目的：以白介素13（IL-13）作为肿瘤主动靶向配体，构建能够穿透血脑屏障的胶束递药系统，延长卡莫司汀（carmustine，BCNU）在脑部消除半衰期，以实现其增效减毒。方法：以二硬脂酰基磷脂酰乙醇胺-聚乙二醇（DSPE-PEG）/二氨基聚乙二醇硬脂酰基磷脂酰乙醇胺（DSPE-PEG-NH2）为载体，包载抗肿瘤药物BCNU，采用薄膜水合法制备载药胶束，再通过EDC/NHS缩合法将IL-13锚定在聚合物胶束的表面，制备具有主动脑靶向能力的胶束载药系统（BCNU-loaded IL-13 modified micelle，BCNU-M-IL13）。通过考察胶束粒径、Zeta电位、形态学、包封率、体外累计释放等指标，评价胶束的药剂学性能；通过MTT法考察载药胶束对人源脑胶质瘤BT325细胞的抗增殖作用；同时通过考察静脉注射载药胶束后脑组织匀浆的药物半衰期，评价其脑部靶向及滞留性能。结果：BCNU-M-IL13粒径为（86.6±1.2） nm，表面电位为（-18.6±2.1） mV，透射电镜结果显示胶束外观圆整，粒径分布窄，BCNU载药量为（3.8±0.1）%，包封率为（93.5±2.7）%；其48 h累计释放率为（48.6±2.7）%；体外抗肿瘤活性实验表明BCNU-M-IL13对BT325的IC50为（44.9±0.5）μmol·L-1；脑组织匀浆的半衰期为1.7 h。结论：本研究首次制备得到BCNU-M-IL13，制备工艺简单，并对其制剂学性质进行了考察，结果表明其制剂学性能优异，且与游离药物相比，体外抗肿瘤活性明显增强，脑内半衰期得到显著改善。%Objective: To prepare BCNU-loaded micelles modified with interleukin-13 (IL13) as gliomas-tar-geting ligand that can penetrate the blood-brain barrier and raise the concentration of BCNU in brain, and en-hance the anti-tumor activity. Methods: BCNU-loaded micelles (BCNU-M) were prepared by film hydration with DSPE-PEG and then IL13 was anchored on the particle surface by EDC/NHS aqueous phase condensation in or-der to build active glioma-targeting BCNU micelles (BCNU-M-IL13). Preparation conditions were screened and optimized based on particle size, Zeta potential and encapsulation efficiency of the micelles. Pharmaceutic perfor-mances were investigated for particle size, Zeta potential, morphology, encapsulation efficiency, loading-rate and in vitro release. An MTT method was used to compare the toxicities of BCNU, BCNU-M and BCNU-M-IL13 on BT325 cells. The half-lives of BCNU, BCNU-M and BCNU-M-IL13 in brain were examined after intravenous in-jection. Results: The particle size of BCNU-M-IL13 was (86.6±1.2) nm, the surface potential was (-18.6±2.1) mV, transmission electron microscopy showed that the micelles were round with narrow particle size distribution. The encapsulation efficiency was (93.5±2.7)%; the drug loading rate was (3.8±0.1)%; and the cumulative release rate of BCNU for 48 h was (46.8±3.9)%. IC50 of BCNU-M-IL13 for BT325 was (44.9±0.5)μmol·L-1; the half-life of BC-NU in rat brain after BCNU-M-IL13 injection was 1.7 h. Conclusion: Interleukin-13 modified BCNU micelles prepared in this study are simple in production with excellent pharmaceutical properties. They stay longer in brain with stronger anti-tumor effects.
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