ADI脂质纳米粒的制备表征及药动学研究

  目的  制备并表征维生素E琥珀酸聚乙二醇酯（D-alpha-Tocopheryl polyethylene glycol 1000 succinate, TPGS）修饰载精氨酸脱亚胺酶（arginine deiminase, ADI）磺丁基-β-环糊精脂质体纳米粒（TPSG modified ADI sulfobutyl-β-cyclodextrinol liposome nanoparticles, ATCL），并考察ATCL在动物体内的药动学特征。  方法  采用逆向蒸发法制备ATCL，测定ATCL的粒径和Zeta电位。通过氨基硫脲-二乙酰一肟比色法测定ADI活性，静脉给药后于设定时间点取血并测定血浆中酶活性，绘制酶活性-时间曲线，DAS 2.1.1软件分析药动学特征。  结果  制备的ATCL粒径和电位分别为（216.1±13.6） nm和（?19.4±2.1） mV。ADI和ATCL的催化反应的最适温度和最适pH相同，均为37 ℃，pH6.5。分析得ATCL的AUC_{(0～168 h)}、MRT_{(0～168 h)}、C_max、T_max、t_1/2分别是游离ADI的3.99、2.56、1.58、3.2、9.88倍。ATCL相对ADI生物利用度提高了298.54%。  结论  本研究中制备的ATCL能够提高ADI酶活性以及在SD大鼠体内的生物利用度。

Preparation,Characterization and Pharmacokinetic Study of Arginine Deiminase Lipid Nanoparticles

  Objective  To prepare and characterize D-alpha-Tocopheryl polyethylene glycol 1000 succinate (TPGS) modified arginine deiminase (ADI) sulfobutyl-β-Cyclodextrin liposome nanoparticles (ATCL), and to investigate the pharmacokinetic characteristics of ATCL in animals.  Methods  The reverse evaporation method was used to prepare ATCL, and the particle size and Zeta potential of ATCL were measured. Thiosemicarbazone-diacetylmonooxime colorimetric method was used to measure the activity of ADI. After intravenous administration, blood was drawn at set intervals of time and the enzyme activity in the plasma was measured. Enzyme activity-time curve was drawn subsequently and Debris Assessment Software (DAS) 2.1.1 was used to analyze the pharmacokinetic characteristics.  Results  The particle size and the potential of ATCL were (216.1±13.6) nm and (?19.4±2.1) mV, respectively. The optimal temperature and optimal pH for the catalytic reaction of ADI and ATCL were the same, both being 37 ℃ and pH6.5. Results of the analysis showed that the AUC_{(0-168 h)}, MRT_{(0-168 h)}, C_max, T_max, and t_1/2 of ATCL were 3.99, 2.56, 1.58, 3.2, and 9.88 times those of free ADI, respectively. Compared with ADI, the bioavailability of ATCL increased by 298.54%.  Conclusion  ATCL prepared in the study can effectively improve the enzyme activity and bioavailability of ADI in Sprague-Dawley rats.