联合包载Combretastatin A-4和阿霉素的长循环脂质体的体外体内初步研究  

In vitro and in vivo studies of PEGylated liposomes co-encapsulated combretastatin A-4 and doxorubicin

作　　者：卞冬燕[1,2] 白小玉[1] 白娟[3] 王坚成[3] 陈大为[1] 张强[3] 

机构地区：[1]沈阳药科大学药学院,辽宁沈阳110016 [2]天津市环湖医院药剂科,天津300060 [3]北京大学药学院,北京100191

出　　处：《沈阳药科大学学报》2010年第11期862-866,共5页Journal of Shenyang Pharmaceutical University

摘　　要：目的制备一种具有程序释药功能的联合包载抗肿瘤药物阿霉素(doxorubicin,DOX)和新生血管抑制剂(combretastatin A-4,CA-4)的新型长循环脂质体并进行体内药动学评价。方法以卵磷脂、胆固醇和聚乙二醇磷脂衍生物(1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-polyethylene gly-col,DSPE-PEG)为载体材料,采用薄膜分散法和硫酸铵梯度法分步包载CA-4和DOX制备得到脂质体。通过单因素考察,筛选最佳处方和制备工艺,并评价其体外释放情况。采用正常大鼠考察该制剂在静脉注射后的药动学行为。结果 m(卵磷脂)∶m(胆固醇)∶m(DSPE-PEG)为85∶10∶5、m(药)∶m(脂材)为1∶20、水化脂材浓度为50 mmol.L-1时,CA-4的包封率最高(>85%),DOX的包封率也在95%以上,平均粒径小于80 nm。体外释放结果表明联合包载DOX和CA-4的脂质体在pH7.4磷酸盐介质中可以快速释放CA-4,而DOX释放相对较慢。体内药动学实验结果表明,脂质体包载可明显增加CA-4的体内循环时间,但CA-4的联用并未对DOX体内药动学行为产生明显干扰。结论联合包载CA-4和DOX的脂质体可有效地实现程序释药,并延长药物体内循环时间,将可能成为肿瘤治疗的新策略。Objective To prepare PEGylated liposomes co-encapsulate combretastatin A-4（CA-4）and doxorubicin（DOX）with the function of drug releasing in sequence and evaluate their in vivo pharmacokinetic behavior.Methods EPC/CHOL/DSPE-PEG was chosed as the vehicle materials,thin film dispersion method and the ammonium sulfate gradient method were applied to prepare the CA-4 liposomes and load DOX.Prescription and preparation process were optimized according to the CA-4 entrapment efficiency.In vitro release of the liposomes was evaluated in phosphate buffered saline（pH7.4）.Pharmacokinetic behavior was investigated using normal rats by vein injection.Results As m（EPC）∶m（CHOL）∶m（DSPE-PEG）=85∶10∶5,m（drug）∶m（lipids）=1∶20,total lipids concentration was 50 mmol·L-1 after hydration,CA-4 and DOX could be entrapped over 85%and 95%,separately,particle size was around 80 nm.The in vitro release curve demonstrated that the CA-4 released faster than DOX.The pharmacokinetic experiments showed that liposomes could obviously prolonged CA-4 in vivo circulation time,and CA-4 had no effect on pharmacokinetic condition of DOX liposomes as well.Conclusions Liposomes co-encapsulated CA-4 and DOX together achieve sequential drug releasing and prolonge drugs in vivo circulation time,which might be a new strategy for tumor therapy in future.

关 键 词：CombretastatinA-4 阿霉素 长循环脂质体 程序释放 药动学 

分 类 号：R94[医药卫生—药剂学]