College of Chemistry, Sichuan University, Chengdu 610064, PR China.
College of Chemistry, Sichuan University, Chengdu 610064, PR China.
Acta Biomater. 2022 Jul 15;147:287-298. doi: 10.1016/j.actbio.2022.04.033. Epub 2022 Apr 28.
The reduction of reactive oxygen species (ROS) and inflammatory factor levels plays an important role in the treatment of colitis. A series of ROS-responsive lipids (ZnDPA-R) based on the thioketal structure were designed and synthesized. It was expected that the lipidic materials could combine ROS consumption and siRNA delivery capacity to achieve synergistic treatment of colitis. The target liposomes could combine with the phosphate backbone of siRNA to form lipoplexes of size ∼100 nm and could deliver siRNA cargo into the cell. The results of in vitro anti-inflammatory experiments showed that the lipids may effectively consume ROS in the cells. The lipoplexes significantly reduced the expression levels of TNF-α mRNA and related inflammatory factors in macrophages. After PEGylation, the lipoplex was used for treating mouse colitis, and the biodistribution results proved that the lipoplexes effectively aggregated in the intestine. The delivery system could not only respond to the high ROS level in colitis through breaking of thioketal structure, but it could also assist in treating inflammation by ROS consumption. The treatment results revealed that the levels of TNF-α mRNA and related inflammatory factors in the colon lesion were largely reduced, and the inflammatory symptoms were significantly relieved. Hematology test results indicated that the treatment was safe and induced no side effects in mice. The present study may shed light on the synergistic treatment of colitis through anti-inflammatory siRNA delivery and ROS depletion strategies. STATEMENT OF SIGNIFICANCE: Downregulation of inflammatory factors and reactive oxygen species (ROS) levels is critical in treating colitis. In the present study, a series of ROS-responsive lipid molecules based on the Zn-DPA headgroup and thioketal linkage were synthesized for delivering TNF-α siRNA and for treating colitis. In addition to silencing the expression of TNF-α mRNA and the related inflammatory factors, the material also achieved synergistic treatment by simultaneous consumption of ROS in the colon lesion. In vitro cell experiments and in vivo colitis treatment in mice showed that the lipoplex exerted a satisfactory therapeutic effect on colitis, and the symptoms of colitis in mice were significantly alleviated. The present study may shed light on the synergistic treatment for colitis through anti-inflammatory siRNA delivery and ROS depletion strategies.
活性氧（ROS）和炎症因子水平的降低在结肠炎的治疗中起着重要作用。本研究设计并合成了一系列基于硫缩酮结构的 ROS 响应性脂质（ZnDPA-R）。预期这些脂质材料可以结合 ROS 消耗和 siRNA 递送来实现结肠炎的协同治疗。目标脂质体可以与 siRNA 的磷酸骨架结合，形成大小约为 100nm 的脂质体复合物，并将 siRNA 货物递送到细胞内。体外抗炎实验结果表明，这些脂质可以有效地消耗细胞内的 ROS。脂质体复合物显著降低了巨噬细胞中 TNF-α mRNA 和相关炎症因子的表达水平。经 PEG 化后，脂质体复合物被用于治疗小鼠结肠炎，其体内分布结果证明脂质体复合物可以有效地在肠道中聚集。该递药系统不仅可以通过硫缩酮结构的断裂对结肠炎中的高 ROS 水平做出响应，而且还可以通过 ROS 消耗来辅助治疗炎症。治疗结果表明，结肠病变中 TNF-α mRNA 和相关炎症因子的水平大大降低，炎症症状得到明显缓解。血液学测试结果表明，该治疗方案在小鼠中是安全的，没有引起副作用。本研究为通过抗炎 siRNA 递药和 ROS 耗竭策略协同治疗结肠炎提供了新的思路。
