Stepwise dual targeting and dual responsive polymer micelles for mitochondrion therapy.,Journal of Controlled Release

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Stepwise dual targeting and dual responsive polymer micelles for mitochondrion therapy.
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2020-03-10 , DOI: 10.1016/j.jconrel.2020.03.011
Xiaobin Zhang ₁ , Yi Wang ₂ , Guoqing Wei ₂ , Jingya Zhao ₂ , Guang Yang ₂ , Shaobing Zhou ₂

Affiliation

Methods 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.

中文翻译：

用于线粒体治疗的逐步双重靶向和双重反应性聚合物胶束。

用纳米药物选择性破坏肿瘤细胞线粒体并诱导细胞凋亡的方法在癌症治疗中构成挑战。在本研究中，我们开发了针对线粒体疗法的细胞膜/线粒体双重靶向和pH /氧化还原双重响应纳米颗粒。纳米粒子是通过使用二硫键作为三苯基of（TPP）接枝的聚（乙二醇）（PEG）-聚（d，1-丙交酯）（PLA）共聚物（TPP-PEG-ss-PLA）的自组装而制备的。中间连接子。为了从TPP组合物中屏蔽纳米颗粒的表面正电荷，采用硫酸软骨素（CS）覆盖纳米颗粒，这可以延长血液循环，同时赋予细胞膜以主动靶向能力。在酸性溶酶体/内体中，带负电的CS层掉落以暴露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到线粒体外膜上，从而引起膜电位的降低和通透性过渡孔的开放。因此，线粒体中ROS的过量产生促进细胞凋亡。释放的DOX直接扩散到线粒体中，从而导致线粒体DNA损伤。因此，就线粒体疗法在癌症治疗中的新途径而言，纳米颗粒显示出显着的潜力。释放的DOX直接扩散到线粒体中，从而导致线粒体DNA损伤。因此，就线粒体疗法在癌症治疗中的新途径而言，纳米颗粒显示出显着的潜力。释放的DOX直接扩散到线粒体中，从而导致线粒体DNA损伤。因此，就线粒体疗法在癌症治疗中的新途径而言，纳米颗粒显示出显着的潜力。

更新日期：2020-03-10

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