Journal of Controlled Release ( IF 10.8 ) Pub Date : 2017-08-24 , DOI: 10.1016/j.jconrel.2017.08.026 Jisang Yoo , N. Sanoj Rejinold , DaeYong Lee , Sangyong Jon , Yeu-Chun Kim
Reactive oxygen species (ROS)- or protease-responsive materials have been utilized as carriers in cancer therapies because ROS and specific proteases are overproduced in cancer cells. Methionine-based polypeptides containing a thioether group are promising candidates due to their ROS-responsiveness which provides a phase transition. Herein, we developed protease-activatable cell-penetrating peptide containing a ROS-responsive methionine, a cell permeable lysine chain, and a matrix metalloproteinase (MMP)-cleavable linker. We designed a poly(l-methionine-block-l-lysine)-PLGLAG-PEG (MLMP) and doxorubicin (DOX) was loaded into the micelle core. The MLMP exhibited MMP-sensitive cleavage and ROS-induced DOX release. Moreover, we confirmed efficient DOX delivery into cancer cells and induction of the apoptotic capability in vitro. In a bio-distribution study, IR-780 dye encapsulated MLMP showed superior tumor targetability with long retention. Furthermore, MLMP (DOX) exhibited outstanding tumor inhibition capability with non-toxicity compared to free DOX, indicating that dual stimuli-MLMP has great potential as an anticancer drug delivery platform.
中文翻译:
具有ROS触发的相变的蛋白酶可激活的细胞穿透肽,可用于增强癌症治疗
活性氧(ROS)或蛋白酶反应性材料已被用作癌症治疗的载体,因为ROS和特定蛋白酶在癌细胞中过量产生。含有硫醚基的基于蛋氨酸的多肽是有希望的候选物,因为它们的ROS响应性提供了相变。在本文中,我们开发了蛋白酶可激活的细胞穿透肽,其中含有ROS反应性蛋氨酸,细胞可渗透的赖氨酸链和基质金属蛋白酶(MMP)可裂解的接头。我们设计了一个聚(升-methionine-块-升-赖氨酸)-PLGLAG-PEG(MLMP)和阿霉素(DOX)被装入胶束核心。MLMP表现出MMP敏感的裂解和ROS诱导的DOX释放。此外,我们证实了将DOX有效递送至癌细胞中并诱导了体外的凋亡能力。在一项生物分布研究中,IR-780染料包裹的MLMP显示出优异的肿瘤靶向性,并且保留时间长。此外,与游离DOX相比,MLMP(DOX)表现出出色的肿瘤抑制能力且无毒,这表明双重刺激MLMP具有作为抗癌药物递送平台的巨大潜力。