蒿甲醚固体脂质纳米粒的制备与小鼠体内药动学/药效学评价

Preparation of artemether solid lipid nanoparticles and evaluation of pharmacokinetics and pharmacodynamics in mice

目的制备用于静脉注射的蒿甲醚固体脂质纳米粒(ARM-SLNs),并评价小鼠体内药动学以及抑瘤效果。方法采用热熔乳化超声-低温固化法制备ARM-SLNs,并考察其理化性质;测定了ARM-SLNs在小鼠体内的药动学行为,评价ARM-SLNs对小鼠接种HepG2肿瘤细胞的抑制效果。结果本研究制备的ARM-SLNs呈球形分布,平均粒径大小为(77.6±1.3)nm,Zeta电位为(-20.1±0.4)mV,包封率为(93.5±1.2)%,载药量为(9.2±0.3)%,冻干对ARM-SLNs的粒径大小、包封率和载药量均未产生显著影响;ARM-SLNs在体外显示出缓慢释药特性,符合一级动力学方程;小鼠药动学研究表明ARM-SLNs的t1/2及AUC0-t分别是ARM注射液的9.67倍和3.88倍;小鼠药效学研究表明ARM-SLNs的对HepG2肿瘤生长的抑制率显著高于ARM注射液(P<0.05)。结论本研究制备的ARM-SLNs对HepG2肿瘤细胞起到了良好的抑制效果,有望成为ARM的新型给药系统应用于临床研究中。

Objective To prepare artemether solid lipid nanoparticles(ARM-SLNs)for intravenous injection and to evaluate the anti-tumor effects of ARM-SLNs by in vivo pharmacokinetics and pharmacodynamics in mice.Methods ARM-SLNs were prepared by hot-melt emulsion ultrasonication and low temperature solidification methods.The physicochemical properties of ARM-SLNs were evaluated.The pharmacokinetics of ARM-SLNs in mice was measured and the inhibitory effect of ARM-SLNs on HepG2 cells inoculated with mice was evaluated.Results The average particle size of ARM-SLNs was(77.6±1.3)nm,the Zeta potential was(-20.1±0.4)mV,the encapsulation efficiency was(93.5±1.2)%and the drug loading was(9.2±0.3)%.ARMSLNs had no significant effect on particle size,entrapment efficiency and drug loading.Lyophilization had no significantly effect on the particle size,encapsulation efficiency and drug loading of ARM-SLNs.ARM-SLNs showed slowly release characteristics in vitro and in accordance with first-order kinetic equation.The pharmacokinetics studies in mice showed that the t1/2 and AUC0-t of ARM-SLNs were 9.67-fold and 3.88-fold higher than that of ARM injection,respectively.The pharmacodynamic studies in mice showed that the inhibitory rates of ARM-SLNs on tumor growth were significantly higher than that of ARM injection(P<0.05).Conclusion The preparation of ARM-SLNs,which has a good anti-tumor effect on tumor cells,is expected to become a new drug delivery system of artemether used in clinical studies.