设计并合成了一种具有肿瘤靶向及电荷翻转功能的聚氨基酸前体药物.首先通过抗癌药物阿霉素(DOX)上的氨基引发Nε-苄氧羰基-L-赖氨酸酸酐(Z-Lys-NCA)开环聚合得到端基为阿霉素的聚赖氨酸(DOX-PLL),然后在DOX-PLL末端修饰叶酸靶向配体使其具有肿瘤靶向的功能,最后将聚合物侧链上的氨基通过2,3-二甲基马来酸酐功能化得到具有电荷翻转功能的聚氨基酸前体药物(DOX-PLL(DMA)-FA).该前体药物在水相中通过自组装形成胶束,利用透射电子显微镜(TEM)和动态光散射(DLS)表征其粒径.通过检测不同pH值条件下的胶束的表面电势发现,该前药在弱酸条件下具有电荷翻转的能力.另外,体外释药研究表明,在木瓜蛋白酶的作用下,该前药具有较高的药物释放效率.
A new type of charge-reversal prodrug micelles based on polylysine was designed and fabricated for potential targeting drug delivery in tumor.Firstly, doxorubicin terminated polylysine (DOX-PLL) was synthesized through ring opening polymerization of Nε-carbobenzoxy-L-lysine anhydride (Z-Lys-NCA) initiated by amino group on DOX.After terminal modification with targeting ligands, folic acid (FA), the polymer was de-protected to obtain DOX-PLL-FA.Then the polymer was modified with 2,3-dimethyl maleic anhydride, enabling the final product DOX-PLL(DMA)-FA with charge reversal ability.The prodrug DOX-PLL(DMA)-FA could assemble to form micelles in water.The particle size was characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS).The prodrug micelles could maintain negatively charged under physiological condition while revert to positively charged under mild acidic environment.Furthermore, in vitro drug release studies showed that the prodrug micelles could release drug efficiently under the function of papaya protease.
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