Nanostructured Peptidotoxins as Natural Pro-Oxidants Induced Cancer Cell Death via Amplification of Oxidative Stress
Nanostructured Peptidotoxins as Natural Pro-Oxidants Induced Cancer Cell Death via Amplification of Oxidative Stress
复制标题
纳米结构肽毒素作为天然前氧化剂通过氧化应激的放大诱导癌细胞死亡。
DOI：
10.1021/acsami.7b18809
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发表时间：
2018-02-07
影响因子：
9.5
通讯作者：
Di, Liuqing
中科院分区：
文献类型：
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作者：
Qiao, Hongzhi;Fang, Dong;Di, Liuqing
蜂毒肽（Mel）是一种源自蜜蜂毒液的宿主防御肽，具有显著的抗癌特性，这归因于其能促进活性氧（ROS）的生成。然而，关于其在癌症氧化治疗中的促氧化能力的报道却很少。在本研究中，通过两种天然促氧化剂蜂毒肽（Mel）和缩合表没食子儿茶素没食子酸酯（pEGCG）的直接络合，制备了一种ROS放大纳米装置。所得的纳米复合物（NC）通过ROS响应性硼酸酯配位键，进一步用苯基硼酸衍生的透明质酸（pHA）包覆，得到pHA - NC。pHA - NC经受体介导的内吞作用进入癌细胞后，一旦pHA外壳被透明质酸酶降解，其内核将部分暴露，随后具有细胞溶解作用的蜂毒肽会促使其从溶酶体中逃逸。肿瘤细胞质中升高的ROS水平可破坏硼酸酯键，从而促进药物释放。蜂毒肽和pEGCG可协同放大氧化应激并延长癌细胞内ROS的留存时间，进而增强抗癌效果。这种基于选择性配位键和天然成分固有促氧化特性的ROS级联放大器，能够检测并提升细胞内ROS信号，有可能打破肿瘤的内稳态，使其变得脆弱。与先前报道的化学合成促氧化剂相比，本研究中完全由天然药物组成的ROS自给自足系统，为开发癌症氧化治疗提供了新的思路。
Melittin (Mel), one of the host defense peptides derived from the venom of honeybees, demonstrates substantial anticancer properties, which is attributed to augmenting reactive oxygen species (ROS) generation. However, little has been reported on its pro-oxidation capacity in cancer oxidation therapy. In this study, an ROS amplifying nanodevice was fabricated through direct complexation of two natural pro-oxidants, Mel and condensed epigallocatechin gallate (pEGCG). The obtained nanocomplex (NC) was further covered with phenylboronic acid derivatized hyaluronic acid (pHA) through the ROS-responsive boronate ester coordination bond to produce pHA-NC. Upon undergoing receptor-mediated endocytosis into cancer cells, the inner cores of pHA-NC will be partially uncovered once pHA corona is degraded by hyaluronidase and will then escape from the lysosome by virtue of cytolytic Mel. The elevated ROS level in the tumor cytoplasm can disrupt the boronate ester bond to facilitate drug release. Both Mel and pEGCG could synergistically amplify oxidative stress and prolong ROS retention in cancer cells, leading to enhanced anticancer efficacy. This ROS cascade amplifier based on selective coordination bond and inherent pro-oxidation properties of natural ingredients could detect and elevate intracellular ROS signals, potentiating to move the tumor away from its homeostasis and make the tumor vulnerable. Compared to previously reported chemosynthetic pro-oxidants, the ROS self-sufficient system, fully composed of natural medicine, from this study provides a new insight in developing cancer oxidation therapy.