目的 制备甘草次酸（GA）修饰的马钱子碱（B）-聚乙二醇-二硫代二丙酸-单硬脂酸甘油酯（PSG）纳米粒（NPs）（B-GPSG-NPs）并评价其体内外肝靶向性。方法 采用溶剂乳化超声法制备B-GPSG-NPs和B-PSG-NPs，于透射电镜下观察其外观形态，测定其粒径、多分散性指数（PDI）、Zeta电位、包封率、载药量等理化性质。建立检测心、肝、脾、肺、肾、脑组织中马钱子碱含量的高效液相色谱法。将雌雄各半的小鼠90只随机分为3组：马钱子碱组、B-PSG-NPs组、B-GPSG-NPs组，禁食不禁水12h后，尾iv相应溶液（以马钱子碱计10mg·kg^-1），分别于给药后10、30、60、120、180min取各组织进行HPLC检测，计算相对摄取率（Re）和靶向效率（Te），以评价给药系统的体内靶向性。制备载异硫氰基荧光素（FITC）的FITC-B-PSG-NPs、FITC-B-GPSG-NPs，FITC、空白PSG载体制成的纳米粒（PSG-NPs）、空白GPSG载体制成的纳米粒（GPSG-NPs）以及含马钱子碱质量浓度分别为500、250、125μg·mL^-1的FITC-B-PSG-NPs和FITC-B-GPSG-NPs与CBRH-7919肝癌细胞共培养24h，荧光显微镜下观察CBRH-7919细胞对各受试物的摄取情况，以评价给药系统的体外靶向性。结果 B-GPSG-NPs的粒径为（98.91±3.62）nm，呈正态分布；PDI值为（0.221±0.006），Zeta电位为-（19.63±0.40）mV，包封率为（78.37±1.83）%，载药量为（2.86±0.05）%；B-PSG-NPs与B-GPSG-NPs组肝脏的Re分别为1.49和1.72，明显高于其他组织；马钱子碱组肾脏Te最高，脑Te最低，而B-PSG-NPs和B-GPSG-NPs组肝脏中马钱子碱的Te明显高于其他各组织；CBRH-7919细胞摄取B-GPSG-NPs效率明显高于B-PSG-NPs，并表现出剂量相关性。结论 制备的BGPSG-NPs在体内外均表现出良好的肝靶向效应，且优于无GA修饰的B-PSG-NPs。

Objective To prepare the glycyrrhetinic acid (GA) modified brucine (B) -polyethylene glycol-dithiodipropionic acidmonostearate (PSG) nanoparticles (NPs) (B-GPSG-NPs) and evaluate its hepatic targeting property in vivo and in vitro.Methods B-GPSG-NPs and B-PSG-NPs were prepared by solvoemulsification ultrasonic method. Their appearance was observed under transmission electron microscope, and their physical and chemical properties such as particle size, polydispersity index (PDI), Zeta potential, encapsulation rate and drug loading were determined. To establish a HPLC method for the determination of brucine in heart, liver, spleen, lung, kidney and brain. Ninety mice, half male and half female, were randomly divided into three groups: brucine group, B-PSG-NPs group and B-GPSG-NPs group, after fasting without water for 12 h, tail iv corresponding solution (10 mg·kg^-1 by brucine) was taken from each tissue at 10, 30, 60, 120 and 180 min after administration, respectively, for HPLC detection. Relative uptake rate (Re) and targeting efficiency (Te) were calculated to evaluate the in vivo targeting of the drug delivery system. FITC-BPSG-NPs and FITC-B-GPSG-NPs containing isothiocyaniferin (FITC) were prepared. FITC, blank PSG carrier nanoparticles (PSGNPs), blank GPSG carrier nanoparticles (GPSG-NPs) and FITC-B-PSG-NPs, FITC-B-GPSG-NPs whose brucine containing mass concentration were 500, 250 and 125 μg·mL^-1 were co-cultured with CBRH-7919 hepatocellular carcinoma cells for 24 h. The uptake of CBRH-7919 cells to each subject was observed under fluorescence microscope to evaluate the in vitro targeting of the drug delivery system.Results The particle size of B-GPSG-NPs was (98.91 ±3.62) nm, and the distribution was normal. PDI value was (0.221 ±0.006), Zeta potential was -(19.63 ±0.40) mV, encapsulation rate was (78.37 ±1.83)%, drug loading was (2.86 ±0.05)%. The Re of liver in B-PSG-NPs and B-GPSG-NPs groups was 1.49 and 1.72, respectively, which were significantly higher than those in other tissues. The highest Te in kidney and the lowest Te in brain were observed in brucine group, while the Te of brucine in liver in B-PSG-NPs and B-GPSG-NPs groups was significantly higher than that in other tissues. The uptake efficacy of the B-GPSG-NPs by CBRH-7919 cells was higher than that of the B-PSG-NPs, and exhibited dose dependence.Conclusion The prepared B-GPSGNPs showed improved hepatic targeting efficacy both in vivo and in vitro, compared with the B-PSG-NPs unmodified by GA.

R943

黑龙江自然科学基金面上项目(H2016076);黑龙江省教育厅科学技术研究项目(12531624);哈尔滨市应用技术研究与开发项目(青年后备人才A类,2017RAQXJ090)