pH/葡萄糖双响应载药胶束的制备及性能研究

针对肿瘤部位低pH值、高葡萄糖浓度的微环境特点,设计并制备了pH/葡萄糖双响应载药胶束对葡聚糖进行改性,先通过酯化反应与苯硼酸结合,再通过葡萄糖响应的苯硼酸酯键与具有二醇结构的维生素B₂偶联,形成两亲性聚合物,该聚合物在水溶液中能够自组装形成胶束,包封疏水药物阿霉素.用核磁共振氢谱和动态光散射等对该载药胶束进行表征,并模拟人体生理环境进行药物体外释放行为研究.结果表明,阿霉素在载药胶束内能够持续释放,且能降低环境pH值、增大葡萄糖浓度,从而加快药物释放速度.由于肿瘤部位的pH值低于正常组织、葡萄糖浓度高于正常组织,而具有四面体结构的苯硼酸可以与顺式二醇化合物(如葡萄糖)形成稳定的苯硼酸酯,使平衡向亲水形式增加、疏水形式减少的方向改变.因此,以苯硼酸为基底的材料具有葡萄糖响应性,使其成为治疗肿瘤相关疾病的理想材料.

Preparation and properties of pH/glucose dual responsive micelles system for drug delivery

In view of the microenvironmental characteristics of low pH value and high glucose concentration in tumor site, pH and glucose dual responsive drug loading micelles are designed and prepared accordingly in this study. Dextran is modified and combined with phenylboric acid through esterification reaction, and then coupled with vitamin B2 with diol structure through glucose response phenylboric acid ester bond to form amphiphilic polymer. The polymer can self-assemble into micelles in aqueous solution, which encapsulate the hydrophobic drug doxorubicin. The drug-loaded micelles are characterized by 1H NMR and dynamic light scattering, and the drug release behavior in vitro is studied by simulating human physiological environment. The results show that doxorubicin can be released continuously in the loaded micelles, and the release rate can be accelerated by decreasing pH value and increasing glucose concentration. Because tumor sites have lower pH and higher glucose concentrations than normal tissue and tetrahedral phenylboric acid can form stable phenylborate esters with diol compounds such as glucose, this shifts equilibrium in the direction of increasing hydrophilic forms and decreasing hydrophobic forms. As a result, phenylboric acid-based materials are glucose responsive, and the transformation of this material makes them ideal for diagnosing tumor-related diseases.