脑靶向3′,5′-二辛酰基-5-氟脲嘧啶脱氧核苷药质体研究

目的　为提高氟苷的脑靶向性,以增强疗效,降低毒副作用,制备其前体药物3′,5′-二辛酰基-氟苷的药质体。方法　用薄膜 超声分散法制备药质体,中心组合设计优化制备工艺,反向动态透析法测定体外释药情况,HPLC法测定小鼠iv后在体内各组织的分布。结果　药质体平均粒径为76nm ,载药量为29.02% ,包封率为96.62% ;体外释药过程符合双指数方程;以氟苷注射液为对照,药物在小鼠脑中靶向指数为对照液的10.97倍;并可显著延长药物在血液中的滞留时间。结论　氟苷酯化前体药物的药质体在体内有良好的脑靶向性,可作为新型的脑给药系统

Study on brain targeting 3',5'-dioctanoyl-5-fluoro-2'-deoxyuridine pharmacosomes]

AIM: To investigate the specific brain drug targeting of 5-fluoro-2'-deoxyuridine (FUdR) by synthesis of 3', 5'-dioctanoyl-5-fluoro-2'-deoxyuridine (DO-FUdR) and incorporation into DO-FUdR pharmacosomes (DO-FUdR-PS). METHODS: DO-FUdR-PS was prepared by thin-layer ultrasonication technique. In vitro drug release was studied in pH 7.4 phosphate-buffered saline containing 0.3% pancreatic enzyme at 37 degrees C using bulk-equilirium reverse dialysis bag technique. The concentration of FUdR in various organs were determined by reversed phase HPLC after i.v. administration of DO-FUdR-PS and FUdR. RESULTS: The mean particle size of DO-FUdR-PS was 76 nm with drug loading of 29.02% and entrapment efficiency of 96.62%. The in vitro drug release kinetics could be characterized by bioexponential equation. Compared with FUdR injection, DO-FUdR-PS showed high concentration in tested organs. The brain AUC ratio of DO-FUdR-PS to FUdR was 10.97. CONCLUSION: DO-FUdR-PS showed a good targeting efficiency in vivo. PS can improve the ability of drug to cross blood-brain barrier and is a promising drug targeting system for the treatment of central nervous system disorders.