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

以N-十六烷基三甲基溴化铵为模板,硅酸四乙酯经水解和缩聚反应制备了介孔二氧化硅(MSN)纳米球,其经表面氨丙基化、苯硼酸化、环磷腺苷负载、荧光标记葡萄糖酸修饰的胰岛素(Flu-G-Ins,Flu为异硫氰酸荧光素)封盖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电位对材料进行了表征。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对Flu-G-Ins和环磷腺苷释放效果的影响。结果表明,当MSN纳米球质量浓度为10 g/L、环磷腺苷浓度为0.10 mmol/L时,经24 h避光负载,Flu-G-Ins-MSN对环磷腺苷的载药量可达25.9μmol/g;糖触发Flu-G-Ins和环磷腺苷的释放具有明显的pH依赖性,p H越高,释药量越大;在人体正常生理p H 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;质量浓度2 g/L的载药粒子在50 mmol/L葡萄糖溶液刺激下,Flu-G-Ins 0.5 h的释放量可达8.35μmol/L,环磷腺苷20 h的释放量可达75%。葡萄糖能实现对载药粒子的反复刺激解封,进而实现对Flu-G-Ins和环磷腺苷的持续控释。

A dual drug delivery system Flu-G-Ins-MSN (Flu represents for fluorescein isothiocyanate) was prepared by surface aminopropylation,phenylboration,cyclic adenosine monophosphate (cAMP) loading and fluorescein-labeled gluconate insulin (Flu-G-Ins) capping of mesoporous silica nanospheres (MSN),which was prepared by hydrolysis and polycondensation of tetraethyl orthosilicate (TEOS) using N-hexadecyltrimethylammonium bromide (CTAB) as template.The samples obtained were then characterized by TEM,FTIR,XRD,N2adsorption-desorption,Zeta potential analysis,followed by investigation on the effect of loading time on drug loading capability and the effect of sugar sources,sugar concentration and p H on the release of Flu-G-Ins and cAMP.The results demonstrated that,when the mass concentration of Flu-G-Ins-MSN was 10 g/L and the concentration of cAMP was 0.10 mmol/L,the drug loading capability could reach 25.9μmol/g after stirring for 24 h with no light irradiation.The release of Flu-G-Ins and cAMP trigger by glucose was significantly p H-dependent and enhanced as p H increased.In the normal human physiological p H=7.4 environment,fructose and glucose exhibited the strongest stimulatory effect on drug-loaded particles.Flu-G-Ins release from 2 g/L drug-loaded particles stimulated with 50 mmol/L glucose solution for 0.5 h was up to 8.35μmol/L,while cAMP release was up to 75%in20 h.Glucose could repeatedly stimulate and unseal drug-loaded particles,thus achieving sustained controlled release of Flu-G-Ins and cAMP.