Stepwise dual targeting and dual responsive polymer micelles for mitochondrion therapy
Stepwise dual targeting and dual responsive polymer micelles for mitochondrion therapy
复制标题
用于线粒体治疗的逐步双靶向和双响应聚合物胶束
DOI：
10.1016/j.jconrel.2020.03.011
复制
发表时间：
2020
影响因子：
10.8
通讯作者：
Zhou Shaobing
中科院分区：
文献类型：
--
作者：
Zhang Xiaobin;Wang Yi;Wei Guoqing;Zhao Jingya;Yang Guang;Zhou Shaobing
摘要利用纳米药物选择性破坏肿瘤细胞线粒体并诱导细胞凋亡是目前肿瘤治疗的难点。在本研究中，我们开发了用于线粒体治疗的细胞膜/线粒体双靶向和pH/氧化还原双响应纳米颗粒。采用二硫键作为中间连接剂，将三苯基膦（TPP）接枝聚乙二醇(PEG)-聚d，l-丙交酯（PLA）共聚物（TPP-PEG-ss-PLA）自组装制备纳米颗粒。为了保护纳米颗粒表面的正电荷不受TPP成分的影响，硫酸软骨素（CS）被包裹在纳米颗粒表面，这延长了血液循环，同时赋予了细胞膜主动靶向能力。在酸性溶酶体/内体中，带负电荷的CS层脱落以暴露TPP成分。随后，在细胞质中，纳米颗粒可以通过tpp介导的靶向作用锚定在线粒体外膜上，从而诱导膜电位降低，通透过渡孔打开。因此，线粒体中ROS的过量产生促进了细胞凋亡。释放的DOX直接扩散到线粒体，从而导致线粒体DNA损伤。因此，纳米颗粒在线粒体治疗癌症的新途径方面显示出巨大的潜力。
AbstractsMethods to selectively destroy mitochondria of tumor cells and induce cell apoptosis with nanomedicine constitute challenges in cancer therapy. In the present study, we develop cell membrane/mitochondria dual targeting and pH/redox dual responsive nanoparticles for mitochondrion therapy. The nanoparticles are fabricated by the self-assembly of triphenylphosphonium (TPP) grafted poly(ethylene glycol)(PEG)-poly(d,l-lactide)(PLA) copolymers (TPP-PEG-ss-PLA) using disulfide bonds as the intermediate linkers. To shield the surface positive charge of the nanoparticles from TPP composition, chondroitin sulfate (CS) is employed to coat the nanoparticles, and this prolongs blood circulation while endowing an active targeting ability to the cell membrane. In acidic lyso-somes/endosomes, the negatively charged CS layer falls away to expose the TPP component. Subsequently, in the cyto-plasm, the nanoparticles can anchor to the mitochondrial outer membrane by TPP-mediated targeting, thereby inducing a decrease in the membrane potential and opening of the permeability transition pore. Thus, the overproduction of ROS in the mitochondria promotes cell apoptosis. The released DOX directly diffuse into the mitochondria, thereby resulting in mito-chondrial DNA damage. Therefore, the nanoparticles exhibit significant potential in terms of a new avenue for mitochondrion therapy in cancer treatment.