基于葡萄糖响应的胰岛素与环磷腺苷双重载药系统的构筑及释药性能

Fabrication of glucose-responsive double drug delivery system for the release of insulin and cyclic adenosine monophosphate

摘要:

以N-十六烷基三甲基溴化铵（CTAB）为模板，利用硅酸四乙酯（TEOS）的水解和缩聚反应制备了介孔二氧化硅（MSN）纳米球，经表面氨丙基化、苯硼酸化、环磷腺苷负载、葡萄糖酸修饰的胰岛素封盖等途径制备了一种双重载药系统Flu-G-Ins-MSN。通过TEM、FTIR、XRD、N2吸附-脱附、表面Zeta电位等对材料微观形貌、化学结构、孔结构、表面电性等进行了表征。考察了负载时间对载药量的影响，探究了不同糖源、糖浓度、pH等因素对胰岛素和环磷腺苷释放效果的影响。结果表明，当硅球质量浓度为10 g/L、环磷腺苷浓度为0.1 mmol/L时，经24 h避光负载，硅球对环磷腺苷的载药量可达25.9 μmol/g；糖触发胰岛素和环磷腺苷的释放具有明显的pH依赖性，pH越高，释药量越大；在人体正常生理pH 7.4环境中，果糖和葡萄糖对载药粒子的刺激响应效果最佳；2 g/L的载药粒子在50 mmol/L葡萄糖刺激下，胰岛素0.5 h的释放量可达8.35 μmol/L，环磷腺苷20 h的释放量可达75%。间歇释放实验表明，葡萄糖能实现对载药粒子的反复刺激解封，进而实现对胰岛素和环磷腺苷的持续控释。

Abstract:

Mesoporous silica nanospheres (MSN) was prepared by hydrolysis and polycondensation of tetraethyl orthosilicate (TEOS) using N-hexadecyltrimethylammonium bromide (CTAB) as a template. The dual drug delivery system (Flu-G-Ins-MSN) was prepared by surface aminopropylation, phenylboration, cyclic adenosine monophosphate (cAMP) loading and gluconate insulin capping. The surface micromorphology, chemical structure, pore structure and surface charge were characterized by TEM, FTIR, XRD, N2 adsoorption-desorption, Zeta-potential analysis. Effect of stirring time on drug loading was examined. The effect of sugar sources, sugar concentration and pH on the release of insulin and cAMP was investigated. The results demonstrated that when the mass concentration of silica spheres was 10 g/L, the concentration of cAMP was 0.1 mmol/L, the drug loading could reach 25.9 μmol/g after stirring for 24 h. The release of glucose-triggered insulin and cAMP was significantly pH-dependent and increased with increasing pH. In the normal human physiological pH 7.4 environment, fructose and glucose exhibited the strongest stimulatory response to drug-loaded particles. Insulin release from 2 mg/mL drug-loaded particles stimulated with 50 mmol/L glucose for 0.5 h was up to 8.35 μmol/L, while the cAMP release for 20 h was up to 75%. The intermittent release experiments showed that glucose enables repeated stimulation of the uncapping for drug-loaded particles, and thus achieving a sustained controlled release of insulin and cAMP.