Construction and characterization of folate-functionalized curdlan-trilysine siRNA delivery platform for in vivo hepatic carcinoma treatment
Construction and characterization of folate-functionalized curdlan-trilysine siRNA delivery platform for in vivo hepatic carcinoma treatment
复制标题
用于体内肝癌治疗的叶酸功能化凝胶多糖-三赖氨酸 siRNA 递送平台的构建和表征
DOI：
10.1016/j.colsurfb.2020.111491
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发表时间：
2021-02-01
影响因子：
5.8
通讯作者：
Han, Jingfen
中科院分区：
文献类型：
--
作者：
Qi, Yuxuan;Pan, Yiwen;Han, Jingfen
RNA干扰技术是一种具有临床应用前景的肿瘤治疗工具，其中dsRNA的高效性和特异性仍然是一个关键问题。本文以高效、安全地递送dsRNA为目标，通过点击反应将凝胶多糖与三赖氨酸接枝，再用PEG连接的叶酸修饰，构建了靶向递送平台（CTL-PEG-FA）。CTL-PEG-FA载体表现出优异的基因结合能力以浓缩siRNA并显著降低细胞毒性。CTL-PEG-FA/Bcl-2 siRNA通过叶酸介导的细胞内吞作用和电荷相互作用的协同作用增加细胞摄取，下调Bcl-2蛋白后通过凋亡机制进一步导致HepG 2细胞严重损伤。体内实验中，CTL-PEG-FA/Bcl-2 siRNA复合物在肿瘤部位明显蓄积，对肿瘤生长有明显抑制作用，未见明显毒性。因此，CTL-PEG-FA具有良好的生物相容性，有望成为临床基因治疗的候选材料。
RNA interference technology is a powerful tool with substantially clinical prospects for carcinoma therapy, in which efficiency and specificity of delivery of dsRNA remains a critical issue. Herein, aiming at delivery of dsRNA in efficient and safe way, we constructed targeting delivery platform (CTL-PEG-FA) by grafting curdlan with trilysine through click reaction, then modifying with PEG linked folic acid. The CTL-PEG-FA vector exhibited excellent gene binding capacity to condense siRNA and dramatically reduced cytotoxicity. Increased cell uptake of CTL-PEG-FA/Bcl-2 siRNA was achieved by the synergism of folate mediated endocytosis and charge interaction, and further causing severe HepG2 cells injury through apoptosis mechanism after down-regulation of Bcl-2 protein. In vivo experiments, CTL-PEG-FA/Bcl-2 siRNA complex distinctly accumulated in tumor site and significantly inhibited the growth of tumor, while no obvious toxicity was observed. Therefore, well-performed CTL-PEG-FA with excellent biocompatibility, has the potential to be the candidate of gene therapy for clinical applications.