2-脱氧葡萄糖修饰共载siPD-L1及替莫唑胺脂质纳米粒的脑靶向性研究

Brain targeting of 2-deoxyglucose modified lipid nanoparticles co-loaded with siPD-L1 and temozolomide

目的考察2脱氧葡萄糖(2-DG)修饰共载siPD-L1及替莫唑胺(TMZ)脂质纳米粒(TMZ/siPD-L1@GLPN)在小鼠体内的药物动力学及脑内分布,阐明TMZ/siPD-L1@GLPN的脑靶向性,为脑靶向递药系统的设计提供依据。方法采用高效液相色谱及活体成像仪考察游离TMZ、TMZ/siPD-L1@GLPN以及未经2-DG修饰共载siPD-L1及TMZ脂质纳米粒(TMZ/siPD-L1@LPN)小鼠尾静脉给药后,TMZ在血浆中的消除动力学以及在小鼠脑内的分布动力学。结果与游离TMZ相比,TMZ/siPD-L1@GLPN在小鼠血浆中的消除速度明显减缓,TMZ/siPD-L1@GLPN在小鼠体内的循环时间明显延长。游离TMZ、TMZ/siPD-L1@GLPN以及TMZ/siPD-L1@LPN给药后,TMZ在血浆中的AUC 0~∞分别为(139.49±14.39)、(585.50±44.91)和(705.73±173.02)h/(mg·L),TMZ在脑组织中的AUC 0~∞分别为(32.39±3.12)、(532.89±46.44)和(162.79±18.38)h/(mg·kg)。活体成像仪观察结果显示,相较于TMZ/siPD-L1@LPN,TMZ/siPD-L1@GLPN在脑内的分布更多。结论2-DG修饰脂质纳米粒后能够显著提高脂质纳米粒的脑靶向性,显著延长TMZ在小鼠体内的循环时间。

Objective To investigate the pharmacokinetics and brain distribution of 2-deoxyglucose(2-DG)modified lipid nanoparticles co-loaded siPD-L1 and temozolomide(TMZ)(TMZ/siPD-L1@GLPN)in mice,and to clarify the brain targeting of TMZ/siPD-L1@GLPN,so as to provide a basis for the design of brain targeted drug delivery system.Methods High performance liquid chromatography and in vivo imager were used to study the elimination kinetics of TMZ in plasma and the distribution kinetics of TMZ in the brain of mice after the administration of free TMZ,TMZ/siPD-L1@GLPN and TMZ/siPD-L1@LPN via tail vein injection.Results Compared with free TMZ,the elimination rate of TMZ/siPD-L1@GLPN in mouse plasma was significantly slowed down,and the circulation time of TMZ/siPD-L1@GLPN in mice was significantly prolonged.After the administration of free TMZ,TMZ/siPD-L1@GLPN and TMZ/siPD-L1@LPN,the AUC 0-∞of TMZ in plasma were(139.49±14.39),(585.50±44.91)and(705.73±173.02)h/(mg·L),respectively.The AUC 0-∞of TMZ in brain tissue were(32.39±3.12),(532.89±46.44)and(162.79±18.38)h/(mg·kg),respectively.The results of in vivo imager observation showed that TMZ/siPD-L1@GLPN was more distributed in the brain than TMZ/siPD-L1@LPN.Conclusion 2-DG modified lipid nanoparticles can significantly improve the brain targeting of lipid nanoparticles,and significantly prolong the circulation time of TMZ in mice.