聚乙二醇化聚十六烷基氰基丙烯酸酯的合成及其作为纳米药物载体的应用研究

Study on Synthesis of Adriamycin-loaded mPEG-PHDCA and Their Application as Nanoparticle Drug Carriers

目的:合成有机聚合物聚乙二醇化聚十六烷基氰基丙烯酸酯(m PEG-PHDCA),制备载药m PEG-PHDCA纳米粒,并研究其体外释药行为。方法:采用Knoevenagel反应和阴离子聚合反应合成m PEG-PHDCA,通过核磁共振氢谱(1H-NMR)进行表征,凝胶渗透色谱(GPC)法测定重均分子量和多分散系数(PDI)。以阿霉素为模型药,采用复乳-溶剂挥发法制备载阿霉素的m PEGPHDCA纳米粒,透射电镜观察其微观形貌,粒径仪测定其粒径和Zeta电位。高效液相色谱法测定纳米粒中阿霉素的含量并计算载药量和包封率,透析袋法考察其体外释药特性,比较其与阿霉素溶液的体外释药效果。结果:经过1H-NMR和GPC表征,成功合成m PEG-PHDCA,重均分子量约为6 000,PDI为1.13。所制载阿霉素的m PEG-PHDCA纳米粒呈圆球颗粒状,表面光滑、大小均匀、分布良好,无团聚现象,粒径、Zeta电位、载药量和包封率分别为(94.61±3.91)nm、(-11.68±0.83)m V、(2.17±0.67)%、(79.54±4.66)%(n=3)。载阿霉素的m PEG-PHDCA纳米粒48 h的体外累积释药率达到85.38%,释药曲线符合Weibull方程(R2=0.979 4);阿霉素溶液体外4 h已基本释药完全。结论:成功合成具有良好载药性能、生物相容性和缓释特性的m PEG-PHDCA,其有望成为新型纳米递药载体。

OBJECTIVE：To synthesize Monomethoxy-polyethyleneglycolcyanoacrylate-co-poly-hexadecylcyanoacrylate（m PEGPHDCA）,prepare adriamycin-loaded m PEG-PHDCA nanoparticle and study its in vitro drug release behavior. METHODS：Knoevenagel reaction and anionic polymerization were adopted to synthesize m PEG-PHDCA,and it was characterized with1 HNMR. Weight-average molecular weight and polydispersity index（PDI） were determined by gel permeation chromatography（GPC）. Using adriamycin as model drug,complex emulsion-solvent evaporation method was used to prepare adriamycin-loaded m PEG-PHDCA nanoparticle. TEM was adopted to observe its micromorphology;particle size and Zeta potential were determined by particle size instrument. The content of adriamycin,drug-loading amount and encapsulated efficiency in nanoparticle were determined by HPLC. The characteristics of drug release in vitro were investigated by dialysis bag method. The drug release in vitro of it was compared with that of adriamycin. RESULTS：After characterized with1 H-NMR and GPC, m PEG-PHDCA was synthesized successfully;mass average molar mass was about 6 000,and PDI was 1.13. Prepared adriamycin-loaded m PEGPHDCA nanoparticle was round ball-like granule and had smooth appearance, uniform size and good distribution without agglomeration. Particle size,Zeta-potential,drug-loading amount and entrapment efficiency were（94.61±3.91）nm,（-11.68±0.83）m V,（2.17±0.67）%,（79.54±4.66）%（n=3）. Accumulative release rate of adriamycin-loaded m PEG-PHDCA nanoparticle reached 85.38% within 48 h. Drug release curve was Weibull equation distribution（R2=0.979 4）. The adriamycin solution was released completely in vitro after 4 h. CONCLUSIONS： m PEG-PHDCA is synthesized with good drug loading efficiency,biocompatibility and sustained-release properties. It is expected to be a new nano drug delivery carrier.