胡小娟,陈维良,俞 洋,张学农*.N-脂肪酰-N-三甲基壳聚糖的合成及其对蛇床子素的增溶作用[J].中草药,2013,44():
N-脂肪酰-N-三甲基壳聚糖的合成及其对蛇床子素的增溶作用
Synthesis on N-fatty acyl-N-trimethyl chitosan and it micellar solubilization to osthole
  
DOI:
中文关键词:  关键词:N-软脂酰-N-三甲基壳聚糖  N-癸酰-N-三甲基壳聚糖  N-脂肪酰-N-三甲基壳聚糖  胶束增溶  蛇床子素
英文关键词:Key words: N-palmitoyl-N-Trimethyl chitosan  N-caprinoyl-N-Trimethyl chitosan  N-fatty acyl-N-Trimethyl chitosan  micelles solubilization  osthole
基金项目:基金项目:国家自然基金资助项目(81273463);江苏省科技支撑计划(BE2011670);国家大学生创新性试验计划课题资助(111028533,微机编号5731503311)
作者单位
胡小娟,陈维良,俞 洋,张学农* 苏州大学药学院江苏 苏州 215123 
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中文摘要:
      摘 要:目的 合成2 种两亲性壳聚糖(CS)衍生物,自组装成聚合物胶束作为难溶性药物的新型递药载体。方法 先将 CS 与碘甲烷反应生成N-三甲基壳聚糖(trimethyl chitosan,TMC),然后在TMC 的氨基上引入长链脂肪酸(软脂酸和癸酸), 合成了两亲性的N-脂肪酰-N-三甲基壳聚糖(N-fatty acyl-N-Trimethyl chitosan,FA-TMC)衍生物。通过FT-IR、1H-NMR 和 元素分析法,对衍生物的分子结构和N-位取代度进行表征,同时以疏水性药物蛇床子素(osthole,OST)为模型,探讨其胶 束增溶特性。结果 实验合成了2 类6 种不同的新型CS 衍生物,分析显示季胺化程度和脂肪酰基接枝率对FA-TMC 的胶束 性质有较大的影响;对于超声法制备的OST 载药胶束,季胺化程度为62.00%、软脂酰基接枝率为13.37%的N-软脂酰-N-三 甲基壳聚糖(N-palmitoyl-N-Trimethyl chitosan,PA-TMC)和季胺化程度为43.06%、癸酰基接枝率为22.00%的N-癸酰-N-三 甲基壳聚糖(N-caprinoyl-N-Trimethyl chitosan,CA-TMC)的包封率分别为76.67%、79.11%,载药量分别为19.01%、19.08%, 可使OST 在水中的溶解度提高两个数量级。结论 FA-TMC 是一种具有潜在应用价值的增溶载体,其在水中能自主装形成 胶束,并对OST 有明显的增溶作用,为OST 制剂深入研究与应用奠定了基础。
英文摘要:
      Abstract: Objective To synthesize two kinds of amphipathic chitosan derivatives, which could be self-assembling to polymeric micelles as novel drug carriers. Methods Different DQ (degree of quaternisation, DQ) of N-Trimethyl chitosan (TMC) were synthesized by the reaction between chitosan and CH3I. Coupling reaction between TMC and PA or CA were reacted under the effort of EDC·HCl and NHS. The polymer structure was confirmed by FT-IR, 1HNMR spectra and element analysis. Then the hydrophobicity drug of osthole was used as model drug to evaluate the solubilizing ability of those polymeric micelles. Results Two kinds of novel chitosan derivatives were synthesize, the results indicated that DQ and DS (degree of substitution, DS) were important parameters to FA-TMC, which could influence its micelle properties. To the ultrasonic method prepared OST loaded micelles, the best candidate materials of the PA-TMC was the polyer with DQ of 62.00% and DS of 13.37%, while the CA-TMC was the polyer with DQ of 43.06% and DS of 22.00%. The entrapment rate of the OST micelles were 76.67%, 79.11%, respectively. The drug-loading rate of the OST micelles were 19.01%, 19.08%, respectively. The solubility of OST increased up to two orders of magnitude in the OST loaded micelles. Conclusion PA-TMC and CA-TMC are candidate materials of hydrophobicity drugs, and the OST loaded micelles are the praeparatum foundation for deeply researches on the antitumor activity of OST.
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