紫杉醇聚合物胶束的制备及其pH响应性能

Preparation of Paclitaxel-loaded Copolymer Micelles and Its pH-responsive Properties

目的:制备以具有p H响应性能的聚乙二醇-聚乳酸[poly(ethylene glycol)-poly(lactic acid),PELA]-聚-β-氨基酯(PBAE)为载体的纳米胶束,提高紫杉醇在水中溶解度。方法:Michael加成合成PBAE共聚物,通过核磁共振波谱法表征其结构,酸碱滴定法测定碱解离常数(dissociation contant of a base,p Kb),荧光法测定临界胶束浓度(criticle micelle concentration,CMC)。采用薄膜水化法制备载紫杉醇纳米胶束,HPLC测定载药量和包封率,激光粒度仪测定粒径及分布,透射电镜表征其形态,透析袋透析法测定纳米胶束在不同p H条件下的释放特性。结果:PELA和PBAE的p Kb分别为7.1和6.5,CMC分别为3.31,4.79 mg·L-1,载药量分别为12.37%和12.05%,包封率分别为70.55%和68.53%,且紫杉醇胶束1周内稳定。体外释放试验表明非p H响应材料随介质p H降低,药物释放略微增加;而p H敏感材料在弱酸性条件下药物释放明显加快。结论:PBAE作为纳米载体能明显提高紫杉醇的水溶性,载药量较高且稳定,具有明显的p H敏感性。

Objective： To synthesize poly（ethylene glycol）-poly（lactic acid）-poly（β-amino ester）（PBAE） block polymer and prepare paclitaxel-loaded micelles to enhance its solubility in aqueous milieu.Method： PBAE was synthesized by Michael addition reaction,its structure was characterized by1H-NMR,its dissociation contant of a base（p Kb） was determined by acid-base titration,critical micelle concentration（CMC）of copolymer was measured by pyrene fluorescence spectroscopy. Paclitaxel loaded copolymer micelles were prepared by membrane hydration methods. Drug loading efficiency（DL） and entrapment efficiency（EE） of micelles were evaluated by high-performance liquid chromatography（HPLC）. The size and size distribution of micelles were determined by nanoparticle size analyzer. The structure of micelles was manifested by transmission electron microscopy. In vitro release was performed in phosphate buffered saline at different p H values. Result：CMC of PELA and PBAE were 3. 31,4. 79 mg · L- 1,p Kbvalues of them were 7. 1 and 6. 5,their DL were12. 37% and 12. 05%,EE were 70. 55% and 68. 53%,respectively. Paclitaxel loaded micelles were stable up to one week at 4 ℃. In vitro release study showed that drug release from PELA micelles increased slightly with decrease of p H. However,drug release accelerated obviously upon acidic environment（p H 6. 5 and 5. 5） from p H responsive polymer micelles. Conclusion： PBAE shows high performance in increasing paclitaxel solubility,high drug loading and long stability,as well as p H controlled drug release from micelles.