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Zn-dipicolylamine-based reactive oxygen species-responsive lipids for siRNA delivery and in vivo colitis treatment.
Guo, Yu; He, Xi; Zhao, Rui-Mo; Yang, Hui-Zhen; Huang, Zheng; Zhang, Ji; Yu, Xiao-Qi.
Afiliación
  • Guo Y; College of Chemistry, Sichuan University, Chengdu 610064, PR China.
  • He X; College of Chemistry, Sichuan University, Chengdu 610064, PR China.
  • Zhao RM; College of Chemistry, Sichuan University, Chengdu 610064, PR China.
  • Yang HZ; College of Chemistry, Sichuan University, Chengdu 610064, PR China.
  • Huang Z; College of Chemistry, Sichuan University, Chengdu 610064, PR China.
  • Zhang J; College of Chemistry, Sichuan University, Chengdu 610064, PR China. Electronic address: jzhang@scu.edu.cn.
  • Yu XQ; College of Chemistry, Sichuan University, Chengdu 610064, PR China; Department of Chemistry, Xihua University, Chengdu 610039, PR China. Electronic address: xqyu@scu.edu.cn.
Acta Biomater ; 147: 287-298, 2022 07 15.
Article en En | MEDLINE | ID: mdl-35489607
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.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Factor de Necrosis Tumoral alfa / Colitis Idioma: En Revista: Acta Biomater Año: 2022 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Factor de Necrosis Tumoral alfa / Colitis Idioma: En Revista: Acta Biomater Año: 2022 Tipo del documento: Article