羟基喜树碱脂质聚合物杂化纳米粒的制备及体内外性能评价

Preparation and evaluation of in vitro and in vivo characteristics of hydroxycamptothecin lipid-polymer hybrid nanoparticles

目的以二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000(1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000],DSPE-PEG2000),大豆卵磷脂(soy lecithin-100M,SL-100M),共聚物材料聚乳酸(polylactic acid,PLA),聚乳酸-羟基乙酸共聚物(poly(lactic-co-glycolic acid),PLGA),聚己内酯(polycaprolactone,PCL)为载体包载羟基喜树碱(hydroxycamptothecin,HCPT),采用乳化溶剂挥发法制备HCPT脂质聚合物杂化纳米粒(hydroxycamptothecin lipid-polymer hybrid nanoparticles,HCPT-LPNs),以期提高制剂的载药量并改善其体外血浆稳定性,体外释放性能,体外抗肿瘤活性,体内药代动力学效果以及体内肿瘤抑制效果。方法以粒径、多分散指数、电位为评价指标,采用单因素考察法筛选出HCPT-LPNs的最优处方工艺。以不同聚合物(PLA,PLGA,PCL)为HCPT-LPNs的内核,比较其在10%大鼠血浆中的稳定性。以不同pH值的缓冲液作为释放介质,考察HCPT-LPNs的体外释放情况。以游离的HCPT作为参比制剂,用MTT法测定HCPT-LPNs对MCF-7细胞的体外细胞毒性,考察HCPT-LPNs在大鼠体内药物代谢动力学特性。结果PLA及PLGA内核的HCPT-LPNs较PCL内核的HCPT-LPNs相比具有较好的血浆胶体稳定性。HCPT-LPNs具有pH敏感的释放特性。HCPT-LPNs的体外细胞毒性较游离HCPT大。结论HCPT-LPNs为安全有效的递送HCPT的纳米制剂。

Objective Distearic acyl phosphatidyl ethanolamine-polyethylene glycol 2000(DSPE-PEG2000),soy lecithin SL-100 M,copolymer material(PLA,PLGA,PCL)were used as the carriers for encapsulating encapsulate hydroxycamptothecin(HCPT).HCPT lipid polymer hybrid nanoparticles(HCPT-LPNs)were prepared by emulsification solvent evaporation method to improve the drug loading efficiency,in vitro plasma stability,in vitro release performance,in vitro anti-tumor activity and in vivo pharmacokinetic effect of the preparation.Methods The optimal formulation process of HCPT-LPNs was selected using particle size,multiple dispersion index and zeta potential as the evaluation indexes by single factor method.Different polymers(PLA,PLGA,PCL)were used as the inner core of HCPT-LPNs,the stability of the preparations in 10%rat plasma was compared.The in vitro release characteristics of HCPT-LPNs were investigated using buffers with different pH values as the release media.The cytotoxicity of HCPT-LPNs on MCF-7 cells was determined by MTT assay,and the pharmacokinetic characteristics of HCPT-LPNs in rats were investigated.Results HCPT-LPNs with PLA and PLGA inner cores had better plasma stability than HCPT-LPNs with PCL inner core.HCPT-LPNs had a pH-sensitive release characteristic.In vitro cytotoxicity of HCPT-LPNs was greater than HCPT solution.HCPT-LPNs had higher AUC than HCPT solution.Conclusion HCPT-LPNs are safe and effective nanopreparations for the delivery of HCPT.