替莫唑胺固体脂质纳米粒在动物体内药动学及组织分布研究

Study on Pharmacokinetics in Rabbit and Body Distribution in Mice of Temozolomide Solid Lipid Nanoparticles by Intravenously Injection

目的制备替莫唑胺固体脂质纳米粒(TMZ-SLN),考察其在家兔体内的药动学及小鼠组织分布特性。方法采用乳化-低温固化法制备TMZ-SLN,透射电镜观察纳米粒的形态,激光散射测定其Zeta电位和粒度分布,反相高效液相色谱测定了体外和体内替莫唑胺的浓度。结果纳米粒平均粒径dav=(65.0±6.2)nm,载药量为(5.9±0.9)%,包封率为(58.9±1.2)%,表面带有负电荷,Zeta电位为(-37.2±3.6)mV,在pH 6.8磷酸缓冲溶液中体外释药符合Higuchi方程,以替莫唑胺溶液(TMZ-Sol)为对照,TMZ-SLN静脉注射后药物在家兔血液中的平均滞留时间显著延长,由3.82 h延长到44.88 h,小鼠肝、脾、肺、脑的分布显著增加,其中脑靶向效率由6.76%提高至13.25%(提高了96.01%),心和肾中的分布显著下降。结论TMZ-SLN在体内具有良好的脑靶向性,对提高药物的疗效,降低心、肾毒副作用有一定意义。

OBJECTIVE To prepare the temozolomide solid lipid nanoparticles （TMZ-SLN） and to evaluate the characteristics of pharmaeokinetics in rabbits and tissue distribution in mice. METHODS TMZ-SLN was prepared by emulsification-low temperature solidification method. The morphology was detected by transmission electron microscope. The Zeta potentials and the particle size distribution were evaluated by Laser Dopple Anemometry. Concentrations of temozolomide in plasma and various organs as well as in vitro were determined by reversed phase high performance liquid chromatography. RESULTS The characteristic data showed that the mean particle size of the prepared TMZ-SLN was dav = （ 65.0 ± 6. 2 ） nm, drug loading was （ 5.9 ± 0. 9 ） %, entrapment efficiency was （58.9 ± 1.2） % , and the particles carried negative charge,Zeta potential was （ - 37.2 ± 3.6） mV in pH 6. 8 phosphate buffer solution, in vitro release characteristics was well in accord with Higuchi equation. Compared with temozolomide solution, TMZ-SLN showed high tissure distribution in liver, spleen,lung and brain, and low concentration in heart and kidney , leading to a prolonged plasma mean residence time（MRT） from 3.82 h to 44.88 h,and resulting in a evident brain targeting efficiency from 6.76% increasing to 13.25% （ raised by 96.01% ）. CONCLUSION The results indicated that TMZ-SLN have a good targeting efficiency in brain,and the biodegradable TMZ-SLN may decrease the temozolomide side effects in heart and kidney and improve its treatment efficacy in brain.