基于壳聚糖的pH响应双重药物释放系统研究

A p H-Responsive Dual-drug Delivery System Based on Chitosan

以腙键连接的壳聚糖阿霉素前药偶联物(Chitosan-hz-DOX)为载体,通过物理包埋法制备了负载喜树碱(CPT)的双药共传递纳米输送体系(CPT-CS-DOX).通过紫外可见吸收光谱、动态光散射、透射扫描电镜等方法研究了体系的粒径、形貌、药物负载及释放性能,发现制备CPT-CS-DOX纳米颗粒的最佳CPT投放量为20%,其粒径随着Chitosan-hz-DOX中阿霉素(DOX)含量的增加而不断降低,共传递体系有效地抑制了DOX和CPT的早期泄露,并呈现出显著的p H依赖药物释放行为.利用Peppas方程对释放曲线进行分析,发现第一阶段DOX和CPT在中性环境中的释放遵循Fick扩散控制和溶胀控制机理,在酸性环境中CPT的释放机理保持不变,而DOX的释放则转变为聚合物松弛机理;第二阶段则两者均符合Fick扩散机理.

Chitosan-doxorubicin prodrug with the linkage of hydrazone bond （Chitosan-hz-DOX） was employed as the carrier ofcamptothecin （CPT） to develop a dual-drugdelivery system （CPT-CS-DOX）. UV- Vis, DLS, and TEM analyses were conducted to investigate the diameter, morphology, drug loading and releasebehaviors of the system. With the increase in the grafting content of DOX on chitosan, the resultant Chitosan-hz-DOX prodrug showed an enhanced loading capacity of CPT. The optimal addition amount of CPT to prepare CPT-CS-DOX was determined to be 20%. After loading CPT, the Chitosan-hz-DOX nanoparticles still remained the spherical morphology but their diameters were increased. In addition, the diameter of CPT-CS- DOX was decreased gradually with the DOX content of Chitosan-hz-DOXbecause of the strong hydrophobic interactions. The premature releases of DOX and CPT at pH = 7.4 were effectively inhibited from the delivery system,that is,their cumulative releases were 10% and 20% , respectively. Compared with that,in particular, their release rates were remarkably increased at acidic conditions, showing a highly pH-dependent drug release behavior. Furthermore,Peppas equation was employed to analyze the release mechanism of DOX and CPT at different environment conditions. Their release process can be divided into two stages. Thereleases of DOX and CPT at the first stagefollowedthe Fick-diffusion controlled and swelling controlled mechanisms at neutral condition,while at acidic conditions,the release mechanism of CPT remained unchanged but that of DOX was changed. At the second stage,the releases of both drugs obeyedtheFick-diffusion controlledmeehanism.