School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan 430070, PR China; School of Materials Science and Engineering, Wuhan University of Technology, Wuhan 430070, PR China.
Key laboratory of Biomedical Polymers, Ministry of Education, Department of Chemistry, Wuhan University, Wuhan 430072, PR China.
Int J Biol Macromol. 2018 Jul 1;113:737-747. doi: 10.1016/j.ijbiomac.2018.03.004. Epub 2018 Mar 29.
In this study, intracellular pH-responsive nanoparticles (NPs) of hyaluronic acid-hydrazone linkage-doxorubicin (HA-hyd-DOX) were designed and prepared for acid-triggered release of doxorubicin through a hydrazone linkage. A series of amphiphilic polymeric prodrugs were obtained, which can be self-assembled in aqueous media, the formed NPs exhibited a spherical core-shell type and the uniform size was ranging from 167 to 220nm. Moreover, the HA-hyd-DOX NPs exhibited a good stability in vitro and the drug release profiles showed that the DOX release was obviously mediated by pH gradient. Additionally, the cell counting assay kit-8 (CCK-8) demonstrated that the drug delivery system in this study performed a lower cytotoxicity on normal cells (Mouse fibroblast cells, L929) and higher inhibition ratio on tumor cells (Human cervical cancer cells, HeLa) in response to drug release with the intracellular pH environment. Furthermore, confocal laser scanning microscopy (CLSM) images and flow cytometric profiles of HeLa cells showed an efficiently cellular uptake due to the receptor-mediated affinity of CD44 for HA with high specificity. These results suggest that this pH dependent drug delivery system based on HA will provide insights into the design of potential prodrugs for the cancer therapy.
在这项研究中，设计并制备了具有细胞内 pH 响应性的透明质酸腙键连接阿霉素纳米粒子（HA-hyd-DOX），通过腙键实现阿霉素的酸触发释放。得到了一系列两亲性聚合物前药，它们可以在水介质中自组装，形成的 NPs 呈球形核壳型，粒径均匀，范围为 167 至 220nm。此外，HA-hyd-DOX NPs 在体外具有良好的稳定性，药物释放曲线表明 DOX 的释放明显受到 pH 梯度的调节。此外，细胞计数试剂盒-8（CCK-8）实验表明，与正常细胞（小鼠成纤维细胞，L929）相比，该研究中的药物传递系统在细胞内 pH 环境下响应药物释放时表现出较低的细胞毒性，对肿瘤细胞（人宫颈癌细胞，HeLa）的抑制率更高。此外，HeLa 细胞的共聚焦激光扫描显微镜（CLSM）图像和流式细胞术分析表明，由于 CD44 对 HA 的高特异性受体介导亲和力，细胞摄取效率很高。这些结果表明，基于 HA 的这种 pH 依赖性药物传递系统将为癌症治疗的潜在前药设计提供新的思路。
