Star-shape paclitaxel prodrug self-assembled nanomedicine: combining high drug loading and enhanced cytotoxicity
Star-shape paclitaxel prodrug self-assembled nanomedicine: combining high drug loading and enhanced cytotoxicity
复制标题
DOI：
10.1039/c6ra23169a
复制
发表时间：
2016-01-01
期刊：
影响因子：
3.9
通讯作者：
He, Zhonggui
中科院分区：
文献类型：
--
作者：
Jiang, Mengjuan;Han, Xiangfei;He, Zhonggui
传统的紫杉醇纳米粒给药系统存在载药率低和潜在的生物材料毒性等问题。本文合成了以维生素E琥珀酸酯修饰的新型星形PTX前体药，通过碳酸酯(PC)或琥珀酸酯(PE)作为PTX 2‘端的连接物，使其具有良好的疏水性，能够高效地自组装成纳米粒子(NP)。体外实验表明，所制备的前药具有较高的物理稳定性，在大鼠血浆中几乎不发生水解性反应。此外，在PBS中，PC中的碳酸键比PE中的酯键更容易被水解。与PENPs相比，PCNPs在体外对MCF-7细胞和A549细胞显示出更高的细胞毒性，这是由于PC更多地转化为PTX所致。体内荧光成像结果表明，PCNPs可通过EPR效应在肿瘤体内被动蓄积。这些结果表明，与PTX的琥珀酸酯结合物相比，具有胞外稳定性的双PTX碳酸酯结合物的自组装纳米粒具有更强的细胞毒性，被癌细胞内化后更适合于肿瘤的治疗，并且碳酸酯连接更适合于与PTX分子连接以设计这类前药。总之，负载双PTX分子的新型星形前体药物的自组装纳米技术为开发高负载效率和增强细胞毒性的纳米药物开辟了新的前景。
Conventional nanoparticulate drug delivery systems of paclitaxel (PTX) are challenged with low drug loading efficiency and potential biomaterials-induced toxicity. In this work, novel star-shape PTX prodrugs modified by vitamin E succinate with a load of double PTX molecules via carbonate (PC) or succinate (PE) as the linkers at the 2' position of PTX were synthesized, which were capable of self-assembling into nanoparticles (NPs) with high loading efficiency despite their remarkably hydrophobic character. The in vitro studies revealed that the prodrugs in the form of nanoparticles with high physical stability were little hydrolyzed in rat plasma. In addition, the carbonate bond in PC was more susceptible to hydrolysis than the ester bond in PE in PBS. Compared with PENPs, PCNPs exhibited comparably higher in vitro cytotoxicity against MCF-7 cells and A549 cells due to more conversion of PC to PTX. The in vivo fluorescence imaging demonstrated that PCNPs could passively accumulate in tumors by EPR effect. These results suggested that compared with the succinate conjugate of PTX, the self-assembled NPs of the double PTX loaded carbonate conjugate with extracellular stability can be a more suitable candidate for treatment of cancers after being internalized by cancer cells for its stronger cytotoxicity, and the carbonate linkage is more feasible to be linked with PTX molecules for the design of such type of prodrugs. Overall, the self-assembled nanotechnology of novel star-shape prodrugs with a load of double PTX molecules opens new perspectives for the development of nanomedicines with high loading efficiency and enhanced cytotoxicity.