多西紫杉醇-海豹油纳米结构脂质载体的抗肿瘤活性评价  

Evaluation of anti-tumor activity of docetaxel loaded nanostructured lipid carriers with seal oil

作　　者：史凡[1] 崔纯莹[1] 吴建辉[2] 王玉记[2] 

机构地区：[1]首都医科大学化学生物学与药学院药剂学系,北京100069 [2]首都医科大学化学生物学与药学院药药物化学系,北京100069

出　　处：《首都医科大学学报》2015年第2期185-191,共7页Journal of Capital Medical University

基　　金："十二五"重大新药创制科技重大专项(2011ZX09302-007-01)~~

摘　　要：目的探讨多西紫杉醇(docetaxel,DTX)海豹油脂质体的抗肿瘤活性以及与脂肪乳的比较。方法采用正交试验设计法筛选处方,通过高压乳匀法制备多西紫杉醇海豹油脂质体。测定其粒径、电位、包封率、体外释药、血浆中稳定性等。并采用四甲基偶氮唑盐〔3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide,MTT〕进行体外抗肿瘤活性研究,以及采用荷肉瘤S180小鼠进行体内抗肿瘤活性研究,考察各组抑瘤率和存活率。结果多西紫杉醇海豹油脂质体的粒径在200 nm左右,Zeta电位为-30^-50 m V,包封率达95%以上。体外释放研究证明多西紫杉醇脂肪乳与多西紫杉醇海豹油脂质体具有一定的p H敏感性,且推测多西紫杉醇海豹油脂质体具有更强的缓释作用。血浆中稳定性研究证明多西紫杉醇脂肪乳与多西紫杉醇海豹油脂质体在血浆中较稳定,释放行为缓慢。结论由MTT法结果得多西紫杉醇海豹油脂质体、多西紫杉醇脂肪乳与DTX均表现出较强的细胞毒性作用,且多西紫杉醇海豹油脂质体具有一定的缓释作用。以荷肉瘤S180小鼠为模型的体内抗肿瘤活性研究表明多西紫杉醇脂肪乳与多西紫杉醇海豹油脂质体在血浆中12 h内累积释放量分别为(13.82±0.59)%与(12.91±0.60)%。说明剂型在血浆中较稳定,释放行为缓慢。另外,DTX组小鼠9 d存活率为0,多西紫杉醇脂肪乳组于9 d存活率为93.3%,而多西紫杉醇海豹油脂质体组小鼠9 d存活率为100%,说明多西紫杉醇海豹油脂质体使得耐受剂量提高,降低了药物的不良反应,提高用药安全性与用药的顺应性。Objective To design and prepare the nanostructured lipid carriers（ NLC） and the lipid emulsion（ LE） containing seal oil, and the anti-cancer drug docetaxel（ DTX） as a model drug. Methods The DTX-NLC was obtained by high pressure homogenization. The release of DTX-NLC and DTX-LE in vitro were determined by dynamic dialysis method in PBS with 0. 5% DMSO（pH7. 4 and pH5. 4）, and in plasma. In vitro anti-tumor studies of DTX-NLC and DTX-LE were determined by 3-（ 4, 5-dimethylthiazol-2-yl ）-2, 5-diphenyltetrazolium bromide（ MTT） assay. While, in vivo anti-tumor activities of DTX-NLC and DTX-LE were determined in S180 bearing mice. Results The morphology of DTX-NLC was in spherical shape with approximately 200 nm in diameter and the zeta potential ranged from -30 to -50 mV, and the encapsulation efficiency is about 95%. The release percentage of DTX-NLC is（4. 30±0. 32）% and （8. 12±0. 32）% in PBS with 0. 5% DMSO at pH 7. 4 and pH 5. 4, and the releasing of the DTX from the DTX-NLC was more sustained from the DTX-LE. The DTX-NLC and DTX-LE showed a good stability in plasma. MTT assays showed that the DTX-NLC, DTX-LE and DTX could inhibit the growth of the cells. Conclusion Vivo anti-tumor studies in S180 bearing mice showed thatthe NLC had better sustained-release effect than that of LE, and extend the dosing interval further, increase tolerated dose, reduce the side effects of drugs, and improve the compliance of medication safety and medication.

关 键 词：多西紫杉醇 纳米结构脂质载体 脂肪乳 海豹油 抗肿瘤 

分 类 号：R965.1[医药卫生—药理学]