Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Collaborative Innovation Center of Suzhou Nano Science & Technology, Soochow University, Suzhou 215123, China.
Beijing National Laboratory for Molecular Sciences, Center for Soft Matter Science and Engineering, Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
Biomacromolecules. 2022 Jun 13;23(6):2647-2654. doi: 10.1021/acs.biomac.2c00399. Epub 2022 May 12.
Sulfur-containing polypeptides, capable of reactive oxygen species (ROS)-responsive structural change, are one of the most important building blocks for the construction of polypeptide-based drug delivery systems. However, the relatively low ROS sensitivity of side-chain thioethers limits the biomedical applications of these polypeptides because they usually require a high concentration of ROS beyond the pathological ROS level in the tumor microenvironment. Herein, we report the design and synthesis of a selenium-containing polypeptide, which undergoes random coil-to-extended helix and hydrophobic-to-hydrophilic transitions in the presence of 0.1% HO, a concentration that is much lower than the ROS requirement for thioether. ROS-responsive micelles were thus prepared from the amphiphilic copolymer consisting of the hydrophilic poly(ethylene glycol) (PEG) segment and hydrophobic selenopolypeptide segment and were used to encapsulate doxorubicin (DOX). The micelles could be sensitively dissociated inside tumor cells in consequence of ROS-triggered oxidation of side-chain selenoether and structural change of the micelles, thereby efficiently and selectively releasing the encapsulated DOX to kill cancer cells. This work provides an alternative design of ROS-responsive polypeptides with higher sensitivity than that of the existing sulfur-containing polypeptides, which may expand the biomedical applications of polypeptide materials.
含硫多肽能够响应活性氧（ROS）发生结构变化，是构建基于多肽的药物输送系统的最重要的构建块之一。然而，侧链硫醚的相对较低的 ROS 敏感性限制了这些多肽的生物医学应用，因为它们通常需要高于肿瘤微环境中病理 ROS 水平的高浓度 ROS。在此，我们报告了一种含硒多肽的设计和合成，该多肽在 0.1% HO 的存在下经历随机卷曲到延伸螺旋和疏水性到亲水性的转变，这一浓度远低于硫醚的 ROS 需求。因此，由亲水性聚乙二醇（PEG）段和疏水性硒代多肽段组成的两亲共聚物可以制备 ROS 响应性胶束，并用于包封阿霉素（DOX）。由于侧链硒醚的 ROS 触发氧化和胶束的结构变化，胶束可以在肿瘤细胞内被敏感地解离，从而有效地、选择性地释放包封的 DOX 以杀死癌细胞。这项工作提供了一种比现有含硫多肽具有更高敏感性的 ROS 响应性多肽的替代设计，这可能会扩展多肽材料的生物医学应用。
