摘要
目的合成乳糖化-去甲斑蝥素作为主动肝靶向性修饰物,并将其制成纳米粒。方法利用乙二胺为连接臂合成乳糖化-去甲斑蝥素修饰物,并考察其相关理化性质;采用离子诱导法制备乳糖化-去甲斑蝥素壳聚糖纳米粒,以粒径分布、包封率、载药量为综合指标,正交设计优化载药纳米粒的制备工艺,并考察其体外释放特性。结果乳糖化-去甲斑蝥素是一种具有良好水溶性的多羟基化合物,其合成产率为68.35%;经优化工艺制备的乳糖化-去甲斑蝥素的纳米粒的平均粒径(149.46±1.79)nm,包封率(80.29±0.56)%,载药量(9.58±0.09)%,其体外释药遵循Higuchi方程。结论乳糖化-去甲斑蝥素合成简单,产率高,其纳米粒体外释放具有良好的缓释特性。
Abstract
OBJECTIVE To synthesize lactosyl-norcantharidin(Lac-NCTD) as active liver-tageting modified drug and prepare its nanoparticles.METHODS Lac-NCTD was synthesized with ethanediamine as truss arm,and then its properties were studied.Chitosan nanoparticles(CS-NP) were achieved by ionic cross-linkage process with lactosyl-norcantharidin as a model drug.Orthogonal experiment design was applied to optimize the formulation and preparation procedure with particle distribution,entrapment rate and drug-loading rate as integrated indexes.The in vitro release was investigated.RESULTS Lac-NCTD was a kind of polyhydroxy compound and the yield was 68.35%.CS-NP were spherical,average particle size was(149.46±1.79)nm,entrapment rate was(80.29±0.56) %,drug-loading rate was(9.58±0.09)%,and in vitro release followed Higuchi equation.CONCLUSION The synthesis procedure of Lac-NCTD was simple and the yield was high.Sustained release of CS-NP was identified.
关键词
乳糖化-去甲斑蝥素 /
主动肝靶向 /
壳聚糖 /
纳米粒
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Key words
lactosyl-norcantharidin /
active liver-targeting /
chitosan /
nanoparticle
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胡展红;章良;周奕;张学农.
肝靶向去甲斑蝥素修饰物的合成及其纳米粒的制备[J]. 中国药学杂志, 2009, 44(09): 679-684
HU Zhn-hong;ZHNG Ling;ZHOU Yi;ZHNG Xue-nong.
Synthesis of Hepatocyte-Targeting Norcantharidin Prodrug and Preparation of Its Nanoparticles [J]. Chinese Pharmaceutical Journal, 2009, 44(09): 679-684
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参考文献
[1] WU J M,REN T C,YU M. Pharmacy research and clinic application progress on norcantharidin [J].Chin Pharm J(中国药学杂志),2002,37(8):566-569.
[2] HASHIDA M,NISHIKAWA M,YAMASHITA F,et al. Cell-specific delivery of genes with glycosylated carriers [J]. Adv Drug Deliver Rev,2001,52(3):187-196.
[3] HILL T A,STEWART S G,ACKLAND S P,et al. Synthesis and anticancer activity: Synthesis of new norcantharidin analogues and their anticancer evaluation[J]. Bioorgan Med Chem,2007,15(18):6126-6134.
[4] MANTOVANI G,LECOLLEY F,TAO L,et al. Design and synthesis of N-maleimido-functionalized hydrophilic polymers via copper-mediated living radical polymerization: a suitable alternative to PEGylation chemistry[J]. Am Chem Soc,2005,127 (9):127-133.
[5] BIJSTERBOSCH M K,YING C,VRUEH R L,et a1.Carrier-mediated delivery improves the efficacy of 9-(2-pho-sphonylmethoxyethy1)adenine against hepatitis B virus [J]. Mol Pharmacol,2001,60(3):521-527.
[6] STEWART S G,HILL T A,GILBERT J,et al. Synthesis and biological evaluation of norcantharidin analogues:Towards PP1 selectivity[J]. Bioorgan Med Chem,2007,15 (23):7301-7310.
[7] WILLIAMS T J,PLESSAS N R,GOLDSTEIN I J,et al. A new class of model glycolipids: synthesis,characterization,and interaction with lectins[J]. Arch Biochem Biophys,1979,195(1):145-151.
[8] ZHANG Z Z,FUKUNAGA K,SUFIMURA Y.Practical method for synthesis of new glycolipids N-[4-(Dialkyl-L-Glutamatecarbonyle thylethylcarbo-Nylamino) Butyl ] Lactobionamides[J]. Chin Chem Lett,1996,7(2):119-122.
[9] PARK I K,KIM T H,PARK Y H,et al. Galactosylated chitosan-graft-poly (ethylene glycol) as hepatocyte-targeting DNA carrier[J]. J Controlled Release,2001,76 (3 ):349-362.
[10] GAO S Y,CHEN J G,XU X R,et al. Galactosylated low molecular weight chitosan as DNA carrier for hepatocyte-targeting[J]. Inter J Pharm,2003,255 (1-2):57-68.
[11] LIU X H,HENG W S,PAUL,et al. Novel polymeric microspheres containing norcantharidin for chemoembolization[J]. J Controlled Release,2006,116(1):35-41.
[12] ZHANG W,GONG J H,ZHANG X N,et al. Multi-variable regression analysis applied to synchronously optimize preparation of nanoparticles[J]. Chin Pharm J(中国药学杂志),2008,43(15):1162-1166.
[13] STEWART S G,HILL T A,GILBERT J,et al.Synthesis and biological evaluation of norcantharidin analogues:Towards PP1 selectivity[J]. Bioorg Med Chem,2007,15 (23):7301-7310.
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脚注
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基金
国家科技支撑计划课题资助(2006BAI09B00);国家科技部科技型中小企业技术创新基金(07C26223201333);江苏省“六大人才高峰”资助项目;江苏省卫生厅招标项目(H200630)
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