目的 研究叶酸受体靶向性熊果酸脂质体的体内组织分布及肿瘤靶向作用。方法 以叶酸靶向材料叶酸-聚乙二醇-胆固醇的半琥珀酸盐作为靶向分子,再用聚乙二醇-二硬脂酰磷脂酰乙醇胺(mPEG-DSPE)对脂质体表面进行结构修饰,利用薄膜分散法制备长循环脂质体(F-PEG-L-UA);测定裸鼠心、肝、脾、胃、肾及肿瘤组织的药物含量,考察熊果酸体内的分布差异,比较叶酸受体靶向作用和单纯给药在组织分布的不同;并构建裸鼠口腔癌皮下移植瘤模型观察F-PEG-L-UA对裸鼠口腔癌的抑制作用。结果 与游离熊果酸相比,熊果酸脂质体明显增加药物在体内长循环的时间,在肝、肾和肿瘤组织中药物浓度明显高于其他组织,说明熊果酸集中分布于肝脏和肾脏进行代谢,并且具有良好的肿瘤靶向性。F-PEG-L-UA与其他各组相比较,肿瘤生长受到明显抑制,其瘤体积减少约50%(P<0.05);而游离熊果酸和非靶向组的瘤体积没有得到有效控制。结论 本实验制备的F-PEG-L-UA具备高效的肿瘤靶向性,是一种有效的抗肿瘤药物传递系统。
Abstract
OBJECTIVE To study the distribution of folate receptor targeted ursolic acid liposomes and evaluate its antitumor effects on human epidermoid carcinoma xenografts in nude mice. METHODS Folate derivative was used as targeting molecule and conjugated with mPEG-DSPE for obtaining liposome with long circulation features. This novel targeted agent was prepared by a thin-film dispersion method and ursolic acid was loaded into the liposomes as the anticancer drugs. Tissue distribution of liposomes in heart, liver, spleen, stomach, kidney and tumor were investigated. The antitumor effect of the targeted ursolic acid liposomes (F-PEG-L-UA) on human epidermoid carcinoma xenografts in nude mice was also studied. RESULTS Compared with free ursolic acid liposome, UA liposome was slowly removed from blood circulation and the concentration of F-PEG-L-UA in liver, kidney and tumor tissue is significantly higher than other groups. The growth speed of tumor in the group of F-PEG-L-UA was significantly slowed down compared with other groups. The tumor volume in F-PEG-L-UA group was about 50% reduction compared with PBS-treated mice (P<0.05). CONCLUSION A novel targeted ursolic acid compound is synthesized as the folate receptor targeting functional material. It has obvious inhibitory effect on human epidermoid carcinoma xenografts and it might be an effective antitumor drug delivery system.
关键词
熊果酸 /
脂质体 /
叶酸受体靶向 /
人源性口腔肿瘤细胞 /
抑瘤作用
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Key words
ursolic acid /
liposome /
folate receptor targeting /
human epidermoid carcinoma cell /
anti-tumor effect
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中图分类号：
R944
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参考文献
[1] DEVITA V T. Dose-response in alive and well[J]. J Clin Oncol, 1986,4(5):1157-1159.
[2] LIU J. Oleanolic acid and ursolic acid:research perspectives [J]. J Ethnopharmacol,2005,100(1-2):92-94.
[3] SAEIDNIA S,GOHARI A R,UCHIYAMA N,et al. Trypanocidal terpenoids from Dracocephalum kotschyi [J]. Chem Pharm Bull,2004,52(10):1249-1250.
[4] XIONG B, LEI Z Y, CHEN H. Research progress on ursolic acid pharmacology[J]. Foreign Med(Sci Pharm),2004,31(3):133-136.
[5] LIU X S,JIANG J. Induction of apoptosis and regulation of the MAPK pathway by ursolic acid in human leukemia K562 cells [J]. Planta Med,2007,73(11):1192-1194.
[6] MANU K A,KUTTAN G. Ursolic acid induces apoptosis by activating p53 and caspase-3 gene expressions and suppressing NFkappaB mediated activation of bcl-2 in B16F-10 melanoma cells [J]. Int Immunopharmacol,2008,8(7):974-981.
[7] ACHIWA Y, HASEGAWA K, KOMIYA T, et al. Ursolic acid induces Bax-dependent apoptosis through the caspase-3 pathway in endometrial cancer SNG-Ⅱ cells [J]. Oncol Rep,2005,13 (1):51-57.
[8] OFELIA C, FLORIN B. Syntheses of new cyclodextrin complexes with oleanolic and ursolic acids [J]. Journal of Agroalimentary Processes and Technologies,2011,17(4):405-409.
[9] ZHAO Y. Inchoate Clinical Research on Ursolic Acid Liposomes, a Natural Antitumor Drug [D]. Tianjin:Tianjin University,2012-04.
[10] YANG G, TAN Y. In vitro and in vivo antitumor effects of folate-targeted ursolic acid stealth liposome[J]. J Agric Food Chem, 2014, 62(10):2207-2215.
[11] ZHAO C C, QIAN Z Z, WANG Q H, et al. A phase Ⅰ clinical trial of ursolic acid nanoliposome for evaluating its single-dose tolerance and safety[J]. Chin J New Drugs(中国新药杂志),2011, 20(2):148-151.
[12] WU X H, LI Z H, WANG H M, et al. Inhibition of lung cancer by transfer of P53 gene using Tie2-rnediated gene delivery system[J]. Tumor, 2007, 27(5):256-259.
[13] TSAI B Y, LIN Y L, CHIANG B L. Autoimmune response induced by dendritic cell exerts anti-tumor effect in murine model of leukemia[J]. J Autoimmu, 2010, 34(7):364-370.
[14] SOUKAINA R L, HARIVARDHAN R, AMOR H. Squalenoyl gemcitabine nanomedicine overcomes the low efficacy of gemcitabine therapy in pancreatic cancer[J]. Nanomedicine, 2011, 7(6):841-849.
[15] SARASWAT B, VISEN P K, AGARWAL D P. Ursolic acid isolated from eucalyptus tereticomis protects against ethanol toxicity in isolated rat hepatocytes [J]. Phytother Res, 2000, 14(3):163-166.
[16] MIURA N, MATSUMOTO Y, MIYAIRI S, et al. Protective effects of triterpene compounds against the cytotoxicity of cadmiumin HepG2 cells [J]. Mol Pharmacol, 1999, 56(6):1324-1328.
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脚注
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基金
国家自然科学基金资助项目(81072596)
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