目的 制備甘草次酸（GA）修飾的馬錢子堿（B）-聚乙二醇-二硫代二丙酸-單硬脂酸甘油酯（PSG）納米粒（NPs）（B-GPSG-NPs）并評價其體內(nèi)外肝靶向性。方法 采用溶劑乳化超聲法制備B-GPSG-NPs和B-PSG-NPs，于透射電鏡下觀察其外觀形態(tài)，測定其粒徑、多分散性指數(shù)（PDI）、Zeta電位、包封率、載藥量等理化性質。建立檢測心、肝、脾、肺、腎、腦組織中馬錢子堿含量的高效液相色譜法。將雌雄各半的小鼠90只隨機分為3組：馬錢子堿組、B-PSG-NPs組、B-GPSG-NPs組，禁食不禁水12h后，尾iv相應溶液（以馬錢子堿計10mg·kg^-1），分別于給藥后10、30、60、120、180min取各組織進行HPLC檢測，計算相對攝取率（Re）和靶向效率（Te），以評價給藥系統(tǒng)的體內(nèi)靶向性。制備載異硫氰基熒光素（FITC）的FITC-B-PSG-NPs、FITC-B-GPSG-NPs，F(xiàn)ITC、空白PSG載體制成的納米粒（PSG-NPs）、空白GPSG載體制成的納米粒（GPSG-NPs）以及含馬錢子堿質量濃度分別為500、250、125μg·mL^-1的FITC-B-PSG-NPs和FITC-B-GPSG-NPs與CBRH-7919肝癌細胞共培養(yǎng)24h，熒光顯微鏡下觀察CBRH-7919細胞對各受試物的攝取情況，以評價給藥系統(tǒng)的體外靶向性。結果 B-GPSG-NPs的粒徑為（98.91±3.62）nm，呈正態(tài)分布；PDI值為（0.221±0.006），Zeta電位為-（19.63±0.40）mV，包封率為（78.37±1.83）%，載藥量為（2.86±0.05）%；B-PSG-NPs與B-GPSG-NPs組肝臟的Re分別為1.49和1.72，明顯高于其他組織；馬錢子堿組腎臟Te最高，腦Te最低，而B-PSG-NPs和B-GPSG-NPs組肝臟中馬錢子堿的Te明顯高于其他各組織；CBRH-7919細胞攝取B-GPSG-NPs效率明顯高于B-PSG-NPs，并表現(xiàn)出劑量相關性。結論 制備的BGPSG-NPs在體內(nèi)外均表現(xiàn)出良好的肝靶向效應，且優(yōu)于無GA修飾的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

黑龍江自然科學基金面上項目(H2016076);黑龍江省教育廳科學技術研究項目(12531624);哈爾濱市應用技術研究與開發(fā)項目(青年后備人才A類,2017RAQXJ090)