Negative Surface Shielded Polymeric Micelles with Colloidal Stability for Intracellular Endosomal/Lysosomal Escape.
Negative Surface Shielded Polymeric Micelles with Colloidal Stability for Intracellular Endosomal/Lysosomal Escape.
复制标题
DOI：
10.1021/acs.molpharmaceut.8b00842
复制
发表时间：
2018-09
影响因子：
4.9
通讯作者：
Yun Zhu;Tingting Meng;Ya'nan Tan;Xiqin Yang;Yupeng Liu;Xuan Liu;Fang-ying Yu;Lijuan Wen;
中科院分区：
文献类型：
--
作者：
Yun Zhu;Tingting Meng;Ya'nan Tan;Xiqin Yang;Yupeng Liu;Xuan Liu;Fang-ying Yu;Lijuan Wen;
实现有效的抗肿瘤治疗的关键过程和步骤是促进内体逃逸，这可以增强治疗剂的细胞内靶向递送。然而，通常采用的方法往往会导致胶体不稳定性，这是由于胶束和蛋白质在体内的正电荷表面之间不可避免的相互作用。本文中，构建了由聚甲基丙烯酰胺衍生物和亲水性壳聚糖（Mw = 18.8kDa）通过3，3 '-二硫代二丙酸连接的带负电荷的表面屏蔽的聚合物胶束。直到pH降低到小于4.5，DOX-负载的聚合物胶束（CSO-SS-PDPA/DOX）保留负表面电荷，作为丰富的酰胺基团的结果，这可以抵抗蛋白质“冠”的形成，如通过透射电子显微镜观察到的。由于质子化胺基团和特定的氧化还原反应性药物释放，在数十分钟内的强大内体逃逸通过共聚焦显微镜可视化。在3D肿瘤球状体和MCF-7荷瘤小鼠中的上级治疗功效进一步表明，制备的CSO-SS-PDPA/DOX是用于维持胶体稳定性同时实现细胞内内体/溶酶体逃逸的有前景的方法，这为药物递送打开了新的机会。
The critical process and step in achieving effective antitumor therapies is facilitating endosomal escape, which can enhance the intracellular target delivery of therapeutics. However, the normally adopted approaches tend to result in colloidal instability as a result of the inevitable interactions between the resulting positively charged surfaces of micelles and proteins in vivo. Herein, negatively charged surface shielded polymeric micelles, consisting of polymethylacrylamide derivatives and hydrophilic chitosan ( Mw = 18.8 kDa) linked by 3,3'-dithiodipropionic, are constructed. Until the pH decreases to less than 4.5, the DOX-loaded polymeric micelles (CSO-SS-PDPA/DOX) retain a negative surface charge as a result of the abundant amide groups, which could resist formation of the protein "corona" as visualized by transmission electron microscopy. Robust endosomal escape within tens of minutes due to protonated amine groups and specific redox-responsive drug release is visualized by confocal microscopy. The superior therapeutic efficacy in both 3D tumor spheroids and MCF-7 bearing mice further suggested that the prepared CSO-SS-PDPA/DOX is a promising approach for maintaining colloidal stability while achieving intracellular endosomal/lysosomal escape, which opens new opportunities for drug delivery.