Lung-targeted delivery of TGF-beta antisense oligonucleotides to treat pulmonary fibrosis
- 주제(키워드) Pulmonary fibrosis , Polymeric antisense oligonucleotides , Human beta-defensin , Rolling circle amplification
- 주제(기타) Chemistry, Multidisciplinary
- 주제(기타) Pharmacology & Pharmacy
- 설명문(일반) [Kim, Junghyun; Kang, Seong Jae; Kim, Kyoung-Ran; Hien Bao Dieu Thai; Lee, Seokyung; Kim, Sehoon; Ahn, Dae-Ro] Korea Inst Sci & Technol, Biomed Res Inst, Ctr Theragnosis, Hwarangno 14 Gil 5, Seoul 02792, South Korea; [Jeon, Seulgi; Lee, Yun-Sil] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Ewhayeodae Gil 52, Seoul 03760, South Korea; [Ahn, Dae-Ro] Univ Sci & Technol, KIST Sch, Div Biomed Sci & Technol, Hwarangno 14 Gil 5, Seoul 02792, South Korea
- 등재 SCIE, SCOPUS
- 발행기관 ELSEVIER
- 발행년도 2020
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000168918
- 본문언어 영어
- Published As https://dx.doi.org/10.1016/j.jconrel.2020.03.016
- PubMed https://pubmed.ncbi.nlm.nih.gov/32179111
초록/요약
Pulmonary fibrosis is a serious respiratory disease, with limited therapeutic options. Since TGF-beta is a critical factor in the fibrotic process, downregulation of this cytokine has been considered a potential approach for disease treatment. Herein, we designed a new lung-targeted delivery technology based on the complexation of polymeric antisense oligonucleotides (pASO) and dimeric human beta-defensin 23 (DhBD23). Antisense oligonucleotides targeting TGF-beta mRNA were polymerized by rolling circle amplification and complexed with DhBD23. After complexation with DhBD23, pASO showed improved serum stability and enhanced uptake by fibroblasts in vitro and lung-specific accumulation upon intravenous injection in vivo. The pASO/DhBD23 complex delivered into the lung downregulated target mRNA, and subsequently alleviated lung fibrosis in mice, as demonstrated by western blotting, quantitative reverse-transcriptase PCR (qRT-PCR), immunohistochemistry, and immunofluorescence imaging. Moreover, as the complex was prepared only with highly biocompatible materials such as DNA and human-derived peptides, no systemic toxicity was observed in major organs. Therefore, the pASO/DhBD23 complex is a promising gene therapy platform with lung-targeting ability to treat various pulmonary diseases, including pulmonary fibrosis, with low side effects.
more