Chen Cheng, Zhou Jiang-Ling, Han Xue, Song Fei, Wang Xiu-Li, Wang Yu-Zhong
Center for Degradable and Flame-Retardant Polymeric Materials (ERCPM-MoE), College of Chemistry, State Key Laboratory of Polymer Materials Engineering, National Engineering Laboratory of Eco-Friendly Polymeric Materials (Sichuan), Sichuan University, 29 Wangjiang Road, Chengdu 610064, People's Republic of China.
Nanotechnology. 2014 Jun 27;25(25):255101. doi: 10.1088/0957-4484/25/25/255101. Epub 2014 Jun 4.
Doxorubicin (DOX), one of the most widely used anticancer drugs, is restricted in clinical application due to its severe side effects and inefficient cellular uptake. To overcome the drawbacks, herein, an endosomal pH-activated prodrug was designed and fabricated by conjugating DOX with chitosan via an acid-cleavable hydrazone bond. The resulting DOX conjugates can self-assemble into nano-sized particles, which were very stable and presented no burst release of DOX at a neutral pH condition. Notably, the nanoparticles exhibited excellent cell uptake properties and a remarkable drug accumulation in tumor cells. Once internalized into the cells, moreover, DOX can be fast released from the nanoparticles, and the release mechanism changed from the anomalous transport at pH 7.4 to the combination pattern of diffusion- and erosion-controlled release at pH 6.0 or 5.0. The prodrugs showed obvious cytotoxicity for HeLa cells with fairly low IC50 values, offering a new platform for targeted cancer therapy.
阿霉素（DOX）是使用最广泛的抗癌药物之一，由于其严重的副作用和低效的细胞摄取，在临床应用中受到限制。为了克服这些缺点，本文通过酸可裂解的腙键将DOX与壳聚糖共轭，设计并制备了一种内体pH激活前药。所得的DOX共轭物可自组装成纳米级颗粒，这些颗粒非常稳定，在中性pH条件下不会出现DOX的突释。值得注意的是，纳米颗粒表现出优异的细胞摄取特性，并在肿瘤细胞中具有显著的药物积累。此外，一旦内化到细胞中，DOX可以从纳米颗粒中快速释放，释放机制从pH 7.4时的异常转运转变为pH 6.0或5.0时扩散和侵蚀控制释放的组合模式。前药对HeLa细胞显示出明显的细胞毒性，IC50值相当低，为靶向癌症治疗提供了一个新平台。
