多西他赛包合物脂质体的制备与体外评价

Preparation and in vitro Evaluation of Docetaxel Inclusion Complex-loaded Liposomes

以羟丙基倍他环糊精(HP-β-CD)为包合物的载体,采用喷雾干燥法制备了多西他赛包合物(DC),并用X射线粉末衍射(XRPD)法进行表征,用高效液相色谱法对包合率及载药量进行测定,并研究了包合物的平衡溶解度、稳定性、体外释放及对肿瘤细胞的毒性。进一步采用薄膜分散法,以氢化大豆磷脂、胆固醇及二硬脂酰磷脂酰乙醇胺-聚乙二醇2000为载体,制备了多西他赛包合物脂质体(DCL),并对DCL的粒径、ζ电位、包封率、稳定性、体外释放及细胞毒性进行考察。结果表明,所制得的多西他赛包合物脂质体粒径为(55.1±0.1)nm,ζ电位为(-5.7±0.5)mV,包封率为(64.3±0.3)%,载药量为(1.1±0.2)%。对比研究了原料药、DC和DCL在含0.5%Tween-80的磷酸盐缓冲液(pH7.4)的体外释放情况以及对小鼠乳腺癌细胞株4T1细胞毒性。体外释放试验结果表明,相较于原料药和DC,DCL具有较好的缓释效果(48 h的累积释放率为82%)。小鼠乳腺癌细胞毒性试验结果表明,游离1、DC和DCL对4T1细胞的半数抑制浓度(IC50)分别为0.5、0.2和0.05μg/ml。可见,DCL能够显著抑制小鼠乳腺癌细胞的生长,具有较好的细胞毒性,从而增加药物的疗效。

Docetaxel-loaded inclusion complexes(DC) were prepared by spray drying using hydroxylpropyl-β-cyclodextrin(HP-β-CD) as the main carrier. X-ray powder diffraction(XRPD) was used to characterize the inclusion complexes and an HPLC method was used to determine the inclusion rate and drug loading. The equilibrium solubility,in vitro release, stability and cytotoxicity were also investigated. Docetaxel inclusion complex-loaded liposomes(DCL) were prepared by thin-film dispersion using hydrogenated soybean phospholipid, cholesterol and distearyl phosphatidylethanolamine-polyethylene glycol 2000 as carrier. The particle size,ζ potential, encapsulation efficiency,stability, in vitro release and cytotoxicity were also performed. Results showed that the average size,ζ potential,encapsulation efficiency and drug loading of DCL were(55.1±0.1)nm,(-5.7±0.5)mV,(64.3±0.3)% and(1.1±0.2)%,respectively. The DCL could release more slowly(the cumulative release was 82% at 48 h) in phosphate buffer containing 0.5% Tween-80 compared with 1 and DC. Moreover, the IC50 values for 1, DC and DCL against 4 T1 cells were 0.5, 0.2 and 0.05 μg/ml, respectively. It indicated that the docetaxel inclusion complex-loaded liposomes had a significant effect on inhibiting the growth of breast cancer cells.