【作者】 邓正玉； 刘世勇；

【Author】 Zhengyu Deng;Shiyong Liu;Department of Polymer Science and Engineering,University of Science and Technology of China;

【机构】 中国科学技术大学高分子科学与工程系；

【摘要】 很多生理和病理过程与活性氧物质和氧化压力直接相关,这就为设计治疗和诊断功能的纳米材料提供了非常重要的生化基础。由两亲性聚合物自组装制备的氧化响应性聚合物胶束或者囊泡已经进行了大量的研究。然而,在以前的氧化响应性体系研究中,包括H₂O₂在内的活性氧物质都会导致聚合物组装体微结构的破坏。以氧化性聚合物囊泡为例,微结构的破坏会使囊泡内包覆的亲水性药物和活性分子快速释放,在某些特定情况下,限制了聚合物囊泡作为缓释药物载体和长效活体内纳米反应器的应用。另外,传统聚合物囊泡由于其双层膜较厚、膜渗透性差,因而不能作为有效的药物载体和纳米反应器。我们设计制备了一种多功能的氧化响应性聚合物囊泡,可以在细胞内被氧化微环境刺激触发后发生囊泡双层膜的交联,同时双层膜渗透性提高,表现出成像能力增强和药物释放性能提高的性质。通过自组装疏水嵌段含有芳基硼酸酯保护的具有自降解侧基的两亲性嵌段聚合物制备聚合物囊泡,在其表面进一步用多肽进行修饰从而得到具有线粒体靶向的H₂O₂响应性聚合物囊泡。内吞进入细胞后,胞内H₂O₂触发引发连续的脱保护反应产生伯胺,由于新产生的伯胺在疏水的双层膜中会发生酰胺化反应,导致囊泡双层膜发生同步的交联和疏水到亲水的转变过程。这一过程可以用于实现药物可控释放、组合化疗,同时化疗效果可以通过磁共振成像和荧光成像能力的增强进行实时监测,进一步构筑了检测细胞质中的含巯基的生物活性分子的荧光产生型纳米反应器。更多还原

【Abstract】 Reactive oxygen species（ROS） and oxidative stress are implicated in various physiological and pathological processes and this feature provides a vital biochemical basis for designing novel therapeutic and diagnostic nanomedicines.Among them,oxidation-responsive micelles andvesicles（polymersomes） of amphiphilic block copolymers have been extensively explored; however,in previous works,oxidation by ROS including H₂O₂ exclusively leads to microstructural destruction of polymeric assemblies.For oxidation-responsive polymersomes,fast release of encapsulated hydrophilic drugs and bioactive macromolecules will occur upon microstructural disintegration.Under certain application circumstances,this does not meet design requirements for sustained-release drug nanocarriers and long-acting in vivo nanoreactors.Also note that conventional polymersomes possess thick hydrophobic bilayers and compromised membrane permeability,rendering them as ineffective nanocarriers and nanoreactors.We herein report the fabrication of oxidation-responsive multifunctional polymersomes exhibiting intracellular milieu-triggered vesicle bilayer crosslinking,permeability switching,and enhanced imaging/drug release features.Mitochondria-targeted H₂O₂ reactive polymersomes were obtained through the self-assembly of amphiphilic block copolymers containing arylboronate ester-capped self-immolative side linkages in the hydrophobic block,followed by surface functionalization with targeting peptides.Upon cellular uptake,intracellular H₂O₂ triggers cascade decaging reactions and generates primary amine moieties; prominent amidation reaction then occurs within hydrophobic bilayer membranes,resulting in concurrent crosslinking and hydrophobic-to-hydrophilic transition of polymersome bilayers inside live cells.This process was further utilized to achieve integrated functions such as sustained drug release,（combination） chemotherapy monitored by fluorescence and magnetic resonance（MR） imaging turn-on,and to construct intracellular fluorogenic nanoreactors for cytosolic thiol-containing bioactive molecules.更多还原