groups(10,20,30 mg/kg),then the body weight,tumor weight were recorded and tumor inhibitory rate was calculated at 3 d after the last administration.RESULTS The optimal formulation was determined to be 10.18∶1 for(mPEG-PLA-PHis)-drug ratio,0.48 mg/mL fo artesunate concentration,and 0.96 h for hydration time,the encapsulation efficiency,drug loading,settling rate,particle size and Zeta potential were(94.27±1.26)%,(8.26±0.18)%,(4.19±0.20)%,(65.14±4.96)nm and-(17.64±1.06)mV,respectively.The accumulative release rate of nanomicelles in mild acidic medium was higher than that in mild alkaline medium,demonstrating pH-sensitivity.Compared with injection,the nanomicelles displayed prolonged t1/2,MRT(P＜0.01),decreased CL(P＜0.01),and increased AUC0-t(P＜0.01).Compared with the model group,the different doses of artesunate nanomicelles groups exhibited no obvious changes in mouse body weight(P＞0.05)and decreased tumor weight(P＜0.05,P＜0.01),especially for the medium-dose group with the tumor inhibitory rate of 55.40%.CONCLUSION High encapsulation efficiency and strong in vivo anti-tumor activity are observable in artesunate nanomicelles.
artesunatenanomicellespreparationin vivo pharmacokineticsanti-tumor activitypoly(ethylene glycol)-poly(D,L-lactide)-poly(L-histidine)(mPEG-PLA-PHis)HPLCH22 liver cancer cells
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维普
