肝靶向氟尿嘧啶类脂纳米粒的研究

目的　为了提高氟尿嘧啶(5-Fu)的疗效，降低其毒副作用，制备具肝靶向的5-Fu类脂纳米粒。方法　利用氟尿嘧啶与硬脂酰氯进行反应，制备了5-Fu前体药物N₁-硬脂酰-5-Fu，通过红外光谱及核磁共振谱对合成的目标化合物进行结构确认。同时研究了前体药物的性质及稳定性。采用物理凝聚法制备类脂纳米粒，并研究其形态、粒径及粒径分布、载药量、体外释药特征、动物体内分布与药代动力学参数等。结果　平均粒径d_av=240.19 nm，载药量为20.53%。体外释药速率符合一级动力学模型。与5-Fu水针剂比较，类脂纳米粒组在肝脏中药物含量平均增加了一倍以上。家兔体内主要药动学参数为：V_c=0.04336 L.kg^-1，T_1/2β=1.2834 h，CL=0.1632 L.h^-1。结论　利用前体药物可提高药物的脂溶性，首次以物理凝聚法制备类脂纳米粒，小鼠体内分布研究表明类脂纳米粒有明显的肝靶向，有一定的优越性和参考价值。

STUDY ON THE LIVER TARGETED 5-FLUOROURACIL SOLID LIPID NANOPARTICLES

AIM　To improve the treatment efficacy and reduce the side effect of 5-fluorouracil (5-Fu), liver targeted 5-Fu solid lipid nanoparticles (5-FuE-SLN) were prepared. METHODS　5-Fu as model drug, was esterified with stearyl chloride. The resulted compound N₁-stearyl-5-Fu (prodrug) was determined by nuclear magnetic resonance and infrared spectrometry. The prodrug was used to prepare 5-Fu solid lipid nanoparticles (5-FuE-SLN) by the method of physical agglomeration. Transmission electron microscopy was employed to study the shape, mean size and particle distribution of 5-FuE-SLN. The drug loading, the in vitro drug release characteristics, the in vivo drug distribution and pharmacokinetics in animal were also investigated. RESULTS　The finding showed that the average diameter was 240.19 nm, drug loading was 20.53%. The in vitro release characteristics investigated fitted to first-order pharmacokinetic model. In order to investigate the targeting effect of 5-FuE-SLN, the concentrations of 5-fluorouracil in plasma, liver, lung, heart, spleen and kidney of mice were determined by high-performance liquid chromatography (HPLC) after intravenous administration. The study on in vivo distribution indicated that the fate of 5-FuE-SLN was different from that of free 5-Fu. The mean content of 5-Fu in liver was 67.3% for 5-FuE-SLN group, 37.52% greater than the control group. It was demonstrated that 5-FuE-SLN has selective targeting to liver tissue. The pharmacokinetics of 5-FuE-SLN lyophilized powders in rabbits after intravenous administration was studied by HPLC. The plasma concentration-time curve of 5-FuE-SLN obeyed two-compartment model. The pharmacokinetic parameters of 5-FuE-SLN were as follows: V_c=0.043361 L.kg^-1, T_1/2α= 0.080714 h, T_1/2β=1.283457 h, CL_s=0.163265 L.h^-1. CONCLUSION　Using prodrug to enhance drug liposoluble properties and the method of preparation of the liver targeted 5-FuE-SLN lyophilized powders by physical agglomeration presented in this paper seem to have significant advantages and important reference value.