Shi Zhen, Yang Yuhan, Guo Ziyang, Feng Shun, Wan Yu
Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
Bioorg Chem. 2023 Jun;135:106485. doi: 10.1016/j.bioorg.2023.106485. Epub 2023 Mar 20.
Small interfering RNA (siRNA) can be exploited to silence specific genes associated with cancer development, and successful siRNA therapy is highly dependent on the efficiency of the siRNA delivery vector. Herein, a well-designed novel redox- and enzyme-responsive fluorinated polyarginine (PFC-PR) was developed to be used as an anti-cancer siRNA carrier. The multiple guanidine groups could provide positive charges and bind with siRNA efficiently, and further fluorination modification enhanced the interaction with siRNA, resulting in a more stable PFC-PR/siRNA nanocomplex, improving serum tolerance, and promoting cellular uptake and endosome escape. Meanwhile, the PFC-PR was responsive to overexpressed cathepsin B and high levels of glutathione in cancer cells, conferring its ability to enhance siRNA release within cancer cells and making it cancer-targeting. Consequently, PFC-PR showed good biocompatibility and high gene silencing efficiency, which could inhibit cancer cell growth when delivered the siRNA targeting vascular endothelial growth factor, suggesting that it can be potentially used for anti-cancer gene therapy applications.
小干扰RNA（siRNA）可用于沉默与癌症发展相关的特定基因，而成功的siRNA疗法高度依赖于siRNA递送载体的效率。在此，我们开发了一种精心设计的新型氧化还原和酶响应性氟化聚精氨酸（PFC-PR），用作抗癌siRNA载体。多个胍基可提供正电荷并与siRNA有效结合，进一步的氟化修饰增强了与siRNA的相互作用，形成了更稳定的PFC-PR/siRNA纳米复合物，提高了血清耐受性，促进了细胞摄取和内体逃逸。同时，PFC-PR对癌细胞中过表达的组织蛋白酶B和高水平的谷胱甘肽有响应，赋予其增强siRNA在癌细胞内释放的能力并使其具有癌症靶向性。因此，PFC-PR表现出良好的生物相容性和高基因沉默效率，当递送靶向血管内皮生长因子的siRNA时，它可以抑制癌细胞生长，表明它有潜力用于抗癌基因治疗应用。
